Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][S:4]([CH2:7]P(OCC)(OCC)=O)(=[O:6])=[O:5])[CH3:2].C([Li])CCC.[Cl:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:31]1[CH:35]2[O:36][C:37]([CH3:40])([CH3:39])[O:38][CH:34]2[CH:33]([CH:41]=O)[O:32]1>C1COCC1.CCCCCC>[Cl:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[C@H:31]1[C@@H:35]2[O:36][C:37]([CH3:40])([CH3:39])[O:38][C@@H:34]2[C@@H:33]([CH:41]=[CH:7][S:4]([O:3][CH2:1][CH3:2])(=[O:5])=[O:6])[O:32]1
Reactant: CCOP(=O)(CS(=O)(=O)OCC)OCC
Reactant: CC1(C)OC2C(C=O)OC(n3cnc4c(Cl)ncnc43)C2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOS(=O)(=O)C=C[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of (diethoxy-phosphoryl)-methanesulfonic acid ethyl ester (7.991 g, 0.03070 mol) in THF (100 mL), at −78° C. under an atmosphere of nitrogen, was added dropwise 2.5M n-butyllithium in hexane (13 mL), and the solution was stirred for 30 minutes. Freshly prepared 6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]-dioxole-4-carbaldehyde (13.10 g, 0.03026 mol) in THF (100 mL) was added over 15 min at −78° C. The reaction was allowed to slowly warm to −10° C. over 4 hours with stirring. The reaction was quenched with water (400 mL) and 5M ammonium chloride in water (100 mL) and extracted with methylene chloride (600 mL). The organic phase was concentrated in vacuo and the residue was purified by flash chromatography (30 to 100% EtOAc:hexanes) to yield the product as a foam (10.5 g, 81%).
Reaction SMILES: [CH2:1](I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[Mg]Br>C1COCC1>[CH2:1]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1cccs1
Reactant: ICc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(Cc2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.8 g (52 mmol) of NaI and 5 mL (43 mmol) of benzyl chloride in THF was heated at reflux for 2 h to form benzyl iodide in situ and then the reaction was cooled to rt. In a separate flask, 37 mg (0.87 mmol) of LiCl and 58 mg (0.43 mmol) of copper(II) chloride were dissolved in 5 mL of THF and stirred at rt for 5 min to form Li2CuCl4 in situ. The benzyl iodide reaction flask was fitted with an addition funnel and 3 mL (3 mmol) of a 1 M solution of 2-thienylmagnesium bromide in THF was added dropwise, followed by addition of the Li2CuCl4 solution, and then the remaining 2-thienylmagnesium bromide solution (49 mL, 49 mmol) was added at such a rate as to maintain the reaction temperature <40° C. and the reaction solution was stirred for 2 h at rt. The THF was removed in vacuo, and the residue was partitioned between 250 mL of Et2O and 150 mL of NH4Cl and separated. The organic layer was treated with 15 mL of piperidine and stirred for 18 h, then washed twice with 10% (w/v) aqueous HCl, filtered, concentrated and the dark red residue was purified by flash chromatography eluting with neat hexane to yield the title compound. GC-MS (M)+ 174.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Cl:36][C:37]1[C:38]2[CH:48]=[CH:47][CH:46]=[CH:45][C:39]=2[S:40][C:41]=1[C:42](Cl)=[O:43]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:42]([C:41]2[S:40][C:39]3[CH:45]=[CH:46][CH:47]=[CH:48][C:38]=3[C:37]=2[Cl:36])=[O:43])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NCc2cccc(-c3ccncc3)c2)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(N(Cc2cccc(-c3ccncc3)c2)C(=O)c2sc3ccccc3c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of 18 (410 mg, 1.1 mmol) and Et3N (280 μL, 2.0 mmol) in CH2Cl2 (10 mL) was added 3-chlorobenzo[b]thiophene-2-carbonyl chloride 12 (278 mg, 1.2 mmol), and the reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed and the residue was purified by a flash chromatography on silica gel (acetone/PE=5:1) to give the desired product 19 (587 mg) in 96% yield; 1H-NMR (400 MHz, CDCl3): 8.65 (br, 2H), 7.20-8.20 (m, 10H), 3.70-5.00 (m, 4H), 3.20-3.40 (br, 1H), 1.75-2.20 (m, 4H), 1.42-1.75 (br, 2H), 1.38 (s, 9H), 0.90-1.30 (br, 2H); 13C NMR (100 MHz, CDCl3): 163.7, 155.1, 150.2, 148.1, 147.7, 139.2, 138.4, 137.2, 135.6, 130.0, 129.3, 127.6, 126.5, 126.2, 125.5, 122.7, 122.5, 121.6, 119.0, 79.2, 58.7, 48.5, 45.1, 32.1, 30.5, 29.7, 29.3, 28.3; HRMS (EI) calcd for C32H34ClN3O3S (M+) 575.2009; found 575.2018.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][C:9]([Br:13])=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1cccs1
Reactant: O=C1CCC(=O)N1Br
Agent: N#N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.7 %

Procedure:
(The following reaction is carried out in an anhydrous N2 atmosphere.) Dissolve thiophene-2-yl-acetic acid methyl ester (42) (2.0 g, 12.8 mmol) in anhydrous chloroform (9.0 mL) and glacial acetic acid (9.0 mL), add N-bromosuccinimide (2.3 g, 13.0 mmol) in portions and stir the mixture for 3 d at rt. Add water to the reaction mixture, separate layers and extract the aqu. layer with dichloromethane. Wash combined organic layer several times with a 1 M aqu. NaOH and water and once with brine and dry it with Na2SO4. Purify the crude product by preparative radial chromatography (CyH/EtOAc 5+1] to obtain (5-bromo-thiophen-2-yl)-acetic acid methyl ester (43) as a yellow oil (2.46 g, 81%) which is used without any further purification. 1H NMR (400 MHz, CDCl3): 3.71 (s, 3H); 3.75 (s, 2H); 6.67 (d, 1H, J=3.8 Hz); 6.88 (d, 1H, J=3.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[SH:11].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[S:11][CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1cc(Cl)cc(S)c1Cl
Reactant: COC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(Cl)cc(OC)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2,5-dichloro-3-methoxybenzenethiol (2.36 g) and DMF (dry) (60 mL) were added K2CO3 (1.72 g) and methyl 4-chloro-3-oxobutanoate (1.46 mL) at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (3.37 g).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])C.[OH-].[Na+]>C(O)C.CCOC(C)=O>[Br:30][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a solution of 4-[3-[6-(3-Bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.0 g, 1.68 mmol) in hot ethanol (40 mL) was added aqueous 2.0 N sodium hydroxide (10 mL). The resulting solution was heated to 60° C. and stirred for 4 h. Then, the reaction mixture was cooled down and diluted with EtOAc, washed with 10% aq. HCl and brine. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford 805 mg (89%) of title compound as a light yellow oil. HR-ES(+) calcd for C26H33O7Br [M+Na]+ 559.1302, observed 559.1299.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][C:42]([F:45])([F:44])[F:43])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][C:42]([F:45])([F:44])[F:43])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: FC(F)(F)Oc1ccccc1Sc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccccc3OC(F)(F)F)cc2)c1C
Yield: 32.3 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(2-(trifluoromethoxy)phenylsulfanyl)benzene (0.214 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-fluoro-3-methyl-4-[4-(2-trifluoromethoxyphenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.089 g, 32%) as a solid. MS calcd. for C27H19F4O3S [(M−H)−] 499, obsd. 499.1.
Reaction SMILES: CN(S(F)(F)[F:5])C.[C:8]([C:10]1[C:14]([S:15][C:16]([F:19])([F:18])[F:17])=[C:13]([CH2:20]O)[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9].O>ClCCl>[C:8]([C:10]1[C:14]([S:15][C:16]([F:19])([F:18])[F:17])=[C:13]([CH2:20][F:5])[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CO)c1SC(F)(F)F
Reactant: CN(C)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CF)c1SC(F)(F)F
Reaction time: 3 h
Yield: 84 %

Procedure:
Dimethylaminosulfur trifluoride (2.27 mL) was added to a solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole (2.9 g) in dichloromethane. After stirring for 3 hours, water was added followed by dichloromethane. The organic phase was washed with an aqueous solution of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (2.45 g, 84%). 1H NMR: (400 MHz, CDCl3): 5.38 (d, J=47.5 Hz, 2H) and 7.83 (s, 2H). 19F NMR (376 MHz, CDCl3): −43.83 (s, 3F), −63.76 (s, 3F) and −84.12 (t, J=47.5 Hz, 1F).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1ccccc1CCN
Product: Cc1ccccc1CCNC(=O)c1ccc(F)cc1

Procedure:
1-Amino-2-(2-methylphenyl)ethane was reacted with 4-fluorobenzoyl chloride in the same way as in step (a) of Example 1 to afford 1-(4-fluorobenzoylamino)-2-(2-methylphenyl)ethane as colorless needles having a melting point of 82° to 83° C.
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[N:4][N:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=12.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:17]1[CH:16]=[C:15]([C:3]2[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=3)=[C:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][N:5]3[N:4]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Fc1cccc(-c2nn3cc(C(F)(F)F)ccc3c2Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 44.7 %

Procedure:
To a solution of the 3-bromo-2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine (50 mg, 0.139 mmol) in DMF (5 ml) was added 4-methanesulfonylphenylboronic acid (37 mg, 1.3 eq), ground potassium phosphate (83 mg) and tetrakis(triphenylphosphine)palladium(0) (10 mg) and the mixture heated to 90° for 18 h under N2. The cooled mixture was poured into water (10 ml) and extracted into ethyl acetate (4×10 ml). The combined organic phases were washed sequentially with water, brine, 2N sodium hydroxide and brine, dried and concentrated in vacuo to give the title compound as an off-white solid (27 mg, 45%). MH+ 435
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7](OS(C)(=O)=O)[CH2:6]1)(=[O:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@@H:7]([N:15]=[N+:16]=[N-:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@@H]1CC[C@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1CC[C@@H](N=[N+]=[N-])C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a 8 ml DMF solution of 580 mg (2.61 mmol) of (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate, 203 mg (3.13 mmol) of sodium azide and 26 μl (0.13 mmol) of 15-crown-5-ether were added and stirred at 80° C. for 3 hours, followed by concentrating and then by diluting with 50 ml of diethyl ether. The residue was washed with 10 ml of saturated saline and then the solvent was distilled off to obtain 360 mg (82%) of the above-identified compound as a slightly brown oily substance.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:39](Cl)(=[O:41])[CH3:40]>C1COCC1>[C:39]([N:4]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:27])([F:28])[F:29])[CH:1]([CH3:3])[CH3:2])(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CC(C)NCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(4-(2-(isopropylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.05 mmol, 20 mg) in THF (1 mL) was added DIPEA (0.248 mmol, 44 μL) and acetyl chloride (0.149 mmol, 12 mg). The mixture was stirred at r.t. for 16 h and the product was then purified by HPLC to give 6-(4-(2-(N-acetyl-N-isopropylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (CD3OD) δ: 8.38-8.44 (m, 4H), 7.35 (d, 1H), 4.15-4.34 (m, 3H), 4.02 (s, 3H), 3.68-3.85 (m, 2H), 2.19 (2xs, 3H), 1.25-1.29 (m, 6H). MS m/z 446 (M+H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)([CH3:10])[CH2:8][N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6]1)=[O:4].[Li+].[OH-].CO>C1COCC1>[CH2:18]([N:7]1[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)([CH3:10])[CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1(C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)CN(Cc2ccccc2)CC1C(=O)O
Yield: 97.1 %

Procedure:
A mixture of 9.56 g (27.8 mmol) rac-(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-4-methyl-pyrrolidine-3-carboxylic acid methyl ester and 3.5 g (83.4 mmol) LiOH.H20 in 50 mL THF/50 mL water and 5 mL methanol was heated to reflux and stirred over night. The organic solvents were removed under vacuum and the aqueous phase was adjusted to pH=4-5 with 1N HCl aq. Water was decanted off the residue and THF was added. The mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate/THF (1:1) and the organic layers were evaporated to yield 8.9 g (97%) of the title compounds as off-white solid. MS m/e: 328.3 [M−H].
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]Br)[CH2:5]1)(=[O:3])[CH3:2].[CH2:16]([C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17].C(O)(=O)/C=C/C(O)=O>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:21]2[CH2:22][CH2:23][C:18]([CH2:16][CH3:17])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(CCBr)c2ccccc21
Reactant: CCC1(c2ccccc2)CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Product: CCC1(c2ccccc2)CCN(CCC2CN(C(C)=O)c3ccccc32)CC1

Procedure:
In the manner described in Example 1, treatment of 1-acetyl-3-(2-bromoethyl)indoline with 4-ethyl-4-phenylpiperidine gives an oil. On reaction with molar equivalent of fumaric acid, a crystalline fumarate results. After recrystallization from acetone-hexane it melts at 173°-178°C.
Reaction SMILES: FC(F)(F)C(O)=O.[O-:8][C:9]#[N:10].[Na+].NN.[CH3:14][C:15]1[CH:16]=[C:17]([N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[NH2:23])[CH:18]=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[NH2:10][C:9]([NH:23][N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1)=[O:8]
Reactant: COC(=O)CN(N)c1cc(C)cc(C)c1
Reactant: N#C[O-]
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(NC(N)=O)c1cc(C)cc(C)c1
Reaction time: 2 h
Yield: 76 %

Procedure:
Trifluoroacetic acid (1.06 ml, 13.9 mmol) was added under nitrogen to a stirred suspension of sodium cyanate (1.00 g, 15.2 mmol) in a solution of the hydrazine (Intermediate 36; 1.00 g, 4.8 mmol) in dry toluene (30 ml). The mixture was stirred for ca. 2 h, causing formation of a viscous insoluble gum. Saturated aqueous sodium hydrogen carbonate (25 ml) was added (causing effervescence and dissolution of the gum) and the mixture was extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated brine (50 ml) dried and evaporated to afford a light yellow solid which was triturated with hexane/ethyl acetate (1:1) to give the title compound as a white powder (0.92 g, 76%), m.p. 139°-141°.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7](OCCN2CCCC2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:18][N:19]1[CH2:24][CH2:23][N:22](C2C=CC(N)=CC=2)[CH2:21][CH2:20]1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:16][CH:17]=1)=[C:2]=[S:3]
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CN1CCN(c2ccc(N=C=S)cc2)CC1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4-isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-(4-methyl-piperazin-1-yl)-phenylamine. Title compound: ES-MS: 234.0 [M+H]+; single peak at tR=6.60 min (System 1).
Reaction SMILES: [C-]#N.[Na+].C1N2CC[N:6](CC2)[CH2:5]1.[Br:12][C:13]1[CH:14]=[N:15][C:16](Cl)=[N:17][CH:18]=1>CS(C)=O.O>[Br:12][C:13]1[CH:14]=[N:15][C:16]([C:5]#[N:6])=[N:17][CH:18]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 345.1 %

Procedure:
To a solution of NaCN (0.849 g, 17.32 mmol) and DABCO (0.390 g, 3.48 mmol) in a mixture of DMSO (4 ml) and H2O (9 ml) was added a solution of 5-bromo-2-chloropyrimidine (3.05 g, 15.75 mmol) in DMSO (9 ml). The solution was stirred at room temperature overnight, and then diluted with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give 5-bromopyrimidine-2-carbonitrile (2,327 g, 12.01 mmol, 76% yield, 1H NMR (CDCl3 500 MHz): δ 8.94 (s, 2H)).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: CN1CCN(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 6) (20 mg, 0.046 mmol, 1 eq), DIPEA (16 μl, 0.091 mmol, 2 eq) and TBTU (16 mg, 0.05 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 1-amino-4-methylpiperazine (7 mg). The RM was then stirred at rt for 16 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].C(OCCCCCC)(=O)[C:15]1[CH:23]=[CH:22]C(C([O-])=O)=[CH:17][CH:16]=1.[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5])[CH2:17][CH2:16][CH2:15][CH2:23][CH3:22]
Reactant: CCCCCCOC(=O)c1ccc(C(=O)[O-])cc1
Reactant: Cc1cc(C(=O)Cl)ccc1C(=O)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCCCc1cc(C(=O)Cl)ccc1C(=O)Cl

Procedure:
This compound was prepared by the method described for monomethyl terephthaloyl chloride. Typical reagent levels were as follows: potassium monohexyl terephthalate (18.6 g, 0.64 mole), thionyl chloride (9.21 g, 0.774 mole) and 100 ml of toluene. The product was used without further purification.