Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:24]([O:26][CH2:27][CH3:28])C.C(O[K])(C)(C)C.[Br:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][C:47]=2C=O)=[CH:38][CH:37]=1>C1COCC1.O>[Br:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([C:46]2[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][C:51]=2[CH:28]=[CH:27][O:26][CH3:24])=[CH:38][CH:37]=1
Reactant: CCOCC
Reactant: O=Cc1cc(Cl)ccc1-c1ccc(Br)c2ccccc12
Agent: CC(C)(C)O[K]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1cc(Cl)ccc1-c1ccc(Br)c2ccccc12
Yield: 99 %

Procedure:
Subsequently, 9.67 g (28.2 mmol) of (methoxymethyl)triphenylphosphonium chloride and 48 mL of dry diethyl ether were charged into a 300-mL recovery flask filled with nitrogen at room temperature. The mixture was stirred. Then 28.2 mL (28.2 mmol) of 1 M tert-butoxypotassium solution in THF was added thereto. The resulting mixture was stirred for 1 hour. Subsequently, a solution of 3.90 g (11.3 mmol) of 1-bromo-4-(4-chloro-2-formylphenyl)naphthalene dissolved in 93 mL of a THF solvent was added to the reaction mixture. After the resulting mixture was stirred for another 4 hours at room temperature, water was added thereto, terminating the reaction. The separation of two phases was performed to recover the aqueous phase. Extraction of the aqueous phase was performed three times with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated to give a crude product. The crude product was then purified by silica gel column chromatography (eluent: heptane/chloroform=20/1) to give 4.17 g (yield: 99%) of 1-bromo-4-(4-chloro-2-methoxyethenylphenyl)naphthalene.
Reaction SMILES: [C:1]([C:9]1([OH:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH:21]1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:21][O:16][C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:18])=[O:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C1CCCCC1(O)C(=O)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCCCC1(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
9.93 g (0.04 mol) of 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid prepared according to the method of example 1 and 1.4 g of methanol (0.044 mol) are dissolved in 200 ml of dichloromethane. 9.91 g (0.044 mol) dicyclohexylcarbodiimide are added to the solution and the resulting suspension is stirred for 3 hours at room temperature. After this time, no more carboxylic acid is detected by TLC analysis. The reaction mixture is filtered and the solid dicyclohexylurethane is washed with dichloromethane. The organic solution is washed with sodium bicarbonate and water, dried over MgSO2 and evaporated in vacuum. The residual crude product is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1) to give 7.03 g (71%) 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid methyl ester as a viscous resin.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:23]1([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)[CH2:26][CH2:25][CH2:24]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccccc2N2CCN(C3CCC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (20 mg, 0.067 mmol) produced in Example (8b) in tetrahydrofuran (1 mL) were added cyclobutanone (7.0 mg, 0.1 mmol), sodium triacetoxyborohydride (28 mg, 0.13 mmol) and acetic acid (4 mg, 0.067 mmol) in that order, followed by stirring for 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-cyclobutyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine. The obtained compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate (0.025 mL, 0.100 mmol) was added. The solution was concentrated, and hexane was added to the obtained residue to produce a solid. The solid was triturated by sonication and the supernatant hexane solution was removed. The solid residue was dried under reduced pressure to give 17.6 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a suspension of the 254 (26.8 mg, 0.84 mmol) in THF (1.6 ml) was added 2-phenylacetyl isothiocyanate (23 mg, 0.13 mmol). The mixture was stirred for 1 hr transferred onto a chromatography column and eluted sequentially with EtOAc/MeOH (9:1) and EtOAc/hexane (1:1), to afford title compound 255a (30 mg, 72% yield) as a white solid. 1HNMR: (DMSO-d6) δ (ppm): 12.65 (s, 1H), 12.43 (s, 1H), 11.79 (s, 1H), 8.31 (s, 1H), 8.06 (d, J=7.6 Hz, 2H), 7.91 (m, 1H), 7.52 (m, 4H), 7.43 (m, 1H), 7.34, (m, 4H), 7.27 (m, 1H), 7.18 (m, 1H), 3.83 (s, 2H). MS (m/z): 498.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:51][CH2:52][CH2:53][NH2:54]>C(Cl)Cl>[CH3:24][N:2]([CH3:1])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([NH:54][CH2:53][CH2:52][F:51])=[O:21])=[CH:11]2)[C:4]=1[CH3:23]
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3ncnc(N(C)C)c3C)c2c1
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc2c(C(=O)NCCF)cn(Cc3ncnc(N(C)C)c3C)c2c1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
See FIG. 23(d). 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.23 mmol) was taken in a thermal reactor. DCM (5 mL) was added to get a suspension. Triethyl amine (0.064 mL, 0.46 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.274 mL, 0.46 mmol). 2-fluoroethanamine hydrochloride (22.94 mg, 0.23 mmol) was added and stirred at RT for ON. After the completion of the reaction, reaction mixture was concentrated and dissolved in DCM:MeOH. This crude compound was subjected for reverse phase purification. The final compound obtained 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (12.00 mg, 14.05%) as a white solid. ES+MS m/z: 371 (M+). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H ) 2.40 (s, 3 H ) 2.95 (s, 6 H ) 3.66 (d, J=5.46 Hz, 1 H ) 3.75 (d, J=5.27 Hz, 1 H ) 4.49 (t, J=4.99 Hz, 1 H ) 4.65 (t, J=4.99 Hz, 1 H ) 5.54 (s, 2 H ) 7.75 (s, 1 H ) 8.13 (s, 1 H ) 8.22 (s, 1 H ) 8.34 (s, 1 H ) 8.88 (t, J=5.84 Hz, 1 H).
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:32])([F:31])[F:30])[CH2:23][NH2:24]>>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:30])([F:31])[F:32])[CH2:23][NH:24][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:8])=[O:9])=[CH:18][CH:17]=1
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)c1ccc(S(=O)(=O)Nc2ncns2)cc1

Procedure:
The title compound was prepared from 4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]benzoic acid (Preparation 29) and 3-fluoro-4-(trifluoromethoxy)benzylamine following the procedure described in Example 309. The reaction mixture was extracted from saturated sodium hydrogen carbonate into DCM and the crude product purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:5](/[N:7]=[C:8](/[N:10](C)C)\[CH3:9])=[O:6].NO.[OH-].[Na+]>O1CCOCC1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:10]=[C:8]([CH3:9])[N:7]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: C/C(=N\C(=O)c1ccc(C)c(Br)c1)N(C)C
Agent: NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1noc(-c2ccc(C)c(Br)c2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
A solution of (E)-3-bromo-N-(1-(dimethylamino)ethylidene)-4-methylbenzamide (preparation 57b, 0.20 g, 0.71 mmol) in dioxane (1.20 mL) was added dropwise to a stirred solution of hydroxylamine (0.06 g, 0.85 mmol) and sodium hydroxide (0.03 g, 0.85 mmol) in acetic acid (2.50 mL) and the mixture was stirred at 100° C. After 0.5 hours, the mixture was concentrated in vacuo, 4% aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic solution was dried (MgSO4) and the solvent removed in vacuo to give the title compound (0.10 g, 56%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([CH2:7]Cl)[N:3]=1.[NH2:9][CH2:10][CH2:11][SH:12]>>[NH2:9][CH2:10][CH2:11][S:12][CH2:7][C:4]1[N:3]=[C:2]([Cl:1])[S:6][N:5]=1
Reactant: NCCS
Reactant: ClCc1nsc(Cl)n1
Product: NCCSCc1nsc(Cl)n1

Procedure:
Reacting 5-chloro-3-chloromethyl-1,2,4-thiadiazole with cysteamine by the procedure of Example 1(i)(c) gives 3-[ (2-aminoethyl)thiomethyl]-5-chloro-1,2,4-thiadiazole.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH2:16]Br)[C:7]1=2)C.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(Cl)Cl>[CH2:20]([N:22]([CH2:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:3])=[O:19])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([OH:18])[CH:14]=1)[CH2:23][CH3:24])[CH3:21]
Reactant: CCNCC
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(CBr)c21
Solvent: ClCCl
Product: CCN(CC)Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (4-Bromomethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.5 mmol) in DCM (5 mL) was added diethylamine (5 mmol) and the mixture was stirred overnight at r.t. The crude product was evaporated, LiOH (75 mg) in THF/water/methanol (2:1:1, 5 mL) was added and stirred at r.t. for 1 h. The solvent was evaporated to give a residue, which was purified by HPLC, yielded 5 mg of desire product. MS (ESI) m/z: 294 [M+1]+; 1H NMR (300 MHz, CD3OD) δ 7.18 (s, 2H), 5.72-5.76 (dd, 1H), 4.20-4.45 (dd, 2H), 3.05-3.22 (m, 3H), 2.36-2.44 (dd, 1H), 1.40-1.45 (t, 3H), 1.30-1.34 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[S:14]1[C:18]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O)=[CH:17][C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]1=2>>[S:14]1[C:18]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4]2[C:3](=[O:7])[C:2]([CH3:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[OH:6])=[CH:17][C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]1=2
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: OC(c1ccccc1)c1cc2ccccc2s1
Product: CC1(c2ccccc2)C(=O)C(C(c2ccccc2)c2cc3ccccc3s2)=C1O

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with benzo[b]thiophen-2-yl-phenyl-methanol to give the title compound as a colorless solid. MS: 395.3 ([M−H]−).
Reaction SMILES: S(=O)(=O)(O)O.CO[CH:8](OC)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:10].N>>[CH3:19][C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][CH:17]=1)[CH:12]=[N:11][C:9]([OH:10])=[CH:8]2
Reactant: COC(OC)C(=O)NCc1ccc(C)cc1
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1ccc2cnc(O)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (18 M; 11.0 mL) was added to 2,2-dimethoxy-N-(4-methylbenzyl)-acetamide (1.95 g, 8.73 mmol) at ambient temperature, and the solution was stirred overnight at ambient temperature. The reaction mixture was added to ≈100 mL of ice, and the pH of the mixture was adjusted to ≈5 with concentrated aq. NH3 solution. The yellow precipitate was filtered off, washed with water, and dried in vacuo overnight to give the title compound as yellow solid. It was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ=8.79 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.14 (dd, J=1.6, 8.4 Hz, 1H), 6.76 (s, 1H), 2.42 (s, 3H); —OH not apparent. MS(ES+): m/z=160.25 (100) [MH+], 142.13 (12) [MH+—H2O]. HPLC: tR=2.15 min (polar—5 min, ZQ2), 2.25 min (polar—5 min, ZQ3).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][C:12]([CH3:14])=[C:11]([CH2:15][CH:16]=[CH2:17])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:15]([C:11]1[CH2:10][CH:9]([OH:8])[CH2:13][C:12]=1[CH3:14])[CH:16]=[CH2:17]
Reactant: C=CCC1=C(C)CC(O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCC1=C(C)CC(O)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
To a solution of 2 g of (RS)-3-allyl-4-methyl-3-cyclopenten-1-yl (t-butyldimethylsilyl) ether in 20 g of tetrahydrofuran was added under ice-cooling 16 ml of 1 M tetrahydrofuran solution of tetrabutylammonium fluoride, and the resulting mixture was stirred at room temperature for 6 hours. Then the reaction liquid was poured into ice water and extracted with diethyl ether. The ether layer was washed with saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The oily substance thus obtained was subjected to silica gel column chromatography to obtain 0.58 g of (RS)-3-allyl-4-methyl-3-cyclopenten-1-ol. Yield 53%
Reaction SMILES: [N:1]1([C:10]2([CH2:15][C:16]#[N:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH2:18][OH:19].C(OCC)(=O)C>C(O)C.CCCCCC>[OH:19][NH:18][C:16](=[NH:17])[CH2:15][C:10]1([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: N#CCC1(n2ccc3cccnc32)CCCC1
Reactant: NO
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: N=C(CC1(n2ccc3cccnc32)CCCC1)NO
Yield: 112.2 %

Procedure:
To a stirred solution of (1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetonitrile (399) (1.4 g, 6.21 mmol) in ethanol (50 mL) was added 50% aq. NH2OH (4 mL, 62.15 mmol) and the reaction mixture was heated at 60° C. for 16 h (TLC, 30% ethyl acetate in hexane, Rf=0.1). Ethanol was evaporated, water (50 mL) was added and the mixture was extracted with etylacetate (3×50 mL). The organic phase was thereafter dried and concentrated to get crude N-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetamidine (400) (1.8 g, 112%) as an off-white sticky liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[C:3]=1N.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Na+]>C1COCC1>[Br:9][C:4]1[CH:5]=[C:6]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Nc1c(Br)cc(Br)cc1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
10 g (0.023 mol) of 2,4,6-tribromophenylamine are dissolved in 100 ml of THF. In a second apparatus, 228 ml of phenylmagnesium bromide is heated under reflux. The dissolved 2,4,6-tribromophenylamine is added dropwise to the phenylmagnesium bromide solution, stirred under reflux for 1 h and at room temperature for a further 12 h. After addition of saturated sodium chloride solution, the aqueous phase is washed with diethyl ether and dried over sodium sulfate. After removal of the solvent, the product is recrystallised in hexane/dichloromethane. 4.8 g (77%) of clean substance are isolated.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[ClH:1].[NH2:2][CH:3]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: NC(CC(F)(F)F)C(=O)O
Agent: Cl
Product: COC(=O)C(N)CC(F)(F)F

Procedure:
1.186 g (6.127 mmol) of 2-amino-4,4,4-trifluorobutanoic acid hydrochloride (1:1) were initially charged in 11.6 ml of methanol which had been saturated with hydrogen chloride, and the mixture was stirred under reflux for 4 h. The reaction solution was concentrated and dried under high vacuum. This gave 1.275 g of the target compound (100% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:8]=2)=[C:4]([F:23])[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:27][CH:26]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C1COCC1>[F:23][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)c2)c(F)c1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A solution 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyridin-2-amine (11 mg, 0.035 mmol) in THF (1 mL) was cooled in an ice bath and treated with a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 250 μL, 0.070 mmol) and stirred at RT for 2 h. The mixture was concentrated in vacuo and the residue triturated with isopropyl ether to give the title compound (11 mg, 65%) as a white solid. 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.56 (s, 1H), 9.01 (s, 1H), 8.03 (d, 1H, J=5.6 Hz), 7.77 (dd, 1H, J=13.3, 2.0 Hz), 7.63-7.60 (m, 2H), 7.41-7.31 (m, 5H), 7.19-7.14 (m, 2H), 7.05 (dd, 1H, J=9.1, 8.5 Hz), 6.43 (dd, 1H, J=6.2, 2.1 Hz), 6.10 (d, 1H, J=2.1 Hz), 3.74 (s, 2H); MS(ESI+) m/z 493.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:13]([Li])[CH2:14][CH2:15]C.C(Br)C=C>O1CCCC1>[CH3:1][CH:2]([C:8](=[O:10])[CH2:9][CH2:15][CH:14]=[CH2:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: [Li]CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCCC(=O)C(C)C(=O)OCC
Yield: 58.9 %

Procedure:
Ethyl 2-methyl-3-oxobutanoate (10 mL, 70.7 mmol) was added dropwise to an anhydrous tetrahydrofuran suspension of sodium hydride (2.83 g, 74.2 mmol) with stirring under ice cooling. The mixture was stirred for 15 minutes in this bath. Then, n-butyllithium (1.59 M hexane solution, 45.3 mL, 72.1 mmol) was added dropwise thereto, and the mixture was further stirred for 30 minutes. Then, allyl bromide (6.73 mL, 77.7 mmol) was added dropwise thereto. After removal of the ice bath, the mixture was stirred for 2 hours, and the reaction was then terminated by pouring dilute hydrochloric acid to the reaction solution. The reaction solution was subjected to extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated saline and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil (7.67 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.C(OCC)(=O)C.O>Cl.CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(-n2cccc2)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 72.2 %

Procedure:
To a solution of methyl 3-nitro-5-(pyrrol-1-yl)benzoate (35.8 g) in concentrated hydrochloric acid (79 ml) and methanol (73 ml) was added portionwise iron (48.6 g). After stirring for 3.5 hours at room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water and filtered. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was pulverized from petroleum ether and diisopropyl ether to give methyl 3-amino-5-(pyrrol-1-yl)benzoate (22.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[NH2:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH:36][CH3:37])=[O:35])[CH:29]=2)=[CH:25][CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[NH:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH:36][CH3:37])=[O:35])[CH:29]=3)=[CH:25][CH:24]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccccc1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 42.5 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
Phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (100 g, 0.3174 mol) and 4-(4-aminophenoxy)-N-methylpicolinamide (77.14 g, 0.3174 mol) were dissolved in N,N-dimethyl formamide (300 ml) to obtain a clear reaction mass. The reaction mass was agitated at 40-45° C. for 2-3 hours, cooled to room temperature and diluted with ethyl acetate (1000 ml). The organic layer was washed with water (250 ml) followed by 1N HCl (250 ml) and finally with brine (250 ml). The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. This solid was stripped with ethyl acetate and finally slurried in ethyl acetate (1000 ml) at room temperature. It was then filtered and vacuum dried to give (118 g) of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][C:17](O)=[O:18])(=[O:13])=[O:12].[NH2:26][CH:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36]#[N:37])=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[C:36]([C:32]1[CH:31]=[C:30]2[C:35](=[CH:34][CH:33]=1)[CH:27]([NH:26][C:17](=[O:18])[CH2:16][CH:15]([NH:14][S:11]([C:2]1[CH:3]=[CH:4][C:9]3[C:10](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:1]=1)(=[O:13])=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:28][CH2:29]2)#[N:37]
Reactant: N#Cc1ccc2c(c1)CCC2N
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: N#Cc1ccc2c(c1)CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid [Example 1, Step F] and 1-amino-indan-5-carbonitrile (Step E), using essentially the same procedure described in Example 1, Step F, yielding a white solid. MS (ESI) m/z 496 (M+H)+.