Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]1.O>CN(C=O)C>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: N#CCCN1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1C(=O)C(NC2CCN(CCC#N)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 88.7 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.700 mmol), TEA (0.283 g, 2.800 mmol) and 3-(4-aminopiperidin-1-yl)propanenitrile (0.161 g, 1.050 mmol) in DMF (3 mL) was heated in a microwave reactor at 120° C. for 10 mins. Water was added and the mixture was extracted with EtOAc. The organic phase was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using a mixture of heptane and EtOAc (20:80) to 100% EtOAc, then a mixture of MeOH and EtOAc (1:99) as eluant, to give the title compound (0.25 g, 89%); 1H NMR (500 MHz, CDCl3): δ 7.54-7.51 (m, 2H), 7.49-7.44 (m, 3H), 5.20 (br d 1H), 4.46-4.38 (m, 1H), 3.01-2.91 (br m, 1H), 2.70-2.65 (br m, 2H), 2.55 (t, 2H), 2.41 (t 2H), 1.74-1.63 (m 4H), 1.60 (d 6H) 1.44-1.35 (m 2H); 13C NMR (125 MHz, CDCl3): δ 158.7, 134.5, 131.8, 130.1, 128.9, 125.3, 118.8, 106.8, 53.3, 51.5, 50.0, 47.8, 32.4, 20.4, 16.4: Mass Spectrum: M−H+ 403.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6])(=[O:16])[CH3:15]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C(=O)O)ccc1[N+](=O)[O-]

Procedure:
The 3-hydroxy-4-nitrobenzoic acid starting material is acetylated using, for instance, acetic anhydride and pyridine at reflux temperatures for 1-4 hours to afford 3-acetoxy-4-nitrobenzoic acid. This compound is then dissolved in a non-polar, aprotic solvent, such as benzene or toluene, and refluxed with thionyl chloride for a period of about 2-6 hours to form the desired 3-acetoxy-4-nitrobenzoyl chloride.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[SH:14].C(N(CC)CC)C>O1CCCC1>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14][CH:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: Sc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CC(Sc1cccs1)C(=O)O
Yield: 93 %

Procedure:
To a stirred solution of maleic acid (6.38 g, 0.055 mol) in tetrahydrofuran (50 ml) under nitrogen atmosphere was added 2-thiophenethiol (5.0 ml, 0.055 mol) and triethylamine (14.2 g, 0.14 mol). The mixture was stirred at gentle reflux for 16 hours overnight. The solvent was removed in vacuo and the residual oil was poured into 3NHCl (200 ml). The product was extracted into ethyl acetate (125 ml) in three portions, washed with saturated NaCl solution and dried over Na2SO4. The solution was filtered and concentrated in vacuo. This procedure gave the product as a light beige solid, 11.9 g, m.p. 136°-138.5° C. of 95% purity by HPLC. Yield was 93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:53]([C:57]1[CH:58]=[C:59]([NH2:64])[C:60]([NH2:63])=[CH:61][CH:62]=1)([CH3:56])([CH3:55])[CH3:54].CN(C)C=O>>[NH2:64][C:59]1[CH:58]=[C:57]([C:53]([CH3:55])([CH3:54])[CH3:56])[CH:62]=[CH:61][C:60]=1[NH:63][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH3:37])[CH2:31]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl}uronium Hexafluorophosphate (0.44 g, 1.2 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (460 mg, 0.77 mmol) and N,N-Diisopropylethylamine (0.44 mL, 2.6 mmol) and 4-tert-butylbenzene-1,2-diamine (0.15 g, 0.93 mmol) in N,N-Dimethylformamide (5 mL, 60 mmol). The reaction was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4 and concentrated. Purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to yield a solid (0.24 g).
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CCCCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid pentylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (94% yield). m.p. 123-125° C. 1H NMR (300 MHz, CDCl3) δ 8.03, 7.85, 7.62, 7.54, 7.35, 6.97, 4.06-3.99, 3.91-3.69, 3.44, 3.33, 1.62-1.55, 1.37-1.33, 0.95-0.81. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.5, 132.4, 129.5, 127.2, 127.1, 126.9-127.8, 112.5, 77.2, 46.4, 44.6, 44.4, 41.3, 39.4, 29.3, 29.1, 22.4, 14.0. MS (ES+) m/z 450.2 (M+1), 472.2 (M+Na).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[CH3:12][N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][C:17]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:16][CH:15]=1
Reactant: CN(C)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Temperature: 75 °C

Procedure:
A mixture of phthalic anhydride (30 g.), N,N-dimethylaniline (60.5 g.), aluminum chloride (60 g.) and chlorobenzene (180 g.) was heated (to 75° C.) during one hour, then cooled. Ice (500 ml.) was added, the chlorobenzene layer was separated and the chlorobenzene was steam distilled. Addition of base to a solution of the residue in dilute sulfuric acid afforded 2-(4-(dimethylamino)benzoyl)benzoic acid (IV: Y2 = Z4 = Z"5 = Z"6 = Z7 = H, Y'4 = (CH3)2N).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].N([O-])=O.[Na+].[BrH:19]>O>[Br:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14]
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)ccc(C#N)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (3e) (0.8 g, 4.0 mmol) in water (2 mL), cooled to 0° C., 48% aqueous HBr (10 mL, 18.5 mmol) was added followed by NaNO2 (0.33 g, 4.8 mmol) taken in water (2 mL) and stirred for 10 min. To the reaction mixture a solution of CuBr (2.7 g, 18.8 mmol) in HBr (10 mL) was added at 0° C. and slowly warmed to room temperature and then heated to 50° C. for 1 h. The reaction mixture was brought to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (2×20 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to provide the bromo 3f (0.6 g, 60%) as a tan colored solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:30]5[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Reactant: OB(O)c1ccc(Br)cc1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4ccc(Br)cc4)cc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 416, starting from 2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine and 4-bromophenylboronic acid. Mass spectrum (ESI) 472.1 (M+1)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]3[N:10]([C:12]([C:15]4([C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[N:24]=[CH:23][CH:22]=[CH:21]6)[CH2:17][CH2:16]4)=[CH:13][N:14]=3)[CH:11]=2)[CH:3]=[N:2]1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:28][N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]3[N:10]([C:12]([C:15]4([C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[N:24]=[CH:23][CH:22]=[CH:21]6)[CH2:17][CH2:16]4)=[CH:13][N:14]=3)[CH:11]=2)[CH:3]=[N:2]1
Reactant: c1cnc2ccc(C3(c4cnc5ncc(-c6cn[nH]c6)cn45)CC3)cc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-{1-[6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline (6 mg, 0.017 mmol) in N,N-dimethylformamide (200 μL) was added potassium carbonate (4.0 mg, 0.029 mmol) and methyl iodide (3 μL, 0.048 mmol). After stirring at RT for 16 h, the reaction mixture was purified by RP-HPLC to afford the desired product. LCMS: (M+H)=367.0.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][Si](C(C)(C)C)(C)C)[C:14]([Br:20])=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOC(C)=O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:21])[C:14]([Br:20])=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(-c3nnc4ccccn34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1c(Br)ccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
To the product from Step E (2.8 g, 6.15 mmol) was added THF (60 mL). The solution was cooled to 0° C. then TBAF.3H2O (2.33 g, 7.38 mmol) was added and the mixture was stirred for 1 hour. The mixture was then diluted with EtOAc (100 mL) and then washed with saturated aqueous NaHCO3 (75 mL). The layers were separated and the aqueous phase washed with EtOAc (100 mL). The combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated. The crude mixture was triturated with MeOH and filtered. The solid was washed with Et2O to provide 0.730 g (35%) of product.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].[CH2:25]([O:27][C:28](=[O:41])[CH2:29][CH:30]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[C:31]#[C:32][CH3:33])[CH3:26].Cl>CN(C=O)C.O>[CH2:25]([O:27][C:28](=[O:41])[CH2:29][CH:30]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:38][CH:39]=1)[C:31]#[C:32][CH3:33])[CH3:26]
Reactant: CC#CC(CC(=O)OCC)c1ccc(O)cc1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(CC(=O)OCC)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Cesium carbonate (0.51 g, 1.57 mmol) was added to a solution of 18.2 (216 mg, 0.79 mmol) and phenol 16 (220 mg, 0.79 mmol) in DMF (8 mL). The reaction was stirred at room temperature overnight and then taken up in water (500 mL). The solution was adjusted to pH=4.0 with 1N HCl(aq) and extracted with ethyl acetate (2×25 mL). The combined organics were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (20% diethyl ether in hexanes) to yield 304 mg (82%) of 3-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester. LC/MSD m/e: 472.0 (M+H); 1H NMR (400 MHz) (CDCl3) δ 8.16 (2H, d, J=8.0 Hz), 7.73 (2H, d, J=8.0 Hz), 7.33 (2H, m), 6.99 (2H, m), 5.01 (2H, s), 4.14 (3H, m), 2.72 (2H, m), 2.48 (3H, s), 1.85 (3H, s), 1.26 (3H, t, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](N)=[C:16]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15]([S:25][CH3:26])=[N:14]1.N(OCCC(C)C)=O>CN(C=O)C.C(OCC)C>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[CH:17]=[C:16]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15]([S:25][CH3:26])=[N:14]1
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cnccn1
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of aminopyrazole 41 (42 mg, 0.1 mmol) in DMF (5 mL) was warmed up to 65° C. and treated dropwise with excess isoamyl nitrite (150 mL). Stirring was continued for 30 min. The reaction was cooled down to room temperature, diluted with ethyl ether (10 mL) and washed with brine (5×15 mL). The organic layer was dried (magnesium sulfate) and the solvents removed at reduced pressure, leaving a dark oil residue. The desired product was obtained upon flash chromatography eluting with ethyl acetate-hexanes (5-10%), to yield 14 mg (35%) of desired product. 1H-NMR (δ, CDCl3): 2.63 (3H, s); 7.78 (2H, s); 8.1 (1H, s); 8.28 (1H, d, J=2.5 Hz); 8.4 (1H, dd, J=1.4; 8.4 Hz); 9.2 (1H, d, J=1.5 Hz). MS: M+1=404 (calculated: 404).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: NC(=O)c1ccccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccccc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.24 g (1.5 mmol) of 2-fluorobenzamide and 0.19 g (1.6 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-fluorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.28 g (1.5 mmol) of 2,3-dichloro-4-cyano aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.41 g (Yield 73%) of the title compound as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[O-])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[Cl:31])[NH2:27]>C(#N)C>[Cl:31][C:30]1[CH:29]=[CH:28][C:26]([NH:27][C:19](=[O:21])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=3)=[CH:17][CH:16]=2)=[CH:25][C:24]=1[C:23]([F:22])([F:32])[F:33]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)[O-])cc2)ccn1
Solvent: CC#N
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A mixture of 4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylcarbamate (25 g, 0.06871 mol) and 3-trifluoromethyl-4-chloroaniline (13.4 g, 0.06871 mol) in acetonitrile (250 ml) was refluxed for 24 hours when product precipitated out of reaction mass. The reaction mass was cooled to room temperature and obtained product was filtered, washed with acetonitrile till a clear filtrate was obtained. It was then vacuum dried to obtain 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].C[Si]([N:15]=[N+:16]=[N-:17])(C)C>>[CH:5]1[CH:4]=[C:3]([N:8]2[NH:17][N:16]=[N:15][C:9]2=[O:10])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C=Nc1ccccc1Cl
Product: O=c1nn[nH]n1-c1ccccc1Cl
Yield: 73.6 %

Procedure:
A mixture of 2-chlorophenylisocyanate (7 g) and trimethylsilyl azide (7.9 g) was refluxed under heating for either hours and then the mixture was evaporated to remove excess trimethylsilyl azide under reduced pressure distillation, followed by addition of methanol to the resulting residue. Thereafter, the methanol was distilled off under reduced pressure. The resulting residue was purified by flash column chromatography (eluent: hexane:ethyl acetate = 2:1) to obtain the desired 1-(2-chlorophenyl)-5(4H)-tetrazolinone (6.6 g) having a m.p. in the range of from 124° to 125.5° C., in a yield of 73% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:13][C:14]1[CH:32]=[CH:31][C:17]([CH:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.C(O)=O.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:28]1[CH2:27][CH2:26][N:25]([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:32][CH:31]=2)[CH2:30][CH2:29]1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Fc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(CN2CCN(C(c3ccccc3)c3ccc(F)cc3)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
2,4-Dimethoxybenzaldehyde (6.65 g; 40.0 millimoles) and 10.8 g (39.9 millimoles) of 4-fluorobenzhydrylpiperazine (see German OLS 1929330) were melted in an oil bath at 120° C., and 2.3 ml (61.0 millimoles) of formic acid was added dropwise. The mixture was stirred for 1 hour under heat, and then allowed to cool to room temperature. Then, 50 ml of an ethanol solution containing 5.0 g (43.1 millimoles) of fumaric acid was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol gave 6.5 g (yield 30.4%) of 1-(2,4-dimethoxybenzyl)-4-(4-fluorobenzhydryl)piperazine fumarate as colorless crystals.
Reaction SMILES: BrC1C=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[C@@H:11]3[CH2:19][CH2:20][C:21](=O)[N:10]3[CH2:9]2)=[CH:4][CH:3]=1.C1([C@H:29]2[C:38]3[C:33](=CC=C(O)C=3)[C@@H:32]3[CH2:40][CH2:41][C:42](=O)[N:31]3[CH2:30]2)C=CC=CC=1>>[N:31]1([CH2:42][CH2:41][CH2:40][O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[C@@H:11]2[CH2:19][CH2:20][CH2:21][N:10]2[CH2:9][C@H:8]3[C:5]2[CH:4]=[CH:3][C:8]([C:9]#[N:10])=[CH:5][CH:6]=2)[CH2:30][CH2:29][CH2:38][CH2:33][CH2:32]1
Reactant: O=C1CC[C@H]2c3ccc(O)cc3[C@H](c3ccccc3)CN12
Reactant: O=C1CC[C@H]2c3ccc(O)cc3[C@H](c3ccc(Br)cc3)CN12
Product: N#Cc1ccc([C@@H]2CN3CCC[C@H]3c3ccc(OCCCN4CCCCC4)cc32)cc1

Procedure:
Cis-6-(4-Bromo-phenyl)-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Prepared as described in Example 42, Step 11, on a 1.89 mmol scale, to yield 654.3 mg of a mixture of the desired product and cis-6-phenyl-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one, the product of debromination under the reaction conditions. The crude product was taken on to the next step without purification or characterization.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:23][C:24]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:28]([F:40])=[CH:27][C:25]=1[NH2:26]>>[CH2:8]([NH:9][C:11](=[O:12])[NH:26][C:25]1[C:24]([F:23])=[CH:30][C:29]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[C:5]3[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:28]([F:40])[CH:27]=1)[CH3:6]
Reactant: CC1(C)OB(c2cc(F)c(N)cc2F)OC1(C)C
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCNC(=O)Nc1cc(F)c(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)cc1F
Yield: 13 %

Procedure:
Method as described for example 47 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The residue was purified by prep. HPLC at low pH, yielding the title compound (25 mg, 0.06 mmol, 13%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([F:12])[CH:6]=1)=[O:4].[N-:13]=[C:14]=[S:15].[K+]>C(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:15][C:14]#[N:13])=[CH:6][C:7]=1[F:12]
Reactant: [N-]=C=S
Reactant: O=C(CBr)c1ccc(Cl)c(F)c1
Agent: [K+]
Solvent: CCO
Product: N#CSCC(=O)c1ccc(Cl)c(F)c1
Yield: 100.5 %

Procedure:
In the same manner as described in step 4 of Example 78, using 2-bromo-1-(4-chloro-3-fluoro-phenyl)-ethanone (2.7 g, 10.7 mmol), prepared in the previous step, and potassium isothiocyanate (1.25 g, 12.8 mmol) in ethanol (150 mL) the crude product was collected by suction filtration to give 1-(4-chloro-3-fluoro-phenyl)-2-thiocyanato-ethanone (2.47 g, 100%), which was used in the next step without further purification. MS (ES) m/z 230[M+H+].
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 4-ethylaniline (2 g) and triethylamine (13.91 mL) in dichloromethane (40 mL) at 0° C. under nitrogen was treated dropwise with acetic anhydride (4.67 mL). The mixture was warmed to ambient temperature, then stirred for 16 hours at room temperature, then washed with (i) 10% citric acid (40 mL), (ii) water (40 mL) and (iii) brine (40 mL). The organic phase was dried over magnesium sulfate and then evaporated to give 4-ethyl-N-acetyl-aniline (2.36 g) as a pale orange solid which was used without further purification. LC-MS (METHOD B): RT=2.80 minutes; 164.2 (M+H)+. (b) 3-Methyl-4-isopropyl-N-acetyl aniline