Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)C(C)(C)C1C)([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=[O:25])C(C)C.C1(C)C=CC=CC=1>[N+](C)([O-])=O>[CH:1]([C:4]([C:12]1[CH:7]=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=1)=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Cc1ccc(C(=O)C(C)C)cc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To prepare 1-isopropyl-2,3,3,5-tetramethylindane, the procedures of Traas et al., U.S. Pat. No. 4,352,748 are substantially followed. Specifically, a solution of aluminum chloride (75 g) in nitromethane (50 ml) is added to a mixture of isobutyroyl chloride (49 g), nitromethane (50 ml) and toluene (100 ml), and stirred for one hour at about 10° C. The reaction mixture is poured over ice and extracted with ether. The ether solution is washed to neutrality, dried and evaporated. The residue is distilled under diminished pressure to obtain p-tolyl isopropyl ketone. The ketone (11 g) is then dissolved in methanol (50 ml), added to a solution of NaBH4 (10 g) in a methanol/water mixture (100 ml; 1:1). The reaction mixture is stirred for one hour, and then poured into water and extracted with ether. The solution in ether is dried on anhydrous magnesium sulfate and evaporated to yield 2-methyl-1-(p-tolyl)propanol-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+].Br[CH2:23][CH2:24][CH2:25][NH:26][C:27]1[C:36](=[O:37])[C:31]2[N:32]=[C:33]([CH3:35])[S:34][C:30]=2[C:29](=[O:38])[CH:28]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[C:36](=[O:37])[C:31]3[N:32]=[C:33]([CH3:35])[S:34][C:30]=3[C:29](=[O:38])[CH:28]=2)=[CH:5][CH:4]=1
Reactant: Cc1nc2c(s1)C(=O)C=C(NCCCBr)C2=O
Reactant: COc1ccc(CN)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNCCCNC2=CC(=O)c3sc(C)nc3C2=O)cc1
Temperature: 180 °C
Reaction time: 0.08 h

Procedure:
160 μl (1.22 mmol; 1.1 equivalent) of 4-methoxybenzylamine, 213 μl (1.22 mmol; 1.1 equivalent) of diisopropylethylamine and a spatula tip's worth of sodium iodide are added to 0.35 g (1.11 mmol) of 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione in solution in 15 ml of dimethylformamide. The reaction mixture is maintained under stirring under microwaves for 5 minutes at 180° C. Then the solvent is evaporated off under reduced pressure and the reaction residue is taken up in dichloromethane, followed by washing with 3 times 50 ml of water. The organic phases are combined, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. The expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol: 95/5) and obtained in the form of a red oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:31])[C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:32][CH3:33])C1C=CC=CC=1>O1CCCC1.[H][H].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:31])[C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:20]([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:32][CH3:33]
Reactant: [H][H]
Reactant: COc1cc(CCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc1O

Procedure:
50.4 g of (S)-2-(tert-butoxycarbonyl-amino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-amide are dissolved in 1000 ml of tetrahydrofuran and hydrogenated with hydrogen for 2 hours over 10 g of 10% palladium on activated carbon under normal pressure and at room temperature. Filtration with suction is carried out over Celite. The filtrate is concentrated by evaporation, yielding (S)-2-(tert-butoxycarbonyl-amino)-3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-amide in the form of an oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][CH2:13]2)(=[O:18])=[O:19])=[CH:21][CH:22]=1)(=[O:30])[CH:28]=[CH2:29]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NC(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
Diisopropylethylamine (0.14 ml, 0.8 mmol) was added in one portion to a stirred solution of N-[4-(4-amino-piperidine-1-sulfonyl)-phenyl]-acrylamide (0.1 g, 0.32 mmol) in THF (3 ml) at room temperature. To this mixture was added benzoyl chloride (0.048 ml, 0.42 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue purified by flash column chromatography (elution: 70% heptane, 30% ethyl acetate to 40% heptane, 60% ethyl acetate) to give the title compound (7 mg, 5% yield) as a white solid.
Reaction SMILES: [C:1]([C@@:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:12][NH2:13])C(O)=O)([O:3]C(C)(C)C)=[O:2].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[NH2:13][CH2:12][C@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:1]([OH:3])=[O:2].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]
Reactant: CC(C)(C)OC(=O)[C@](CN)(Cc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boc-(S)-3-amino-2-benzylpropionic acid (105 mg, 0.38 mmol, PepTech) was dissolved in TFA (4 mL) and CH2Cl2 (4 mL). The resulting mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was dissolved again in CH2Cl2 (4 mL). The volatiles were removed again in vacuo to give the title compound as its TFA salt, which was used in the subsequent step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9](CC3C=CC(OC)=CC=3OC)[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(=O)OC(C)(C)C)[N:3]=1.[BrH:39]>CC(O)=O>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([Br:39])[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: Br
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Solvent: CC(=O)O
Product: N[C@H]1CCCC[C@H]1Nc1nc(Br)c2c(c1F)CNC2=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (200 mg, 0.364 mmol) and hydrobromic acid in HOAc (10 mL) was stirred at 90° C. for 6 h. The mixture was concentrated under reduced pressure, and the resulting crude material was reconstituted in MeOH (1.0 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-30% gradient, 0.035% TFA). The collected fractions were combined and ACN was removed via rotary evaporation. The resulting aqueous solution was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (38 mg, 30%). [M+H] calc'd for C13H16BrFN4O, 343; found, 343.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:17])[CH2:9][N:10]2[C:14]([S:15][CH3:16])=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)([CH3:17])[CH2:9][N:10]2[C:14]([S:15]([CH3:16])=[O:33])=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncnn1C[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Product: CS(=O)c1ncnn1C[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 111.3 %

Procedure:
To a solution of 1.8 g (0.005 mol) of bis(4-fluorophenyl)methyl(5-methylthio-1H-1,2,4-triazol-1-ylmethyl)silane in 15 mL of methylene chloride cooled to 0° C. was added 1.1 g (0.005 mol) of m-chloroperbenzoic acid (80%). The reaction temperature rose to 10°. The reaction mixture was stirred at 25° for 3 hours, then diluted with methylene chloride, washed with 7% aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to give 2.1 g of the title compound as an oil, pure except for traces of solvent and starting material: nD 1.5717; ir (neat) 3020, 1590, 1500, 1232, 1164, 1110, 1070, 825 cm-1 ; nmr (CDCl3) δ 0.7 (3H, s), 2.8 (3H, s), 4.6 (2H, ABq), 7.1 (4H, m), 7.5 (4H, m), 7.9 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][CH2:22][CH2:23][OH:24]>O>[OH:24][CH2:23][CH2:22][CH2:21][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: OCCCBr
Reactant: Oc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCSc1ccccc1O
Reaction time: 0.33 h

Procedure:
2-Hydroxythiophenol (1.00 g, 8.70 mmol) was added to a mixture of DMF (10 mL) and Cs2CO3 (2.90 g, 8.90 mmol). To this was added 3-bromopropanol (0.80 mL, 9.16 mmol) and the mixture was stirred for 20 min. The mixture was added to into water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a clear oil (2.36 g, 100%). MS [M−H]− 183.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([N:6]1[CH2:5][CH:4]([CH3:8])[NH:3][CH:2]([CH3:1])[CH2:7]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(S(C)(=O)=O)CC(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of cis-2,6-dimethylpiperazine and triethylamine in DCM at 0° C. was added dropwise methanesulphonyl chloride and the reaction mixture stirred at room temperature overnight. After quenching with water, extraction into DCM and being washed with brine, the organics were dried and the solvent removed under reduced pressure to yield 1-methanesulfonyl-3,5-dimethylpiperazine as a pale yellow solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1>[NH:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1nc(Oc2ccccn2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: C1CCOC1
Product: Clc1ccc(-c2c(Oc3ccccn3)nc(C3CCCN3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(2-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 109 (45 mg, 0.09 mmol) was reacted with excess pyrrolidine (0.5 mL) in THF at a sealed tube 60° C. for overnight by general procedure Example 103 to afford the title compound: HPLC/MS: m/e=497 (M++1); Rt4.21 min. 1H-NMR 400 MHz (CDCl3): δ 1.85-1.95 (s 4H), 3.20-3.60 (m, 4H), 7.00-7.19 (m, 8H), 7.31 (d, J=2 Hz, 1H), 7.75-7.80 (m, 1H), 8.38 (m, 1H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][C:20]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][C:20]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:21]1
Reactant: CC1(C)CNc2ccccc21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1(C)CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.7 %

Procedure:
The product is prepared according to the procedure described in example 5, using 177 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 236 mg of 3,3-dimethylindoline (which can be prepared according to T. W. Ramsay et al., Synth. Commun. 1995, 25, 4029) and 169 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.11 ml of pyridine and 5 ml of N,N-dimethylformamide. The reaction mixture is stirred for 15 h at ambient temperature and then concentrated to dryness under reduced pressure. 40 ml of water are added to the residue and triturated with a spatula at ambient temperature. The precipitate formed is filtered off, and then solubilized with a dichloromethanemethanol mixture and dried. After concentration to dryness under reduced pressure, the crude product is purified by chromatography on a 30 g silica (0.02-0.045 mm) column, eluent: 90/10 v/v dichloromethanemethanol. After the various fractions have been evaporated, the pink solid residue is triturated from 10 ml of diisopropyl ether, filtered off, and then dried under a bell jar (1h40° C./20 mbar). 134 mg of 2-[2-(3,3-dimethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are thus obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9]2)[N:3]=1.[C:14]1([CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[C:12]([C:11]1[C:2]([NH:22][CH2:21][CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3][C:4]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)#[N:13]
Reactant: N#Cc1c2cccccc-2nc1Cl
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c2cccccc-2nc1NCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a solution of 0.38 g (0.002 mol) of 2-chloro-3-cyano-1-azaazulene in 7 ml of dimethylformamide were added 0.43 g (0.0022 mol) of 2,2-diphenylethylamine. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water with ice to allow precipitate to separate out. The precipitate was filtered and dried to give 0.55 g of title compoind (yield: 78.6%).
Reaction SMILES: [SH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:4]1([CH:2]([S:1][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[CH3:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(S)c1ccccc1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)SC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
At room temperature, 13.8 g of 1-mercapto-1-phenylethane is dissolved in 50 mL of butyryl chloride. The mixture is stirred at room temperature for 6 hours. It is then cooled down to 0° C. and the reaction is quenched by careful addition of 100 ml of dry methanol in small portions. The mixture is then washed with bicarbonate, dried over magnesium sulfate, filtered and concentrated to give the butyrated compound in 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]2)(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a stirred solution of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.555 mmol) and 3,4-dichlorobenzene-1-sulfonyl chloride (381.8 mg, 1.555 mmol) in anhydrous dichloromethane (3 mL) was added diisopropylethylamine (1.35 mL, 7.775 mmol). The mixture was stirred at room temperature for 30 minutes. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane, washed with saturated Na2CO3 (aq.), water then brine. Organic layer was dried over MgSO4. The reaction mixture was purified via flash column chromatography to yield 1-[(3,4-dichlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine in 75.7% yield (538 mg) as white solid.
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][C@H:10]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12].C[Si](C)(C)Cl.[C:29](Cl)(=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>C1COCC1>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]([NH:9][C@H:10]([C:14]([N:16]2[CH2:23][CH2:22][CH2:21][C@H:17]2[C:18]([OH:20])=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:38])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-methylmorpholine (46 ml) was added to a mixture of L-valyl-L-proline hydrochloride (34 g) in THF (850 ml), followed by trimethylchlorosilane (41 ml) maintaining the temperature below 30° C. The mixture was stirred for 2 hours and then cooled to 0° C. Further N-methylmorpholine (16.5 ml) was added, followed by a solution of 4-anisoyl chloride (18 ml) in THF (25 ml), maintaining the temperature below 5° C. After 15 minutes, the mixture was filtered and the filtrate concentrated in vacuo to a yellow oil. The oil was dissolved in ethyl acetate (100 ml) and basified to pH 7-8 with saturated potassium bicarbonate solution (100 ml). The aqueous layer was separated and washed with ethyl acetate (50 ml). The aqueous layer was then acidified to pH 2-3 with 2M hydrochloric acid solution and extracted with ethyl acetate (150 ml). The organic extract was concentrated under vacuum and toluene (150 ml) was added. The solution was again concentrated under vacuum until about 50 ml of toluene was collected. The solution was then added dropwise to hexane (400 ml) with stirring to give a white solid, which was filtered, washed with hexane and dried under vacuum to give N-(4-methoxybenzoyl)-L-valyl-L-proline (40 g), having a similar NMR to that given in Procedure 1, step (iii) above.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][Br:7].[P:8](OCC)([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9]>>[Br:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][P:8](=[O:9])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: BrCCOCCBr
Reactant: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(CCOCCBr)OCC
Temperature: 160 °C

Procedure:
1-bromo-2-(2-bromoethoxy) ethane (1.0 eq) was mixed with triethyl phosphate (1 eq) then heated to 160° C. for 20 minutes by microwave. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 70-100% EtOAc/Hex to give the product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14]O.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH2:14][C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: OCc1cnoc1-c1ccc(F)cc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2oncc2CCl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of 5-(2,4-difluorophenyl)-4-isoxazolylmethanol (2.50 g) in toluene (50 ml) was added dropwise thionyl chloride (2.11 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(2,4-difluorophenyl)isoxazole (2.20 g, yield 81%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio). NMR (CDCl3) δ: 4.53 (2H, s), 6.95–7.15 (2H, m), 7.6–7.75 (1H, m), 8.43 (1H, s).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][S:9][CH2:10][CH2:11][NH2:12]>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:12][CH2:11][CH2:10][S:9][CH3:8]
Reactant: O=Cc1ccc[nH]1
Reactant: CSCCN
Product: CSCCN=Cc1ccc[nH]1
Yield: 98.7 %

Procedure:
Replicate the preparation of the ligand used in Ex. 7 except use 0.928 g (9.758 mmol) of the pyrrole-2-carbaldehyde and 0.999 mL (10.734 mmol, p=0.980 gcm−3) of 2-(methylthio)ethylamine instead of N1,N1-dimethylethane-1,2-diamine to give 1.62 g (98%) of N-((1H-pyrrol-2-yl)methylene)-2-(methylthio)ethanamine as a pale yellow oil, which is analytically pure by GC-MS & 1H-NMR: 1H NMR (400 MHz, CDCl3) δ 9.45 (s, br, 1H), 7.99 (s, 1H), 6.78 (s, 1H), 6.40 (d, J=1.9 Hz, 1H), 6.14 (s, 1H), 3.64 (t, J=6.9 Hz, 2H), 2.66 (t, J=6.9 Hz, 2H), 2.04 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:46])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:45])=[C:42]([CH3:44])[N:43]=2)[CH:33]=1)=O)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:46])[CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[N:39]=[N:40][C:41]([CH3:45])=[C:42]([CH3:44])[N:43]=4)[CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1nnc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc1C
Product: Cc1nnc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)nc1C

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-[3-(5,6-dimethyl-[1,2,4]triazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K47) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (26 mg).
Reaction SMILES: [CH3:1][C:2]([N+:9]#[C-:10])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[I:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]=[CH2:19])=[N:16][CH:17]=1>CO>[I:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:10]([NH:9][C:2]([CH3:8])([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:19][N:18]=2)[CH:17]=1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: C=Nc1ccc(I)cn1
Solvent: CO
Product: CC(C)(C)CC(C)(C)Nc1cnc2ccc(I)cn12
Yield: 39.6 %

Procedure:
Add 1,1,3,3-tetramethylbutyl isocyanide (Aldrich; 0.57 g, 4.06 mmol) to a solution of (5-iodo-pyridin-2-yl)-methylene-amine (Preparation 15a; 0.8 g, 3.4 mmol) in methanol (20 mL). Reflux for 36 h and concentrate. Purify by flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc/50% hexanes (45 mL/min, 44 min) giving 0.5 g (40%) of the title compound as a dark brown semi-solid. ES+ m/e 371.8 (M+1).