Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C1(C)C=CC=CC=1.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[S:22])=[CH:17][CH:16]=1.Cl>C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[S:22])=[CH:23][CH:24]=1
Reactant: O=C(O)CCS
Reactant: S=C=NCc1ccc(Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CCSC(=S)NCc1ccc(Cl)cc1

Procedure:
To a solution of 1.06 g. of 3-mercaptopropionic acid in 5 ml. of toluene and 2.0 g. of triethylamine, there was added with cooling 1.83 g. of p-chlorobenzylisothiocyanate. Two phases formed. The mixture was acidified with 1-N hydrochloric acid and extracted with chloroform. The chloroform phases were washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile, and 2.1 g. of 3-{[(p-chlorobenzyl)thiocarbamoyl]thio}-propionic acid having a melting point of 126°-127° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].C(=O)=O.CC(C)=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccsc1C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)sc1C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
At -78° C., to a stirred solution of 2,3-dimethylthiophene (5.00 g, 44.6 mmol) in THF (89.3 mL) was added dropwise 2.5M BuLi/hexanes (17.9 mL, 44.6 mmol). After the addition was complete, the dry ice/acetone bath was replaced with a water ice bath and the reaction was stirred for 0.75 h. At -78° C., to the reaction was added a solution of benzyl bromide (5.30 mL, 44.6 mmol) in THF (44.6 mL) that had been previously cooled to -78° C. After the addition was complete, the reaction was stirred for 18 h eventually warming to ambient temerature. The reaction was filtered through a silica gel pad eluting with 1% EtOAc/pet ether and the filtrate was concentrated. Purification on Biotage KP-Sil eluting with 1% EtOAc/pet ether gave 6.960 g (77%) of the title compound as an oil. 1H NMR (DMSO-d6) δ 2.01 (s, 3 H), 2.21 (s, 3 H), 3.98 (s, 2 H), 6.58 (s, 1 H), 7.18-7.37 (m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][CH:9]=[N:10]2)=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:4]=1.[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[CH:25]=[C:24]2[CH:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)#[N:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][CH:9]=[N:10]2)=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C@@H:34]3[CH2:33][CH2:32][C@H:31]([C:24]4[C:23]5[C:27](=[CH:28][CH:29]=[C:21]([C:19]#[N:20])[CH:22]=5)[N:26]([CH3:30])[CH:25]=4)[CH2:36][CH2:35]3)[CH2:15][CH2:14]2)[CH:4]=1
Reactant: COc1cc(N2CCNCC2)c2nccnc2c1
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)c2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-methoxy-5-piperazin-1-yl-quinoxaline (160 mg, 0.66 mmol), 4-(5-cyano-1-methyl-1H-indol-3-yl)-cyclohexanone (170 mg, 0.66 mmol), and sodium triacetoxyborohydride (210 mg, 0.98 mmol) in dichloroethane (30 mL) was added acetic acid (0.1 mL, 1.3 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (100 mL) then extracted in CH2Cl2 (75 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc) affording 120 mg (38%) of the cis isomer as a bright yellow solid: mp 226-229° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])[CH:12]=2)=[CH:4][C:3]=1[O:19][CH:20]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1[Cl:30])[CH3:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:45][N:46]([CH3:51])[CH2:47][CH2:48][CH2:49][NH2:50]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C:13]([CH3:18])([CH3:17])[C:14]([NH:50][CH2:49][CH2:48][CH2:47][N:46]([CH3:51])[CH3:45])=[O:15])[CH:12]=2)=[CH:4][C:3]=1[O:19][CH:20]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1[Cl:30])[CH3:21]
Reactant: CC(Oc1cc(-c2cnn(C(C)(C)C(=O)O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CN(C)CCCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(Oc1cc(-c2cnn(C(C)(C)C(=O)NCCCN(C)C)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
To a solution of 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid (1.00 g, 2.20 mmol) in DMF (5.5 mL) were added HOBT (300 mg, 2.20 mmol), EDC (633 mg, 3.30 mmol), and N,N-dimethyl-propane-1,3-diamine (225 mg, 2.20 mmol). The reaction was stirred overnight at room temperature. The reaction was then purified by reversed phase C-18 prep HPLC eluting with acetonitrile/water with 0.1% acetic acid to afford 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-N-(3-dimethylamino-propyl)-isobutyramide (170 mg, 14% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:10][C:4]=1[NH2:1]
Reactant: Nc1ccc(SCCCCl)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(SCCCCl)cc1N

Procedure:
6 G. of 2-nitro-4-(3-chloropropylthio)aniline is treated in 120 ml. of methanol and 120 ml. of water with 30 g. of sodium hydrosulfite (Na2S2O4) on the steam bath for about 5 minutes. The reaction mixture is concentrated under vacuum and extracted well with chloroform. Evaporation of the dried extract affords 1,2-diamino-4-(3-chloropropylthio)benzene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH2:15][OH:16])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:18][NH2:19]>>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:18][N:19]=2)[CH:12]=[CH:13][C:14]=1[CH2:15][OH:16]
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(CO)c(O)c1
Solvent: O
Product: O=C1CCC(c2ccc(CO)c(O)c2)=NN1

Procedure:
3-(3-Hydroxy-4-hydroxymethylbenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3(i) to give 6-(3-hydroxy-4-hydroxymethylphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1

Procedure:
According to the method in example 29, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and diethanolamine were converted to yield 2-[{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol as light yellow oil, MS: 464 (MH+,1Br).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24](OS(C)(=O)=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2C=O)CC1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A mixture of 2-hydroxy-5-trifluoromethyl-benzaldehyde (1.36 g, 7.17 mmol), 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.2 g, 7.88 mmol) and K2CO3 (2.96 g, 21.5 mmol) in anhydrous N,N-dimethylformamide (15 mL) was heated at 100° C. for 1 h. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (50 mL). The solution was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography to give the title compound (1.43 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
4'-Hydroxyacetophenone (40g) and potassium carbonate (60.9 g) were mixed in dimethyl formamide (250 ml). Benzyl bromide (36.7 ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour and further at 50° to 60° C. for 1 hour. The reaction mixture was poured into ice-water, and the precipitating crystals were collected by filtration and recrystallized from methanol to give 4'-benzyloxyacetophenone (55.4g, 83.3%). m.p. 93°-94° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([OH:10])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:11][O:10][C:7]1[N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]2=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2cc[nH]c2n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridin-6-ol (0.200 g, 1.49 mmol) and K2CO3 (1 g, 7.45 mmol) in acetone (30 mL) was stirred under N2 at room temperature for 1 h. MeI (0.166 g, 1.192 mmol) was added. The reaction mixture was stirred under N2 at 50° C. for 12 h and then filtered. The filtrate was concentrated to half its volume, diluted with water, and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, and evaporated to give a residue, which was purified on a column of silica gel eluting with EtOAc/hexane (1:4) to give 6-methoxy-1H-pyrrolo[2,3-b]pyridine (159 mg, 89%).
Reaction SMILES: [CH2:1]([CH:5]([C:12]1[C:13](=[O:23])[O:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]([CH3:4])=[O:3].[C:24](Cl)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O1CCOCC1.N1C=CC=CC=1>[CH2:1]([CH:5]([C:12]1[C:13](=[O:23])[O:14][C:15]2[C:20]([C:21]=1[O:22][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)Cl
Reactant: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCCCC/C=C/CCCCCCCC(=O)Oc1c(C(CC(C)=O)c2ccccc2)c(=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of 3-(α-acetonylbenzyl)-4-hydroxycoumarin (warfarin) (3.70 g, 12 mmol) in 120 ml anhydrous dioxane and 25 ml pyridine was added elaidic acid chloride (3.60 g, 12 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated at high vacuum. The residue was partitioned between ether and water. The organic phase was washed with tartaric acid (aq), NaHCO3 (aq) and water. The dried organic phase was concentrated and the product purified on a column of slica gel with heptane/ethylacetate (6:1) as the eluent system. Impure fractions were repurified and homogenous fractions were evaporated to give 5.1 g (70%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28](O)=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C2CC(C)(C)c3cc(C(=O)NS(C)(=O)=O)ccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a suspension of methanesulfonamide (480 mg, 5.0 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (200 mg, 5.0 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A36. A solution of 2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (310 mg, 1.0 mmol) and 1,1′-carbonyldiimidazole (320 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B36. Solution B36 was added to Solution A36 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (116 mg, 30%) as a white solid: MS (ESI) M+1=389.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30](=[O:34])[CH2:31][C:32]#[N:33])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)([CH3:39])[CH:37]=O.N1CCCC1.[Si](Cl)(C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30]([C:31](=[CH:37][C:36]([CH3:39])([N:40]3[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]3)[CH3:35])[C:32]#[N:33])=[O:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CN1CCN(C(C)(C)C=O)CC1
Agent: C[Si](C)(C)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a mixture of 3-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile (100.6 mg, 0.220 mmol) and 2-methyl-2-(4-methylpiperazin-1-yl)propanal (118.2 mg, 0.660 mmol) in DCM (5 mL) in an ice bath was added pyrrolidine (0.11 mL, 1.32 mmol) and TMS-Cl (0.11 mL, 0.880 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was loaded on silica gel plate, purified by MeOH:CH2Cl2 to obtain 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile (19 mg) as a white powder. LC-MS (ES, m/z): 610 [M+H]
Reaction SMILES: [H-].[Na+].C([C:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)(CCC(OC)=O)CCC(OC)=O)#N.C[O:34]CCOC>>[CH:30]1([CH2:29][O:28][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=2[O:24][CH:25]([F:27])[F:26])[CH:5]=[O:34])[CH2:32][CH2:31]1
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 60 °C

Procedure:
To a suspension of sodium hydride (80% dispersion in mineral oil, 11.6 g, 388 mmol) in dry 1,2-dimethoxyethane (700 mL) under an argon atmosphere was added a solution of crude dimethyl 4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pimelate (41 g) in dry 1,2-dimethoxyethane (700 mL). The resulting mixture was heated at 60° C. for 1 h, cooled to room temperature, quenched with dilute aqueous hydrochloric acid and concentrated the residue was diluted with water, was acidified to pH 3 and was extracted twice with methylene chloride. The organic extract was washed with acidic water, was dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with methylene chloride, followed by trituration with cold ether provided a solid (17.7 g, 43% from 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde): m.p. 115°-116° C. Analysis Calc. for C20H21F2NO5 : C 61.06, H 5.38, N 3.56; found: C 61.16, H 5.40, N 3.52.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8](Cl)=[O:9].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>C(Cl)Cl.C(OCC)(=O)C>[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([C:19]1[NH:18][CH:22]=[CH:21][CH:20]=1)=[O:9]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Aluminum chloride (2.6 g, 20 mmol) was added to a mixture of 2-chloro-5-nitro-benzoyl chloride (5 g, 20 mmol) and pyrrole (4 g, 30 mmol) in DCM (100 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins. The reaction was diluted with ethyl acetate, washed with brine, water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give 1.5 g (30%) of (2-chloro-5-nitro-phenyl)-(1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Cl:16][C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[OH:6][CH:3]1[CH2:4][CH2:5][N:1]([C:17]([Cl:16])=[O:19])[CH2:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cl)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of pyrrolidin-3-ol (0.083 g, 0.955 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) and cooled 0° C. To the resulting mixture was added triphosgene (0.127 g, 0.429 mmol) and the mixture was stirred for 2 h at an ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH2:21][CH3:22])[C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:19][CH2:18][CH2:17][CH:16]2[C:15](=[CH:25][N:26]([CH3:28])[CH3:27])[C:14](=[O:20])[CH:13]3[CH2:21][CH3:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CCC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-2-ethyl-9-aza-bicyclo[3.3.1]nonan-3-one (180 mg, 0.52 mmol) in DMF (1 mL,) was added N,N-dimethylformamide dimethyl acetal (1 mL). The resulting mixture was heated to 110° C. for 2 h after which the reaction mixture was concentrated under reduced pressure to give the desired product as a brown oil. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=2.365 min, Method [1], MS (ESI) 370 (M-NMe2+OH+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:37])[C:27]=1[N:28]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[N:29]1)[O:5][C@H:6]([C:10]1[CH:24]=[CH:23][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:37])[C:27]=1[N:28]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[N:29]1)[O:5][C@H:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:23][CH:24]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To the solution from step 5 was added methanol (40 mL), water (54 mL) and sodium hydroxide (4.34 g, 108 mmol). The reaction was stirred 1 h at 30° C. The solution was acidified with conc. HCl (9.33 mL) and the aq. phase split. The organic solution was washed with 1 N HCl (40 mL). The organic phase was concentrated and the residue taken up in acetonitrile (300 mL). The solution was cooled to 0° C. and stirred 5 h. The solid product was filtered and washed with cold acetonitrile, giving the desired compound as a white solid (14.6 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ: 7.88 (s, 1H), 7.72 (d, J=8.3 Hz, 2H), 7.65 (s, 1H), 7.38 (d, J=8.3 Hz, 2H), 6.89 (t, J=6.2 Hz, 1H), 6.55 (s, 2H), 5.15 (dd, J=7.8, 4.6 Hz, 1H), 3.68 (q, J=6.2 Hz, 2H), 2.65 (t, J=6.2 Hz, 2H), 1.95 (m, 1H), 1.86 (s, 6H), 1.78 (m, 1H), 1.55-1.38 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). The final compound was recrystallized from acetonitrile (5 vol). The compound was heated to 80° C. and then cooled to 0° C. to provide a purity of 99.01%.
Reaction SMILES: C([Mg]Br)C.[CH3:5][Si:6]([CH3:17])([CH3:16])[NH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:13])=[CH:10][CH:9]=1.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>C1COCC1>[CH3:17][Si:6]([CH3:5])([CH3:16])[N:7]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:13])=[CH:10][CH:9]=1)[Si:19]([CH3:21])([CH3:20])[CH3:18]
Reactant: C=Cc1ccc(N[Si](C)(C)C)cc1
Reactant: C[Si](C)(C)Cl
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: C=Cc1ccc(N([Si](C)(C)C)[Si](C)(C)C)cc1
Yield: 55 %

Procedure:
To a solution of ethylmagnesium bromide in THF (0.6M, 150 mL) was added dropwise 4-[N-(trimethylsilyl)amino]styrene (8.4 g, 44 mmole) with stirring. The mixture was stirred at 40° C. for 16 hours. To the resulting solution was added trimethylsilylchloride (13 g, 120 mmole)and the mixture stirred at room temperature for 6 hours. By fractional distillation, a product was isolated at 45°-48° C./0.32 mm in 55% yield. The product was confirmed by spectral analysis to be the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2.[I-].[CH3:24][N:25]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26](N1C=C[N+](C)=C1)=[O:27]>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][C:26](=[O:27])[N:25]([CH3:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:9]=2
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Cc1c(Cc2c(F)cccc2Cl)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(Cc2c(F)cccc2Cl)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12

Procedure:
The title compound was prepared from 3-(2-chloro-6-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide by applying procedure 3. HPLC-MS m/z=452 (M+1), Rt: 5.15 min.