Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-])=O.CO.[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)CC(=O)N2
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of 1.5 g (8.4 mmol) of 5-nitro-1,3-dihydro-indol-2-one, 150 mg of Pd/C 10%, and 50 ml MeOH in 100 ml of EtOAc was placed on Parr® hydrogenator and charged with 45 psi of Hydrogen gas. The mixture was shaken for 2 hrs. The mixture was filtered and the solvent was removed in vacuo to yield 5-amino 1,3-dihydro-indol-2-one (1.22 g, 98%): 1H NMR (DMSO-d6): δ3.27 (s, 2H), 4.6 (s, 2H), 6.34 (dd, J1=2 Hz, J2=8.1 Hz, 1H), 6.45 (m, 2H), 9.88 (s, 1 H). APCI-MS: m/z 147 (m−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH:12]1([NH:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N+:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O-:19])=[CH:6][CH:5]=1)[CH3:2]
Reactant: ONC1CCCCC1
Reactant: CCOc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOc1ccc(C=[N+]([O-])C2CCCCC2)cc1
Yield: 84.3 %

Procedure:
A solution of 4-ethoxybenzaldehyde (6.62 g, 44.1 mmol) in 200 mL of benzene was refluxed with N-cyclohexylhydroxylamine (6.61 g, 57.4 mmol) in the presence of p-toluenesulfonic acid (0.8 g, 4 mmol) for 72 h. After rotary evaporation, the residue was purified by recrystallization from hexanes and ethylene glycol dimethyl ether (100 mL, 3:1, v:v) to give the title compound (9.2 g, 84% yield) as a solid, m.p. 124.0° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][C:15]([CH2:18]O)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:53]>C(Cl)Cl.CCOC(C)=O>[Br:53][CH2:18][C:15]1[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:17][CH:16]=1
Reactant: BrC(Br)(Br)Br
Reactant: COCCCc1ccccc1-c1cc(C(F)(F)F)c(CO)cn1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCCc1ccccc1-c1cc(C(F)(F)F)c(CBr)cn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of [6-[2-(3-methoxypropyl)phenyl]-4-(trifluoromethyl)pyridin-3-yl]methanol (1 eq.) from step 2, in CH2Cl2 (0.1M) at 0° C. was added 1-2 bis(diphenylphosphine)ethane (1 eq.) the CBr4 (1 eq.). The mixture was stirred at 0° C. for 45 min, diluted with Hex/EtOAc 10%, filtered in celite and concentrated afforded the desired compound as an oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[O:6][C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[O:9][C:10]([F:20])([F:19])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.BrCCCCCBr.FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)CO.[CH2:62]([C:70]1[CH:71]=[N:72][C:73]([C:76]2[CH:81]=[CH:80][C:79]([OH:82])=[CH:78][CH:77]=2)=[N:74][CH:75]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]>>[CH2:62]([C:70]1[CH:75]=[N:74][C:73]([C:76]2[CH:81]=[CH:80][C:79]([O:82][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:10]([O:9][C:8]([F:21])([F:22])[C:7]([F:23])([F:24])[O:6][C:5]([F:25])([F:26])[C:4]([F:27])([F:28])[O:3][C:2]([F:29])([F:30])[F:1])([F:20])[F:19])=[CH:78][CH:77]=2)=[N:72][CH:71]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCCBr
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: BrCCCCCBr
Agent: OCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)1-bromopentane (18.3 g, 38.5 mmol; prepared from 1,5-dibromopentane (107 g, 0.7 mol) and 2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol (125 g, 0.31 mol) essentially as in Example 2 ) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (10 g, 35 mmol) to provide product boiling at 200°-210° C. at 0.4 torr (yield of 20.8 g).
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([N:15]([C:23]1[NH:24][CH:25]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([O:39][C:40]3[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[C:42]([Cl:48])[CH:41]=3)[C:33]=2[F:49])=[O:29])[N:27]=1)C(OC(C)(C)C)=O)=O)(C)C>ClCCl>[NH2:15][C:23]1[NH:24][CH:25]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([O:39][C:40]3[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[C:42]([Cl:48])[CH:41]=3)[C:33]=2[F:49])=[O:29])[N:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c[nH]c(N)n3)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
EDC (0.035 g, 0.183 mmol) and HOBT (0.025 g, 0.183 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.048 g, 0.153 mmol) and 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-imidazole-4-carboxylic acid (0.050 g, 0.153 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. Saturated aqueous sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give crude bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate as an oil. Trifluoroacetic acid (0.3 mL, 3.89 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (0.066 g, 0.106 mmol) in dichloromethane (2 mL). The mixture was stirred at RT overnight, concentrated and purified by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) to give the title compound (0.017 g, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09-8.18 (m, 2H), 7.81 (s, 1H), 7.51 (s, 1H), 7.44-7.50 (m, 2H), 7.30 (t, 1H), 7.10 (s, 1H), 5.45 (br. s., 2H), 4.44 (d, 2H). MS m/z 420 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Cl:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34](O)=[O:35])[CH:29]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:34]([C:30]2[CH:29]=[C:28]([Cl:27])[CH:33]=[CH:32][N:31]=2)=[O:35])[CH2:7]1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cc(Cl)ccn2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-chloro-pyridine-2-carboxylic acid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[S:41]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42]1>O1CCCC1.O>[F:25][C:11]1[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13][N:14]([S:46]([C:43]2[CH:44]=[CH:45][S:41][CH:42]=2)(=[O:48])=[O:47])[C:10]=1[C:9]1[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccsc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a suspension of sodium hydride (60% in oil, 37 mg) in tetrahydrofuran (2 mL) were added a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate in tetrahydrofuran (1 mL), 15-crown-5 (205 mg) and 3-thiophenesulfonyl chloride (136 mg) at room temperature and the mixture was stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 264 mg, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]#[C:23][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[N:10]=3)[CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1cnc2nc(N3CCCC3)nn2c1
Product: C(#Cc1cnc2nc(N3CCCC3)nn2c1)c1ccccc1

Procedure:
The title compound, a light brown solid, MS: m/e=290.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 51, step 1) and phenylacetylene.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3([OH:23])[CH2:21][CH2:20][O:19][CH:18]3[CH3:22])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3([OH:23])[CH2:21][CH2:20][O:19][CH:18]3[CH3:22])=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: CC1OCCC1(O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: [H][H]
Product: CC1OCCC1(O)c1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A62(c) from 3-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-2-methyl-tetrahydro-furan-3-ol and hydrogen. Yellow oil. MS (m/e): 220.3 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[O:19]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl.O>[CH2:1]([N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCN(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1O

Procedure:
A solution of 1.73 g of 1-benzyl-1-(n-butyl)-3-(2-methoxy-3-chlorophenyl)urea and 1.0 ml of boron tribromide in 40 ml of methylene chloride was stirred at ambient temperature for 3 days and diluted with water. The organic layer was separated, dried, and evaporated. The residue was crystallized from hexane to yield 1-benzyl1-(n-butyl)-3-(2-hydroxy-3-chlorophenyl)urea, m.p. 59°-62° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[O:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:15][CH:12]2[CH2:13][CH2:14][O:10][CH2:11]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OC1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cnc(Cl)nc1OC1CCOC1
Temperature: 80 °C
Yield: 28.4 %

Procedure:
A flask was charged with a solution of 2,4-dichloro-5-fluoropyrimidine (1.0 g, 5.99 mmol) in N,N′-dimethylformamide (20 ml). Tetrahydrofuran-3-ol (0.63 m, 7.19 mmol) and cesium carbonate (3.32 g, 10.18 mmol) were added and the resulting mixture was heated to 80° C. overnight. Upon completion, the mixture was diluted with ethyl acetate (20 mL) and washed with 1:1 water:brine (3×40 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by CombiFlash (ethyl acetate/hexanes) provided 374 mg (1.7 mmol, 29%) of 2-chloro-5-fluoro-4-(tetrahydrofuran-3-yloxy)pyrimidine. MS APCI: [M+H]+ m/z 219.0.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C.[C:53]([O:57][C:58]([N:60]1[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62][C@H:61]1[C@H:67]([C:71]1[CH:76]=[CH:75][C:74]([Cl:77])=[CH:73][C:72]=1[F:78])[C:68](O)=[O:69])=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl>[Cl:77][C:74]1[CH:75]=[CH:76][C:71]([C@@H:67]([C@H:61]2[N:60]([C:58]([O:57][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:59])[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62]2)[C:68]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:69])=[C:72]([F:78])[CH:73]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Cl)cc2F)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
(5R,7R)-5-Methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.109 g, 0.356 mmol; see Example 3, Step 12), HATU (0.123 g, 0.324 mmol), and collidine (0.171 mL, 1.30 mmol) were added to a solution of (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chloro-2-fluorophenyl)acetic acid (0.125 g, 0.324 mmol; prepared analogously to that described in Example B) in DCM (25 mL). The reaction was stirred overnight at room temperature. The reaction was partitioned between water (20 mL) and DCM (50 mL), and the layers were separated. The organics were washed with water (2×10 mL). The aqueous portion was back extracted with DCM (25 mL), dried (MgSO4) and concentrated to an oil that was purified by flash chromatography (5% MeOH/DCM) to give (S)-tert-butyl 5-((S)-1-(4-chloro-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.116 g, 0.193 mmol, 59.5% yield). LC/MS=3.79 minutes, (APCI+) m/z=602 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[F:20][C:21]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:6]1[N:7]=[C:2]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)[CH:3]=[C:4]([NH:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=1
Reactant: CC(C)(Cc1ccccc1)Nc1cc(Cl)nc(N)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(Cc1ccccc1)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 140 °C
Yield: 47.6 %

Procedure:
A mixture of 6-chloro-N4-(1,1-dimethyl-2-phenylethyl)-2,4-pyrimidinediamine (338 mg, 1.22 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (452 mg, 1.83 mmol), Pd(PPh3)4 (139 mg, 0.12 mmol) and Na2CO3 (323 mg, 3.05 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was stirred and heated at 140° C. for 30 min in a Biotage Initiator microwave synthesizer. The reaction mixture was cooled to room temperature and concentrated to dryness, and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted by EtOAc (3×50 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. Purification by RPHPLC with CH3CN in water (0.01% ammonium hydrogen carbonate) (gradient: from 70% to 80% in 7.5 min, flow rate: 30 mL/min), afforded the title compound (210 mg) as a white solid. LC-MS (ES) m/z=362 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(N)c1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)c2ccccc2)c1Cl

Procedure:
57 g (0.4 mol) of 2-chloro-3-methyl-aniline [CA 89, 30772h) were dissolved in 1.5 1 of toluene, 55 g of potassium carbonate were added and 62 g (0.4 mol) of benzoyl chloride were added dropwise at 80° C. After reaction is complete, the solid was filtered off in the cold and washed with water, and the filtrate was dried. After concentrating and triturating with petroleum ether 98 g of product (100%) crystallized.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.[H-].[Na+].[Cl:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][N:24]2[C:32]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=3)[CH:36]=O)=[C:31]3[C:26]([C:27]([C:41]([F:44])([F:43])[F:42])=[CH:28][CH:29]=[CH:30]3)=[N:25]2)=[C:21]([F:47])[CH:20]=1>CN1C(=O)N(C)CCC1.C(O)C.[Pt]=O>[Cl:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][N:24]2[C:32]([C:33]3[CH:40]=[CH:39][CH:38]=[C:35]([CH2:36][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:34]=3)=[C:31]3[C:26]([C:27]([C:41]([F:44])([F:43])[F:42])=[CH:28][CH:29]=[CH:30]3)=[N:25]2)=[C:21]([F:47])[CH:20]=1
Reactant: O=Cc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccc(Cl)cc2F)c1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: O=[Pt]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCCN(C)C1=O
Product: Fc1cc(Cl)ccc1Cn1nc2c(C(F)(F)F)cccc2c1-c1cccc(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of benzyl-phosphonic acid diethyl ester (20 μL, 1 eq) and sodium hydride (6 mg, 1.5 eq) in DMPU (0.5 mL), 3-[2-(4-chloro-2-fluoro-benzyl)-7-trifluoromethyl-2H-indazol-3-yl]-benzaldehyde (45 mg, 1 eq) was added. The reaction mixture was stirred for 45 minutes at room temperature, quenched with water and extracted with diethyl ether. The volatiles were removed and the residue purified by flash chromatography (silica, ethyl acetate/n-heptane, 2:8). The product obtained was dissolved in ethanol (2 mL) and hydrogenated at 1 atm using 7% platinum oxide as a catalyst. Filtration through Celite® and flash chromatography, eluent: dichloromethane/n-hepatane, 1:1, furnished the title compound in 11% overall yleld.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)=[O:4].S(=O)(=O)(O)O.[Br:21]Br.C(O)(=O)C.BrBr.CC(O)=O.C([O-])(O)=O.[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:13])[F:14])=[C:7]([Br:21])[N:6]=1)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1ncc(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (9.49 g, 43.16 mmol) was suspended in water (300 ml). Sulfuric acid (4.60 ml, 86 mmol) was added followed by dropwise addition over 30 minutes of a solution of bromine (2.222 ml, 43.1 mmol) in acetic acid (29.6 ml, 517 mmol). The reaction mixture was stirred at RT for 18 hours. A further 100 ml of water was added, followed by a further 0.25 equivalents of the bromine/AcOH mixture (550 μL bromine in 7.4 ml AcOH) and the reaction mixture stirred at RT for an additional 90 minutes. The reaction mixture was diluted with 500 ml water and neutralised by addition of solid NaHCO3 (˜85 g). The suspension was extracted with DCM (3×300 ml) and the combined organic phases washed with sat. NaHCO3(aq) (250 ml), water (250 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo. The crude material was recrystallised from boiling MeOH (˜300 ml) to give the title product as a pale orange solid m/z 301.0 [M+H]+ 1H-NMR: [400 MHz, DMSO-d6 δH 7.77 (1H, s, ArH), 7.17 (2H, s, NH2), 3.86 (3H, s, ArCO2CH3).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C([O-])([O-])=O.[K+].[K+].O.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:13][CH:14]([Cl:18])[C:15]([N:3]([O:4][CH3:5])[CH3:2])=[O:16]
Reactant: CNOC
Reactant: O=C(Cl)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C(Cl)Cl
Temperature: 0 °C
Yield: 92.5 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (7.94 g, 81.4 mmol) and K2CO3 (17.2 g, 124.1 mmol) were added to a water (70 ml) and toluene (70 ml) mixture. The mixture was then cooled to 0° C. Dichloroacetyl chloride (10 g, 67.85 mmol) was added drop wise and the reaction was allowed to warm to room temperature overnight. The toluene was collected and then the aqueous layer was extracted with EtOAc (2×100 ml). The organic layers were dried over sodium sulfate and concentrated in vacuo to give the title product (10.8 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].Cl.Cl.[CH3:28][N:29]1[CH2:32][C:31]2([CH2:35][NH:34][CH2:33]2)[CH2:30]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:34]4[CH2:35][C:31]5([CH2:32][N:29]([CH3:28])[CH2:30]5)[CH2:33]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN1CC2(CNC2)C1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Agent: Cl
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC5(CN(C)C5)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (d, J=2.27 Hz, 3H) 2.80 (d, J=4.55 Hz, 3H) 3.94-4.67 (m, 8H) 7.61 (d, J=8.08 Hz, 1H) 7.69-7.78 (m, 1H) 8.16-8.29 (m, 2H) 8.42 (d, J=8.59 Hz, 1H) 8.69 (br. s., 1H). ESI-MS m/z [M+H]+ 433.3.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][CH:48]1[CH2:52][N:51]([CH2:53][CH3:54])[N:50]([CH2:55][CH3:56])[CH2:49]1>>[CH2:55]([N:50]1[CH2:49][CH:48]([NH:47][C:19](=[O:21])[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:17][CH:16]=2)[CH2:52][N:51]1[CH2:53][CH3:54])[CH3:56]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(CC(=O)O)cc1
Reactant: CCN1CC(N)CN1CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CCN1CC(NC(=O)Cc2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.3 %

Procedure:
To a solution of 4-geranyloxyphenylacetic acid (1.50 g) in tetrahydrofuran anhydride (30 ml) were added 1- hydroxybenzotriazole (0.85 g), N,N'- dicyclohexyl carbodiimide (1.29 g), and 4-amino-1,2- diethylpyrazolidine (0.75 g) while being cooled with ice and then the mixture was stirred for 6 hours at room temperature. The reaction solution was filtered so as to filter out the deposited product and the filtrate was concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), thereby yielding 2.05 g (95%) of the aimed compound.