Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH:9]=[CH2:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1>CC#N>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][CH2:10][CH2:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[O:11])[CH3:20])=[CH:15][CH:14]=1
Reactant: C=CC(=O)c1ccccc1F
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: CC#N
Product: C[C@H](NCCC(=O)c1ccccc1F)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
To a solution of 1-(2-fluorophenyl)-prop-2-en-1-one (5.6 g, 37.3 mmol) in CH3CN (50 mL) was added (S)-1-(4-bromophenyl)-ethylamine (7.4 g, 37 mmol), and the mixture was stirred for 12 h at 40° C. The solution was concentrated to afford the crude product, which was purified by column chromatography to give (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(2-fluorophenyl)-propan-1-one (4 g, yield: 30.7%) as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>O>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([S:14]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)=[O:38])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(Sc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.1 g (3.1 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate and 30 ml of dichloromethane were introduced into a round-bottomed flask, and 970 mg (3.1 mmol) of meta-chloroperbenzoic acid were then added. The entire contents were stirred at room temperature for two hours, the reaction medium poured into water, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica column eluted with dichloromethane. After evaporation of the solvents, 1 g (84%) of the expected ester was recovered.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][C:15]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:11][C:7]1[C:6]2[C:2]([C:18]3[CH:17]=[CH:16][C:15]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[C:14]([O:13][CH3:12])[CH:19]=3)=[CH:3][O:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: Nc1nccc2occ(Br)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2coc3ccnc(N)c23)ccc1NC(=O)OC(C)(C)C
Yield: 98.3 %

Procedure:
A mixture of 3-bromofuro[3,2-c]pyridin-4-amine (0.443 g, 2.1 mmol) in 1,2-dimethoxyethane (16 mL) and water (8 mL) was treated with tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.872 g, 2.5 mmol,), sodium carbonate (0.749 g, 7.1 mmol) and tetrakis triphenylphosphine palladium (0) (0.144 g, 0.12 mmol) at 80° C. for 18 hours. The organic solvent was removed in vacuo and the aqueous mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel using heptane/ethyl acetate (4:1) followed by ethyl acetate as an eluents to give the title compound (0.734 g, 85%) as a tan solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.87 (d, 1H), 7.84 (d, 1H), 7.14 (d, 1H), 7.05 (dd, 1H), 6.94 (d, 1H), 5.55-5.62 (bs, 2H), 3.87 (s, 3H), 1.48 (s, 9H); RP-HPLC (Conditions f) Rt 12.13 min.; MS: MH+ 356.
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:64]1[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.O>ClCCl>[OH:48][CH:29]([CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](=[O:45])[N:64]1[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1)/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH:27]([CH:12]1[O:13][C:14](=[O:26])[C:15]([O:24][CH3:25])=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]([CH3:22])[CH:20]([OH:21])[CH:3]([CH2:1][CH3:2])[CH:4]([OH:53])[CH:5]([CH3:52])[CH2:6][C:7]([CH3:51])=[CH:8][CH:9]=[CH:10][CH:11]1[O:49][CH3:50])[CH3:28]
Reactant: C1CCNCC1
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCCCC1)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCCCC1)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBt (2 mg) were added. After 20 min, piperidine (1.3 mg) was added. The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated. Reaction mixture was extracted with dichloromethane (3×5 mL). The combined organic layer was washed with water (2×5 mL). The organic layer was dried over sodium sulphate, and was concentrated. The crude product was purified by preparative HPLC [Eurospere-100, C18 column (250 mm×8 mm), mobile phase: acetonitrile-water (1:1 isocratic)] to obtain the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1>C(O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:1]#[N:2])=[CH:8][CH:9]=1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: [C-]#N
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)c1ccc(CC#N)cc1
Temperature: 50 °C

Procedure:
A solution of 34.3 g. (0.700 mole) sodium cyanide in 40 ml. of water is warmed to 50°C. and a solution of α-bromo-4-pivaloyl toluene in 85 ml. ethanol is then added dropwise at such a rate as to maintain the temperature at 50°C. After the addition is complete, the mixture is refluxed for four hours. The excess ethanol is removed in vacuo and the resulting residue is treated with ether/water. The layers are separated and the ether is washed with cold 50% sulfuric acid, water and sodium bicarbonate; then the ether layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is distilled in vacuo to give 4-pivaloylphenyl acetonitrile (b.p. 143°-148°C/0.75 mm n22 =1.5244.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C1(C)C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]4[O:16][CH:30]=[N:29][CH:28]=4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Product: Brc1ccc2nc(-c3ccc(-c4cnco4)cc3)cn2c1
Yield: 78.8 %

Procedure:
The procedure of Example 1 was repeated, except that 4-(6-bromoimidazo[1,2-a]pyridin-2-yl)benzaldehyde (255 mg) and p-toluenesulfonylmethylisocyanide (198 mg) were used, to thereby yield the title compound (227 mg).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1(=[O:21])[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>C1C=CC=CC=1>[C:1]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NNC(=O)c1ccccc1
Solvent: c1ccccc1
Product: O=C(NNC(=O)c1ccccc1C(=O)O)c1ccccc1

Procedure:
At a temperature of about 18°, powdered benzhydrazide (126 g, 1 mole) was suspended in stirred benzene (1.6 l), and 24-mesh phthalic anhydride (148 g, 1 mole) was added portionwise over 15 to 20 minutes. After the addition the reaction mixture was stirred for a further hour. The product, 1-benzoyl-2-(2-carboxybenzoyl) hydrazine (III) (R1 =H) was collected on a filter, pressed free of benzene and air dried, 276 g, 98%, M.P., 205°-208°.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:12]=[C:11](Cl)[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([Cl:14])[CH:9]=2)[N:4]=1>O1CCCC1>[Cl:2][C:3]1[N:12]=[C:11]([NH2:1])[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([Cl:14])[CH:9]=2)[N:4]=1
Reactant: N
Reactant: COc1c(Cl)cc2c(Cl)nc(Cl)nc2c1OC
Solvent: C1CCOC1
Product: COc1c(Cl)cc2c(N)nc(Cl)nc2c1OC
Yield: 81 %

Procedure:
Ammonia was passed into a solution of 2,4,6-trichloro-7,8-dimethoxyquinazoline (31.4 g., 0.107 mole) in 650 ml. dry tetrahydrofuran for one hour at room temperature. After stirring for an additional hour, the suspension was concentrated in vacuo and filtered. The solid was resuspended in water, filtered, washed with water and methanol. Recrystallization from dimethylformamide/water yielded 23.7 g. (81%) of the desired product, M.P., 360° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][C:9]#[CH:10])[CH:2]=1.Cl.[NH2:13][OH:14]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:13][OH:14])[CH2:8][C:9]#[CH:10])[CH:2]=1
Reactant: C#CCC(=O)c1cccnc1
Reactant: NO
Agent: Cl
Product: C#CCC(=NO)c1cccnc1

Procedure:
Employing the general method of Example 5 above, 2.95 g (18.5 mmol) of 1-(3-pyridinyl)-3-butyne-1-one was converted to 2.1 g (66%) of the corresponding oxime by reaction with hydroxylamine hydrochloride.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19](O)=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a suspension of 60% sodium hydride (361 mg, 9 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (865 mg, 9.1 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A62. A solution of 6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (520 mg, 1.3 mmol) and 1,1′-carbonyldiimidazole (422 mg, 2.6 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B62. Solution B62 was added to Solution A62 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-[6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (50 mg, 8%) as a white solid: MS (ESI) M+1=478.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1([C:11]([OH:13])=O)[CH2:8][C:7]1([Cl:10])[Cl:9]>C1C=CC=CC=1>[Cl:5][C:6]1([C:11]([Cl:3])=[O:13])[CH2:8][C:7]1([Cl:10])[Cl:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(Cl)CC1(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C1(Cl)CC1(Cl)Cl
Reaction time: 20 h

Procedure:
Thionyl chloride (50 ml) was added to a solution of 1,2,2-trichlorocyclopropane carboxylic acid (47.4 grams) in 300 ml of benzene. The reaction mixture was heated to reflux temperature and stirred for approximately 20 hours. The solvents were evaporated in vacuo to provide the intermediate acid chloride derivative, 1,2,2-trichlorocyclopropane carboxylic acid chloride (43.8 grams).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[CH2:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)[CH3:37]>>[CH2:36]([N:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:50]=[CH:49][C:47]([NH:48][C:32]3[C:27]4[S:26][CH:25]=[C:24]([C:22]([NH:21][C:3]5[CH:4]=[C:5]([C:8](=[O:20])[NH:9][C:10]6[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=6)[CH:6]=[CH:7][C:2]=5[CH3:1])=[O:23])[C:28]=4[N:29]=[CH:30][N:31]=3)=[CH:46][CH:45]=2)[CH2:42][CH2:43]1)[CH3:37]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Product: CCN1CCN(c2ccc(Nc3ncnc4c(C(=O)Nc5cc(C(=O)Nc6cccc(C(F)(F)F)c6)ccc5C)csc34)cc2)CC1

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 4-(4-ethylpiperazine-1-yl)aniline to obtain the title compound (see Table 1).
Reaction SMILES: [Na].[C:2]([NH:5][C:6]#[N:7])(=[O:4])[CH3:3].[CH2:8](Cl)[CH:9]=[CH2:10]>S1(CCCC1)(=O)=O>[C:6]([N:5]([CH2:10][CH:9]=[CH2:8])[C:2](=[O:4])[CH3:3])#[N:7]
Reactant: CC(=O)NC#N
Reactant: C=CCCl
Agent: [Na]
Solvent: O=S1(=O)CCCC1
Product: C=CCN(C#N)C(C)=O

Procedure:
159.1 g (1.5 mols) of the sodium salt of acetylcyanamide and 137.8 g (1.5 mols+20% excess) of allyl chloride are reacted in 400 ml of sulfolane for 9 hours and 45 minutes at 70°-127° C. analogously to Example 1, and the mixture is worked up in accordance with Example 1. This gives 121.7 g (65.4% of theory) of a colourless distillate, boiling at 98° C./43 mbar.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[C:11]([O:14][CH2:15][CH2:16][O:17]C)(=O)C.Cl>C1C=CC=CC=1.O>[CH3:11][O:14][CH2:15][C:16]([CH:6]1[CH2:5][CH:4]([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10])=[O:17]
Reactant: COCCOC(C)=O
Reactant: CC1CCC(=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COCC(=O)C1CC(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
2.5 g of 60% sodium hydride was suspended in 50 ml of benzene and a mixture of 5.6 g of 4methylcyclohexanone and 5.4 g of methoxyethyl acetate was added dropwise thereto under cooling. After stirring at room temperature for two hours, 20 ml of water was added and the pH value of the reaction mixture was adjusted to 3 with concentrated hydrochloric acid. After removing the benzene phase the aqueous phase was extracted with ether. The benzene solution and the ether solution were combined, washed with water, dried and concentrated to give 7.4 g of crude 2-methoxyacetyl4-methylcyclohexanone. This crude product was subjected to the subsequent step.
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)=O.C([O-])=O.[Na+].Cl.[NH2:19]O.C(O)=O>O>[C:1]([C:3]1[C:4]([OH:13])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:19]
Reactant: NO
Reactant: O=Cc1cc(C(F)(F)F)cnc1O
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the compound from Step B above (18 g, 95 mmol), sodium formate (7.1 g, 110 mmol), hydroxylamine hydrochloride (7.3 g, 110 mmol), and formic acid (150 mL) was stirred at room temperature for 2 h and then heated to reflux overnight. The reaction mixture was cooled, allowed to stand at room temperature for 7 d, poured into water and extracted with three portions of ethyl acetate. The combined organic layers were washed sequentially with two portions of water, saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo to yield the desired product as a brown powder. 1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=2.7 Hz, 1H), 8.19 (q, J=0.7 Hz, 0.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]1(C(=O)CCC)C=CC=CC=1>>[CH2:1]([C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:13]
Reactant: Cc1[nH]cnc1-c1ccccc1
Reactant: CCCC(=O)c1ccccc1
Product: CCc1[nH]cnc1-c1ccccc1

Procedure:
The compound is synthesized using the methods described in examples 269C and 103D starting from 1-phenylbutan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.[CH:14]#[N:15].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:14]#[N:15])=[CH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2c(c1)CCC=C2C#N

Procedure:
A process which comprises (1) cyanating 6-methoxy-tetralone by reacting it with hydrogen cyanide and aluminum chloride in nitrobenzene at about 60°-120° C. so as to form 6-methoxy-1-cyano-3,4-dihydronaphthalene, (2) intimately mixing the resultant solution with an aqueous solution of sodium hydroxide or potassium hydroxide in the presence of a phase transfer agent at about 15°-100° C. as as to aromatize the 6-methoxy-1-cyano-3,4-dihydronaphthalene, and (3) brominating the resultant 6-methoxy-1-cyanonaphthalene while still in nitrobenzene so as to form 6-methoxy-5-bromo-1-cyanonaphthalene.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CC1C=C[C:9]([O:12]C)=CC=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>Cl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:9]=[O:12])=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1F
Reactant: COc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C=O)ccc1F
Temperature: 30 °C
Yield: 131.4 %

Procedure:
229.30 g of aluminum chloride (mol. wt. 133.34; 1,719.7 mmol), 110.0 g (4-Methylanisole (mol. Wt. 122.17; 900.4 mmol), and about 500 g of 2-fluorotoluene (mol. Wt. 110.13; 4,540.1 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 30° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 550 psi, the pressure at which the reaction was maintained for the total reaction time of about 66 hours (the reaction temperature was maintained at 30° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a greenish-brown color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 2-fluorotoluene, and left about 98.01 g of 4-fluoro-3-methylbenzaldehyde product (mol. Wt. 138.14; 709.5 mmol; yield of approximately 86.7%). The 4-fluoro-3-methylbenzaldehyde product may then be easily separated from any residual 4-methylanisole by conversion into its corresponding bisulfite adduct, filtration, and decomposition of the bisulfite adduct under acidic or basic conditions.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:33][CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CBr)C4)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To an ice-cooled mixture of 3-(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (1.0 g, 0.0023 mol) and carbon tetrabromide (1.1 g, 0.0034 mol) in DMF (7 mL) was added triphenylphosphine (0.90 g, 0.0034 mol) and the mixture was stirred at this temp. for 30 min. To the resulting dark brown solution was added saturated aq. NaHCO3 (5 mL) followed by water (5 mL) and the mixture was extracted with dichloromethane. The organic layers were combined, washed with water, dried over Na2SO4, concentrated and purified with combiflash (silica gel, 0-40% EtOAc/Hex) to give the desired product (1.0 g, 87%) as light yellow solid. LCMS calculated for C22H30BrN6OSi(M+H)+: 501.1: Found: 501.3.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[NH:24][N:23]=3)[C:18]([Br:30])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1COCC1.O>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24]([C:31](=[O:33])[CH3:32])[N:23]=3)[C:18]([Br:30])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Yield: 98.6 %

Procedure:
To N-(2-acetamidoethyl)-5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxamide (273.8 mg, 0.56 mmol, 1.0 equiv.), acetic anhydride (114.2 mg, 1.1 mmol, 2.0 equiv.) in THF/H2O (10 ml/1 mL) was stirred at 23° C. for 2 hour. Then the mixture was extracted with THF (6×40 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated give N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)thiophene-2-carboxamide (294.0 mg, 98.5%) as pale yellow solid. LC-MS (m/z)=533.1 [M+H]+;