Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH3:16])([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(=Nc1c(C(C)C)cccc1C(C)C)c1ccccc1
Temperature: 205 °C
Yield: 73.3 %

Procedure:
2,6-Diisopropylaniline (3.8 mL, 20 mmol, Aldrich) was mixed with propiophenone (2.7 mL, 20 mmol, Aldrich) and p-TsOH (0.4 g, 2.1 mmol, Aldrich). The resulting mixture was heated at 205° C. for 1.5 h under a slow stream of Ar to remove H2O that formed. After cooling to RT the reaction mixture was poured into hexanes (50 mL), filtered, the precipitate was washed with additional hexanes (2×20 mL) followed by the evaporation of the filtrate and distillation of the residue. After the initial fraction of starting materials (80–110° C./0.5 mm) the product was collected as a yellow oil, bp 110–125° C./0.5 mm. Crystallization from methanol at −30° C. it afforded product as yellow crystals (4.3 g, 73.3%). 1H NMR (CDCl3) 7.99–7.91 (m, 2H); 7.54–7.44 (m, 3H); 7.20–7.13 (m, 2H); 7.12–7.04 (m, 1H); 2.78 (septet, 2H; J=6.9 Hz); 2.53 (q, 2H; J=7.7 Hz); 1.21 (d, 6H; J=6.9 Hz); 1.16 (d, 6H; J=6.9 Hz); 0.99 (t, 3H; J=7.7 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][Mg]Br>C1COCC1>[OH:1][C:2]1([CH3:16])[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:3]1
Reactant: O=C1CC(C(=O)OCc2ccccc2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CC(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Treat a −78° C. solution of benzyl 3-oxocyclobutanecarboxylate (11.05 g, 54.1 mmol) in THF (155 mL) drop-wise with methyl magnesium bromide (3M in diethyl ether, 27.1 mL, 81 mmol) and stir at −78° C. for 0.5 h. Add satd. NH4Cl, extract with EtOAc (2×), dry the combined organics, evaporate and purify via silica gel chromatography (acetone/hexanes) to afford the title compound (5.589 g, 47%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.36-7.29 (m, 5H); 5.08 (m, 3H); 2.75-2.66 (m, 1H); 2.13-2.12 (m, 4H); 1.21 (s, 3H); MS (ESI) m/z: 243.1 (M+Na+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:20]([C:23]2(O)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6]>Cl>[ClH:2].[Cl:2][C:3]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]=2)=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:10][CH:11]3[CH2:17][CH:15]([CH2:14][CH:13]([CH2:12]3)[CH2:18]1)[CH2:16]2)=[O:6]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C2(O)CCNCC2)ccc1Cl
Agent: Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C2=CCNCC2)ccc1Cl
Yield: 25.9 %

Procedure:
A solutuion of 2-chloro-5-(4-hydroxy-piperidin-4-yl)-N-(tricyclo[3.3.1.133,7]dec-1-ylmethyl)-benzamide, hydrochloride salt (0.25 g, Example 52) in concentrated hydrochloric acid (10 mn) was heated at 100° C. for 5 h. The solution was allowed to cool slowly. Colourless crystals separated. These were removed by filtration, washed with diethyl ether then acetonitrile and dried to afford the title compound (0.031 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:27][CH:26]=2)([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C>CS(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:27][CH:26]=2)([CH3:24])[CH2:20][CH2:21][CH:22]=[O:23])=[CH:15][CH:14]=1
Reactant: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(CCC=O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
To a solution in DMSO (20 mL) of 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentan-1-ol (410 mg, 0.74 mmol), prepared as in Example 4, and 1,3-dicyclohexylcarbodiimide (515 mg, 2.5 mmol) was added aqueous 1M phosophoric acid (0.5 mL) and the resulting mixture was stirred at room temperature for 4 hours. Ethyl acetate (80 mL) was added and dicyclohexylurea was filtered off. The filtrate was washed with water and brine dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (methylene chloride-ethyl acetate 9:1) to afford 280 mg of 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2ncc3c(n2)N(c2ccccc2)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 56 mg (0.13 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one and 1 ml of 4-methoxybenzylamine was heated at 100° C. for 30 minutes, then cooled and partitioned between 30 ml of dichloromethane and 30 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 68 mg (100%) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-(4-methoxybenzyl)amino-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid of melting point 56° C.
Reaction SMILES: [OH2:1].[OH-].[Li+].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2>O1CCCC1.CO.O>[Br:4][C:5]1[CH:14]=[CH:13][C:12]([CH2:10][OH:11])=[C:7]([CH:6]=1)[C:8]([OH:1])=[O:9]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (11.80 g, 281.6 mmol) was added at room temperature over several minutes to a solution of 5-bromophthalide (20.0 g, 93.88 mmol) in a 2:1:1 solution of tetrahydrofuran/methanol/water (570 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and azeotropically dried with benzene to give 5-Bromo-2-hydroxymethyl-benzoic acid as a white solid. The material was used without further purification: 1H NMR (300 MHz, CDCl3+CD3OD) δ 7.89 (d, J=8.3 Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.50 (dd, J=8.3, 1.9 Hz, 1H), 3.99 (s, 2H); ESI MS (negative mode) m/z 229 [C8H7BrO3−H]−. Sodium hyride (15.0 g, 375 mmol, 60% dispersion in mineral oil) was added in small portions over the course of 0.5 h at room temperature to a solution of 5-Bromo-2-hydroxymethyl-benzoic acid in tetrahydrofuran (235 mL) containing bromoacetic acid (14.35 g, 103.2 mmol) and sodium iodide (1.41 g, 9.4 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and poured into water and then extracted with diethyl ether. The aqueous phase was acidified with 10% hydrochloric acid to pH 3-4 and extracted several times with ethyl acetate. The combined ethyl acetate phases were washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield -Bromo-2-carboxymethoxymethyl-benzoic acid as a white solid. The material was used without further purification: 1H NMR (300 MHz, CD3OD) δ 7.93-7.86 (m, 2H), 7.55-7.50 (m, 1H), 4.98 (s, 2H), 4.23 (s, 2H); ESI MS (negative mode) m/z 287 [C10H9BrO5−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].O.[N:12]#[C:13]Br.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:13]([NH2:12])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40 %

Procedure:
4,5-Difluorobenzene-1,2-diamine (0.651 g, 0.562 mmol, commercially available from Matrix Scientific) in acetonitrile (10 mL) and water (2 ml) at 0° C. was treated with cyanogen bromide (0.063 g, 0.6 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for 14 hours. The reaction mixture was then treated with saturated aqueous sodium hydrogen carbonate solution (50 ml) and shaken. The resulting solid was filtered off, washed with water and dried under reduced pressure to give 0.39 g of 5,6-difluoro-1H-benzo[d]imidazol-2-amine (yield, 40%). MS (EI): 186 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:24]=1)=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:33]2[CH2:34][CH2:35][CH:30]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:36])[CH:28]=[CH:27][C:26]=3[CH3:29])[CH2:31][CH2:32]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(Cc2ccc(Oc3ccc(F)c(F)c3)cc2)CC1
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 4-(3,4-Difluorophenoxy)benzaldehyde (41.0 mg, 0.170 mmol) and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (45.0 mg, 0.170 mmol) in 1,2-dichloroethane (5.00 mL) was added sodium triacetoxyborohydride (110 mg, 0.520 mmol) and AcOH (10.0 μL, 0.170 mmol) at room temperature. The mixture was stirred overnight. The reaction mixture was quenched by saturated NaHCO3 solution (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo. The crude product was purified by preparative TLC using 5% NH3 {2.0 M in MeOH) in CH2Cl2 to give the desired product N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (44.0 mg, 54.0%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:15]([C:17]([OH:30])([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=2)[CH3:18])=[O:16])([OH:14])[CH3:13])=[CH:7][CH:6]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C1COCC1>[S:32]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:15]([C:17]([OH:30])([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:24][CH:25]=2)[CH3:18])=[O:16])([OH:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:31])(=[O:34])=[O:33]
Reactant: CC(O)(Cc1ccc(OCCO)cc1)C(=O)C(C)(O)Cc1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)C(C)(O)Cc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 2 °C

Procedure:
A 1000 ml three-necked round bottom flask is charged with a solution of 224.26 g (1 Mol) of 4-(2-Hydroxyethoxy)phenyl 2-hydroxy-2-propyl-ketone (Darocure® 2959) in 400 mL of THF and 114.55 g (1 mol) of methanesulfonyl chloride are added to the solution at room temperature. After cooling to 2° C., 101.2 g (1 mol) of triethylamine (TEA) and 200 mL of THF are added to the solution over a 30 min-period under stirring. Slightly exothermal reaction is observed. The reaction mixture is then filtered through a G3 glass frit filter and the TEA hydrochloride washed 2× with THF on the filter. The filtrate is evaporated at 60° C./200 mbar using a Rotavapor. The resulting yellow oil is then dissolved in 800 mL of CH2Cl2. The organic phase is washed 1× with 400 mL of deionized water, 2× with 400 mL of acidic water (pH˜1) and finally with 400 mL of deionized water. The organic phase is dried over MgSO4, filtered and concentrated to constant weight by evaporating the CH2Cl2 under reduced pressure at a Rotavapor to give crude 4-(2-mesyloxyethoxy)phenyl-2-hydroxy-2-propyl-ketone.
Reaction SMILES: I[CH3:2].[NH2:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]([SH:15])[N:5]=1>CN(C)C=O>[NH2:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]([S:15][CH3:2])[N:5]=1
Reactant: CCOC(=O)c1cnc(S)nc1N
Reactant: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Iodomethane (2.6 g, 18 mmol) was added to the hot solution (˜50° C.) of ethyl 4-amino-2-mercaptopyrimidine-5-carboxylate (3.0 g, 15 mmol) in N,N-dimethylformamide (150 mL) and stirred at room temperature for 20 min. Solvent was removed in vacuo and the solid residue was washed by water. After dried in vacuo, desired product was obtained as a white solid (3.1 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Product: N[C@@H](CCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 94 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-chlorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-4-phenylbutanoic acid, gave (S)-2-amino-N-(4-(4-chlorophenoxy)phenyl)-4-phenylbutanamide (320 mg, 94%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CC(N(C)C)=O.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18](Cl)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].[OH-].[Na+]>O>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[C:18]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: Sc1ccccn1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Sc2ccccn2)cc1C(F)(F)F
Yield: 85.5 %

Procedure:
A mixture of 25 g of 2-mercaptopyridine, 70 ml of dimethylacetamide and 45.7 g of 3-trifluoromethyl-4-nitrochlorobenzene was heated at 80° to 90° C. and 35 g of 40% NaOH aq. solution was added to the mixture. After the reaction, the reaction mixture was poured into water and the product was extracted with ethyl ether and the ether phase was washed with a dilute NaOH aq. solution and then, with water and dried with anhydrous sodium sulfate and ether was distilled off to obtain 52 g of 2-trifluoromethyl-4-(pyridine-2-ylthio) nitrobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Si]([C:13]#[CH:14])(C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:13]#[CH:14])[CH:3]=1
Reactant: Brc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.2 %

Procedure:
To an oven-dried flask under N2 was added 1-bromo-3-iodobenzene (5.00 g, 17.73 mmol), anhydrous, degassed THF (100 mL), dichlorobis(triphenyl-phosphine)palladium(II) (620 mg, 0.88 mmol), copper(I) iodide (100 mg, 0.53 mmol), TEA (7.15 g, 71 mmol), and TMS acetylene (1.91 g, 20 mmol). After stirring overnight at rt, the reaction was washed with brine (100 mL), organic layer separated, concentrated under reduced pressure, adsorbed to silica gel and purified by column chromatography (5% EtOAc in hexanes) to afford the desired product (3.57 g, 80%) as a clear oil. This was dissolved in 100 ml 1:1 THF:MeOH and to this was added water (10 mL), and K2CO3 (5.87 g, 43 mmol). After stirring overnight at rt, the reaction was washed with brine (100 mL), adsorbed to silica gel and purified by LC (5% EtOAc in hexanes) to afford the alkyne (1.92 g, 75%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.10 (s, 1H), 7.17 (t, J=7.69 Hz, 1H), 7.38-7.44 (m, 1H), 7.45-7.48 (m, 1H), 7.61-7.62 (s, 1H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Si:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1>[Si:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]3=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]3[CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 42.0 g) in THF (dry) (350% mL) was added 2-chloroethanesulfonyl chloride (44.5 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-((tert-butyl(dimethyl)silyl)oxy)phenyl)pyridin-2-amine (78.8 g) in THF (dry) (350 mL) was added at 0° C. and the mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0° C. carefully. Additional water was added to form precipitates which were washed with water and EtOAc and collected to give the title compound (65.5 g) as an off-white solid.
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]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.CCN(C(C)C)C(C)C.[CH3:38][N:39]=[C:40]=[O:41].Cl>C(Cl)Cl>[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]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]([C:40]([NH:39][CH3:38])=[O:41])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Reactant: CN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A vial was charged with N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide (15 mg, 40 μmol), i-Pr2NEt (11 μL, 60 μmol) and CH2Cl2 (1 mL). Methyl isocyanate (3 μL, 43 μmol) was added and the mixture was stirred overnight at rt. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford N1′(2-adamantyl)-N2-methyl-1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxamide (7.7 mg, 44%). LC-MS Method 1 tR=1.77 min, m/z=437; 1H NMR (CDCl3) δ=1.60-2.10 (18H), 2.80 (1H), 2.88 (s, 3H), 3.25 (m, 2H), 3.77 (s, 2H), 3.88 (d, 2H), 3.98 (s, 1H), 4.52 (s, 2H), 4.87 (1H), 7.05-7.40 (4H).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([CH2:10][CH3:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.CN1CCOCC1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:2]([CH3:1])[C@@H:3]([CH2:10][CH3:11])[CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CC[C@@H](CN1CCCC1)NC
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@@H](CN1CCCC1)N(C)C(=O)c1ccc(Br)cc1
Yield: 61.4 %

Procedure:
To a solution of (S)—N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M5) (75 mg, 0.48 mmol) in DCM (1.5 mL) was NMM (0.058 mL, 0.53 mmol) and 4-bromobenzoyl chloride (137 mg, 0.62 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was diluted with DCM (5 mL), washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (100 mg, 62%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.92, 1.33-1.66, 1.66-1.97, 2.55, 2.94, 3.64, 4.70-4.83, 7.21-7.49, 7.49-7.76. Ratio major:minor:3:2. Total no of protons: 23.
Reaction SMILES: C[O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1.Cl>CC(C)=O>[F:12][C:7]1[CH:6]=[C:5]([CH2:4][CH:3]=[O:2])[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: COCCc1ccc(F)c(F)c1
Agent: Cl
Solvent: CC(C)=O
Product: O=CCc1ccc(F)c(F)c1

Procedure:
Into a 1 liter three-necked flask equipped with a stirrer and a condenser, 46.70 g (274 mmol) of 1-methoxy-2-(3,4-difluorophenyl)ethane, 685 ml of acetone and 114 ml of 3M-hydrochloric acid were charged and the mixture was heated under reflux for 2 hrs. Acetone was distilled off, and water and ether were added. An organic layer and an aqueous layer were separated, the aqueous layer was extracted with ether, the extract combined with the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the solvent distilled off, the solution condensed and purified by vacuum distillation to obtain 33.29 g (78%, bp 98-100° C./16 Torr.).
Reaction SMILES: [Na].[CH:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.Cl[CH:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C.C(OCC)C>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:11]([O:8][C:7]2[CH:2]=[CH:3][C:4]([CH3:9])=[CH:5][CH:6]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][CH:3]=1
Reactant: CCOC(=O)C(Cl)Cl
Reactant: Cc1ccc(O)cc1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Oc1ccc(C)cc1)Oc1ccc(C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Sodium (5.7 g) is dissolved in ethanol (160 cc), and a solution of para-cresol (27 g) in ethanol (20 cc) is added. The mixture is stirred for 1 hour at 20° C. and ethyl dichloroacetate (20 g) in solution in ethanol (20 cc) is then added. The mixture is heated under reflux for 20 hours and then allowed to cool. The white precipitate obtained is filtered off and the filtrate is concentrated to dryness under reduced pressure (20 mmHg) at 40° C. The oil thus obtained is taken up in diethyl ether (300 cc) and washed twice with N sodium hydroxide solution (100 cc each time) and twice with distilled water (100 cc each time). The ethereal phase is then dried over anhydrous sodium sulphate, filtered, and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methylphenoxy)acetate (29 g) is thus obtained as a yellow oil.