Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:42])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]3[CH2:41][CH2:40]3)=[CH:37][CH:38]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:39]1([C:36]2[N:35]=[CH:34][C:33]([C:29]3[CH:28]=[C:27]([C:25]4[CH2:24][C:23](=[O:42])[NH:22][C:9]5[CH:10]=[C:11]([C:18]([F:19])([F:20])[F:21])[C:12]([O:14][CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=5[N:7]=4)[CH:32]=[CH:31][CH:30]=3)=[CH:38][CH:37]=2)[CH2:40][CH2:41]1
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M196) (362 mg, 0.59 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (153 mg, 54%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][CH2:62][C@@H:61]([NH2:65])[CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][C@@H:61]5[CH2:62][CH2:63][CH2:64][N:59]([CH3:58])[CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC[C@@H](N)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-methylpiperidin-3-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.26 (m, 2H) 1.29-1.46 (m, 3H) 1.55-1.73 (m, 5H) 1.75-1.90 (m, 6H) 2.17 (s, 3H) 2.63-2.69 (m, 1H) 2.78-2.84 (m, 1H) 3.31 (s, 3H) 3.90-4.01 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=12.63 Hz, 2H) 4.41-4.51 (m, 1H) 7.47 (dd, J=8.46, 1.64 Hz, 1H) 7.51 (d, J=1.77 Hz, 1H) 7.91 (s, 1H) 8.09 (d, J=8.08 Hz, 1H) 8.21 (s, 1H) 8.27 (d, J=8.32 Hz, 1H). [M+H] calc'd for C28H37F2N7O3 558. found 558.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2].[N-:13]=[N+:14]=[N-:15].[Na+].[Cl-].[NH4+]>>[N:2]1[NH:13][N:14]=[N:15][C:1]=1[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccccc1C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COC(=O)c1ccccc1-c1nn[nH]n1
Reaction time: 20 h

Procedure:
Methyl 2-cyanobenzoate (54 g, 0.33 mole) in D.M.F. (165 ml) was treated with sodium azide (23.4 g, 0.36 mole) and ammonium chloride (19.3 g, 0.36 mole). After the reaction mixture had been stirred on the steam bath for 20 hrs., the D.M.F. was removed under reduced pressure and the residue dissolved in water (200 ml). The solution was filtered, cooled in ice and acidified to give a white precipitate which was filtered, washed with water and dried. This gave methyl 2-(5-2H-tetrazolyl)benzoate, M.P. 132°-5°, 19 g (28%). (Found: C, 53.79, 52.59, 52.33; H, 4.25, 4.17, 4.07; N, 26.79, 26.84, 27.25. C9H8N4O2 requires C, 52.94; H, 3.95; N, 27.44.)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1.[C:13]([O:17][C:18](=[O:21])[CH2:19][NH2:20])([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: COC(=O)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Cl)nc1NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product of step (i) (1.73 g), glycine tert-butyl ester (1.4 g) and N,N-diisopropylethylamine (2.6 ml) in dimethylformamide (20 ml) was stirred at room temperature. After 4 hours, the reaction mixture was partitioned between 2M HCl and ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 5% ethyl acetate in toluene. Yield 1.5 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1>CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)=[S:29])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CO
Product: COc1ccc(C(=O)Nc2cccc(Cl)c2)cc1NC(=S)Nc1ccc(F)cc1
Yield: 89.7 %

Procedure:
Prepared according to the procedure described for Example 100 using 3-amino-N-(3-chlorophenyl)4-methoxy-benzamide from Example 16 (0.5545 g, 2.01 mmol) and 4-fluorophenyl isothiocyanate (0.3073 g, 2.01 mmol), and omitting the trituration in methanol to afford the product (0.775 g); m.p. 184-185° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CC1C=CC=CC=1)=O.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[C:28]([Cl:32])[N:27]=1>>[Cl:32][C:28]1[N:27]=[C:26]([NH:25][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:31]=[N:30][CH:29]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CN1C(C(=O)OCc2ccccc2)=C(O)c2ccccc2S1(=O)=O
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from benzyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1.
Reaction SMILES: [OH:1][C:2]1[C:11](S(O)(=O)=O)=[CH:10][C:9]2[C:4](=CC=C(S(O)(=O)=O)C=2)[C:3]=1[N:20]=[N:21][C:22]1[C:31]2[C:26](=CC=CC=2)[C:25](S(O)(=O)=O)=[CH:24][C:23]=1[OH:36].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>>[OH:36][C:23]1[CH:24]=[CH:25][CH:26]=[CH:31][C:22]=1[N:21]=[N:20][C:3]1[CH:4]=[CH:9][CH:10]=[CH:11][C:2]=1[OH:1]
Reactant: O=S(=O)(O)c1ccc2c(N=Nc3c(O)cc(S(=O)(=O)O)c4ccccc34)c(O)c(S(=O)(=O)O)cc2c1
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: Oc1ccccc1N=Nc1ccccc1O

Procedure:
2-Hydroxy-1-(2-hydroxy-4-sulfo-1-naphthylazo)-3,6-naphthalenedisulfonic acid, trisodium salt
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:56])[C:35]([CH3:55])([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)C>C(O)C>[CH3:55][C:35]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:49][CH:50]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:39][CH:38]=1)[C:34]([OH:56])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3cccs3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 10 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl)-ethyl ester(0.132 mmol) (see Ex. 5, Part B) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 15, Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 95:5 CH2Cl2:MeOH to produce a white solid (10%). MS [EI+] 596 (M+H)+, [EI−] 594 (M−H)+
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[C:7]([CH2:9][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: FC1(F)CCC(n2c(CCl)nc3cc(Cl)ccc32)C1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCC(F)(F)C2)c2cnccc12

Procedure:
The title compound was prepared according to the procedures described in Example 2-1 by using 5-chloro-2-chloromethyl-1-(3,3-difluoro-cyclopentyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:21])[CH:9]=[C:8]([C:10](=S)[NH:11][CH3:12])[C:7]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:6]=2[O:5]1.[I-].ClC1C=CC=C[N+]=1C.[N:31]#[C:32][NH2:33].[H-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:32]([NH:33][C:10]([C:8]1[C:7]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:6]=2[O:5][C:4]([CH2:3][O:2][CH3:1])([CH3:21])[CH:9]=1)=[N:11][CH3:12])#[N:31]
Reactant: N#CN
Reactant: CNC(=S)C1=CC(C)(COC)Oc2ccc([N+](=O)[O-])cc21
Agent: C[n+]1ccccc1Cl
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN=C(NC#N)C1=CC(C)(COC)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 12.3 %

Procedure:
A mixture of 158 mg of 2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 157 mg of 2-chloro-1-methylpyridinium iodide, 172 μl of triethylamine and 4 ml of dried tetrahydrofuran was refluxed with heating for 3 hours. The mixture was cooled to room temperature and to the resultant mixture were added 34 mg of cyanamide and 25 mg sodium hydride (60%) and the mixture was refluxed with heating for 4 hours. Ice water was added to the reaction product and it was extracted with ethyl acetate. An organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 20 mg of N-cyano-2-methoxymethyl-N',2-dimethyl-6-nitro-2H-1-benzopyran-4-amidine with a melting point of 121°-125° C. by recrystallization from ethyl acetate.
Reaction SMILES: CN(C)CC[N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=2[CH2:9][C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@H:7]([CH2:28][CH:29]=[CH2:30])[C:6]1=[O:31]>C(OCC)(=O)C.[Pd]>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]2[CH2:9][C:10]3[C:15]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:13]=[CH:12][C:11]=3[NH:5][C:6](=[O:31])[CH:7]2[CH2:28][CH2:29][CH3:30])=[CH:21][CH:22]=1
Reactant: C=CC[C@@H]1C(=O)N(CCN(C)C)c2cccc(C(F)(F)F)c2C[C@@H]1c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC1C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccc(OC)cc1
Reaction time: 4 h
Yield: 100.8 %

Procedure:
(cis)-1-[2-(Dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-(2-propenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one (4.25 g; 11.3 mmole) was dissolved in ethyl acetate (65 ml). Palladium on charcoal (0.86 g) was added to the degassed solution, and the mixture was placed on a Parr apparatus for four hours. The material was filtered through a pad of Celite and concentrated giving 4.3 g of crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15]>CCO.O.[Fe]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][CH2:4][C:3](=[O:15])[N:2]([CH3:1])[C:7]=2[CH:8]=1
Reactant: CN1C(=O)COc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CN1C(=O)COc2ccc(N)cc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
Fe powder (4.1 g, 73.20 mmol) was added to a solution of 4-methyl-6-nitro-4H-benzo[1,4]oxazin-3-one (3.0 g, 14.42 mmol) in EtOH (100 ml) and water (50 ml). The mixture was stirred at 60° C. vigorously with a mechanic stirrer for 18 hours, then filtered through a celite cake. The filtrate was concentrated under reduced pressure to give 2.50 g of 6-amino-4-methyl-4H-benzo[1,4]oxazin-3-one as a solid, 98%.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][S:5][C:4](=[C:7]([N:21]2[CH:24](SC)[CH2:23][C:22]2=[O:27])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[S:3]1.[Br:28]Br>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[Br:28][CH:24]1[N:21]([C:7](=[C:4]2[S:3][CH:2]([OH:1])[CH2:6][S:5]2)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[C:22](=[O:27])[CH2:23]1
Reactant: CSC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C1SCC(O)S1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(=C1SCC(O)S1)N1C(=O)CC1Br
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
p-Nitrobenzyl 2-(4-hydroxy-1,3-dithiolan-2-ylidene)-2-(4-methylthio-2-azetidinon-1-yl)acetate (121 mg) was dissolved in tetrahydrofuran (1 ml). A solution of bromine (45.2 mg) in carbon tetrachloride was added dropwise to the resulting solution, with ice cooling. The mixture was stirred at that temperature for 10 minutes and then the solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (eluent: a 1:1 by volume mixture of benzene and ethyl acetate), to give 130 mg of the desired product.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[N:15][CH:16]=2)([C:8]([OH:10])=O)[CH2:4][CH2:3]1.Cl.[CH3:20][NH:21][O:22][CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:18][C:2]1([F:1])[CH2:3][CH2:4][C:5]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[N:15][CH:16]=2)([C:8]([N:21]([O:22][CH3:23])[CH3:20])=[O:10])[CH2:6][CH2:7]1
Reactant: Cc1ncc(C2(C(=O)O)CCC(F)(F)CC2)cn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Yield: 27.1 %

Procedure:
A solution of 4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid (1.2 g, 4.68 mmol), N,O-dimethylhydroxylamine hydrochloride (456 mg, 4.68 mmol), HOBt (759.33 mg, 5.62 mmol), EDCI.HCl (1.08 g, 5.62 mmol) and DIPEA (3.23 mL, 18.73 mmol) in DMF (20 mL) was stirred at room temperature. The reaction mixture was added water and extracted with EtOAc (3×50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 4,4-difluoro-N-methoxy-N-methyl-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxamide (380 mg), which was used for the next step directly. About 0.9 g of 4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid was recycled.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH3:9])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.CCCCC.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>[Br:15][C:16]1[C:17]([C:12]2[S:11][C:10]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])=[N:14][CH:13]=2)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(c1ccc(F)cc1)c1nccs1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(F)cc1)c1ncc(-c2nc(Cl)ncc2Br)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 2-(1-(4-fluorophenyl)ethyl)thiazole (200 mg, 0.966 mmol) in 5 mL of tetrahydrofuran was cooled to −78° C. and treated with tert-butyllithitim (0.622 mL, 1.7 M solution in pentane, 1.06 mmol) added dropwise. 5-Bromo-2-chloropyrimidine (205.5 mg, 1.06 mmol) was added to the reaction mixture and stirred for another 30 min before quenching with 1 mL of acetic acid in 5 mL of methanol. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (468 mg, 2.06 mmol) was added to the reaction after cooling to 0° C., stirred for 20 min, diluted with sodium ascorbate (0.5M, 100 mL) and water (300 mL). The crude product was extracted from the aqueous layer with chloroform (3×75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography with 0-40% ethyl acetate in hexane to afford the title compound as a yellow amorphous solid (177 mg). MS (M+H)+ 398/400.
Reaction SMILES: [ClH:1].[CH:2]1([C:5]#[N:6])[CH2:4][CH2:3]1.[CH2:7]([O:9]CC)[CH3:8]>CCO>[ClH:1].[CH2:7]([O:9][C:5]([CH:2]1[CH2:4][CH2:3]1)=[NH:6])[CH3:8]
Reactant: N#CC1CC1
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)C1CC1
Temperature: 0 °C
Yield: 59 %

Procedure:
A steady stream of HCl gas was slowly passed through a solution of cyclopropancarbonitril (25 g, 373 mmol) in EtOH (17.2 ml). After 15 h the reaction mixture was cooled to 0° C. and diethylether was added dropwise. The precipitated title compound was filtered and obtained as a colourless crystalline material (32.9 g, 220 mmol, 59%). MS: m/e=112.2 (M−H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:15]2[C:14]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:13]1)C1C=CC=CC=1>C1C=CC=CC=1.O>[C:29]1([NH:28][C:14]2[C:15]3[C:16](=[N:17][CH:18]=[N:19][C:20]=3[NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:12][N:13]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(Cn2nc(Nc3ccccc3)c3c(Nc4ccccc4)ncnc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(Nc2ncnc3[nH]nc(Nc4ccccc4)c23)cc1
Temperature: 50 °C
Reaction time: 1.75 h

Procedure:
With the exclusion of air and moisture, there is added to a suspension of 203 mg of AlCl3 in 2.5 ml of absolute benzene a solution of 100 mg of 1-benzyl-3,4-diphenylamino-pyrazolo[3,4-d]pyrimidine in 2.5 ml of absolute benzene. The reaction mixture is stirred for 1.5-2 hours at 50° C. until, according to thin-layer chromatography, no starting material remains and is then stirred in approx. 30 ml of water. The precipitate is filtered off and dissolved in ethyl acetate. The ethyl acetate phase is washed several times with 5% aqueous sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried and concentrated to dryness by evaporation. The residue is crystallized from ethyl acetate/hexane, yielding 3,4-diphenylamino-1H-pyrazolo[3,4-d]pyrimidine in the form of colorless crystals, m.p. 263-264° C., FAB-MS: (M+H)+ =303 (C17H14N6).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1)#[N:2]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1F
Agent: [Ni]
Agent: N
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CN)cc1F
Yield: 100.2 %

Procedure:
A mixture of Example 10B (3.40 g, 16.0 mmol) and nickel powder (6.72 g, 114 mmol) in 7M NH3-MeOH (40 mL) in a 250 mL stainless steel pressure bottle at room temperature was stirred at 30 psi for 6 hours. The mixture was filtered through a nylon membrane (MeOH and THF wash) and the filtrate concentrated to afford the title compound (3.5 g), which was used without further purification. 1H NMR (300 MHz, CD3OD) δ 7.43 (t, J=8.2 Hz, 1H), 7.19 (dd, J=11.5, 1.3 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 3.81 (s, 2H), 2.96 (s, 3H); MS (ESI) m/z 219 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH2:27][CH3:28])=[O:8])=[CH:5][CH:4]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>O1CCCC1.O>[C:31]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:12][C:11]=2[CH2:27][CH3:28])=[O:8])=[CH:29][CH:30]=1)(=[O:33])[CH3:32]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
The crude product of 4-(aminomethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro-propan-2-yl)-6-methylphenyl]benzamide (0.30 g) was dissolved in tetrahydrofuran (5 ml). To the solution, acetic anhydride (0.07 g) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain 4-(acetamidomethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methyl-phenyl]benzamide (0.27 g, yield 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccncc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 117.5 %

Procedure:
A mixture of 4-fluorobenzeneboronic acid (38.7 g, 276 mmol), 4-bromopyridine hydrochloride (48.9 g, 250 mmol), [1,4-butanediylbis(diphenylphosphine-κP)]dichloropalladium (Organometallics 1998, 17, 661; 1.52 g, 2.5 mmol), 1,2-dimethoxyethane (500 mL) and sodium carbonate solution (2M, 440 mL) was degassed with bubbling nitrogen and stirred at 80° C. for 24 hours. The mixture was cooled and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the crude title compound as a brown solid (50.87 g) which was used without further purification. 1H NMR (360 MHz, CDCl3) δ 8.65 (2H, m), 7.61 (2H, m), 7.49 (2H, dd, J 1.6, 4.6 Hz), and 7.09 (2H, m).