Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([NH:7]/[N:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1.[N+]([C:24]([CH2:51][CH2:52][CH2:53][CH3:54])=[CH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[C:39]([N:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40])([O-])=O>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:24]([CH2:51][CH2:52][CH2:53][CH3:54])=[C:25]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:28][C:27]=3[C:39]([N:41]3[CH2:50][CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42]3)=[O:40])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=N/Nc1ccc(-c2ccccc2)cc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(-c2ccccc2)cc1
Yield: 61.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(biphenyl-4-yl)hydrazono)acetate (35 mg, 0.13 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (60 mg, 0.13 mmol) were converted to the title compound (55 mg, 62%) as a pale yellow solid. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.13 (dd, J=8, 2 Hz, 1H), 8.09-8.07 (m, 1H), 7.74-7.43 (m, 10H), 7.23-6.86 (m, 4H), 5.02-4.98 (m, 1H), 4.55-4.47 (m, 1H), 4.37-4.31 (m, 2H), 4.20-4.02 (m, 1H), 3.58-3.35 (m, 1H), 2.90-2.51 (m, 4H), 1.61 (s, 9H), 1.32 (t, J=8 Hz, 1.5H), 1.26 (t, J=8 Hz, 1.5H), 1.21-0.97 (m, 4H), 0.66-0.62 (m, 3H); MS (ESI+) m/z 684.4 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20].Cl>O1CCCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:17]([CH2:16][O:14][CH2:13][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:18]([CH:23]=1)[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: OCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1COCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.4 %

Procedure:
To a solution of potassium tert-butoxide (533 mg, 4.75 mmol) in tetrahydrofuran (10 ml) was added cyclohexylmethanol (594 mg, 5.20 mmol) in tetrahydrofuran (2.5 ml), methyl 2-(bromomethyl)-5-chlorobenzoate (250 mg, 0.95 mmol) in tetarahydrofuran (2.5 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was acidified with 2 N hydrochloric acid solution (pH ca. 2) at 0° C. It was extracted with dichloromethane, the organic extracts were dried over sodium sulfate and concentrated to afford 302 mg of crude 5-chloro-2-[(cyclohexylmethoxy)methyl]benzoic acid. This carboxylic acid was converted into 132 mg (31%) of the title compound according to the procedure described in step 6 of Example 1:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:53]=[N:52][C:51]([N:54]3[CH2:59][CH2:58][CH:57]([NH:60][CH3:61])[CH2:56][CH2:55]3)=[C:50]([CH3:62])[C:49]=2[CH3:63])=[CH:44][CH:43]=1.[CH3:64][O:65][C:66]1[CH:84]=[CH:83][C:69]([CH2:70][N:71]2[CH:75]=[C:74]([C:76](O)=[O:77])[C:73]([C:79]([F:82])([F:81])[F:80])=[N:72]2)=[CH:68][CH:67]=1>CN(C=O)C>[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:53]=[N:52][C:51]([N:54]3[CH2:59][CH2:58][CH:57]([N:60]([CH3:61])[C:76]([C:74]4[C:73]([C:79]([F:80])([F:81])[F:82])=[N:72][N:71]([CH2:70][C:69]5[CH:68]=[CH:67][C:66]([O:65][CH3:64])=[CH:84][CH:83]=5)[CH:75]=4)=[O:77])[CH2:56][CH2:55]3)=[C:50]([CH3:62])[C:49]=2[CH3:63])=[CH:44][CH:43]=1
Reactant: COc1ccc(Cn2cc(C(=O)O)c(C(F)(F)F)n2)cc1
Reactant: CNC1CCN(c2nnc(-c3ccc(F)cc3)c(C)c2C)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(C(=O)N(C)C3CCN(c4nnc(-c5ccc(F)cc5)c(C)c4C)CC3)c(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Add PyBOP (343 mg, 0.65 mmol) and triethylamine (0.21 mL, 1.50 mmol) to a stirred solution of 1-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)-N-methylpiperidin-4-amine (157 mg, 0.50 mmol) and 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (165 mg, 0.55 mmol) in anhydrous DMF (2.5 mL). Stir the resulting mixture at ambient temperature under N2 overnight. Concentrate, add MeOH, filter solids, and concentrate the filtrate. Dilute the residue with MeOH, and pour onto an SCX column (Thermo Scientific, 10 g). Wash with MeOH, and then elute the product with 2 M NH3/MeOH. Concentrate and purify by flash silica gel chromatography using a gradient of 0 to 10% (10% 2 M NH3/MeOH in EtOAc) in hexanes to obtain the title compound as a white solid (170 mg, 43%). ES/MS m/z 597.0 (M+1).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH:44]([O:47][C:48]1[CH:49]=[C:50]([CH:54]=[C:55]([N:57]2[CH2:61][CH2:60][CH2:59][C:58]2=[O:62])[CH:56]=1)[C:51]([OH:53])=O)([CH3:46])[CH3:45].[CH:63]12[CH2:69][CH:66]([CH2:67][CH2:68]1)[CH2:65][CH:64]2[NH:70][C:71](=[O:86])[C@H:72]([CH3:85])[CH2:73][C@H:74]([OH:84])[C@@H:75]([NH2:83])[CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>>[CH2:76]([C@H:75]([NH:83][C:51](=[O:53])[C:50]1[CH:54]=[C:55]([N:57]2[CH2:61][CH2:60][CH2:59][C:58]2=[O:62])[CH:56]=[C:48]([O:47][CH:44]([CH3:45])[CH3:46])[CH:49]=1)[C@@H:74]([OH:84])[CH2:73][C@H:72]([C:71](=[O:86])[NH:70][CH:64]1[CH2:65][CH:66]2[CH2:69][CH:63]1[CH2:68][CH2:67]2)[CH3:85])[C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: CC(C)Oc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E6 from 3-isopropoxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D16) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[Cl:22][C:23]1[CH:24]=[C:25](C=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32])CN>>[Cl:22][C:23]1[CH:24]=[CH:25][C:2]([CH2:3][NH:4][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][CH:20]=[CH:21][C:14]=23)=[O:6])=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32]
Reactant: NCc1ccc(C(F)(F)F)c(Cl)c1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: O=C(NCc1ccc(Cl)c(C(F)(F)F)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 3-chloro-4-(trifluoromethyl)benzylamine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 451 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.24 (1H, s) 8.76 (1H, t, J=5.98 Hz) 8.02 (1H, d, J=5.47 Hz) 7.82 (2H, d, J=4.05 Hz) 7.65-7.71 (1H, m) 7.58-7.64 (1H, m) 7.50 (1H, d, J=5.42 Hz) 7.30 (1H, dd, J=3.29, 2.56 Hz) 6.84 (1H, d, J=5.42 Hz) 6.40 (1H, dd, J=3.49, 1.93 Hz) 4.52 (2H, d, J=5.91 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:62][CH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]([CH3:74])([CH3:73])[O:71][B:70]([OH:75])[C:69]=2[CH:76]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:62][CH2:63][CH2:64][C:65]4[CH:66]=[CH:67][C:68]5[C:72]([CH3:73])([CH3:74])[O:71][B:70]([OH:75])[C:69]=5[CH:76]=4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCCc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (320 mg, 0.76 mmol) and HATU (456 mg, 1.2 mmol) in DMF (18 mL), DIPEA (310 mg, 2.4 mmol) was added. The reaction mixture was stirred at rt for 10 min and crude 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (1 mmol) was added. The reaction mixture was continued to stir overnight. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the final title compound 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethyl)-2-methylbenzamide (276 mg; yield 54.4%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.42 (t, J=6.0 Hz, 1H), 7.82 (t, J=2.0 Hz, 1H), 7.53-7.63 (m, 5H), 7.33-7.35 (m, 3H), 4.35 (d, J=18.5 Hz, 1 H), 4.30 (d, J=18.5 Hz, 1 H), 3.50 (q, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.23 (s, 3 H), 1.43 (s, 6H) ppm;
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C)C=O.C(OCC)(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:36]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.452 mmol) produced in Example A7(vi) in N,N-dimethylformamide (2.0 mL) was added chloroacetic acid chloride (79 μL, 0.995 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogencarbonate solution (100 mL), water (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give N-[5-({2-[(chloroacetyl)amino]-1,3-benzothiazol-6-yl}oxy)-2-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: [OH-].[K+].CC(O)C.[C:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH3:8].[H][H]>CC(O)C>[C:10]1([C@H:7]([OH:9])[CH3:8])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: [H][H]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C[C@@H](O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To 100 mL of an autoclave was charged 11.7 mg (0.010 mmol) of the mixture of RuCl2[(R)-binap](dmf)n and RuCl2[(S) -binap][(S)-binaphthyldiamine]. After purging with argon, 2.8 mL of 2-propanol and 50 μL (0.025 mmol) of KOH/2-propanol (0.5M solution) were added. The resulting mixture was stirred at room temperature for 30 minutes. After addition of 0.38 mL (2.5 mmol) of 1′-acetonaphthone, stirring was conducted at room temperature for 4 hours at a hydrogen pressure adjusted to 0.8 Mpa. The reaction mixture was concentrated by distilling off the solvent under reduced pressure. The residue was filtered using silica gel, whereby 228 mg (yield: 53%) of (R)-1-(1-naphthyl)ethanol was obtained. The enantio-selectivity was 4%ee.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[CH2:11]([CH:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[O:26])[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCCCCC
Product: O=C(Nc1ccc2[nH]ccc2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-aminoindole (Aldrich) and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 68-72° C. (hexane)
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.I[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:12][CH3:13]
Reactant: CCCI
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCN1CCC(C(N)=O)CC1

Procedure:
A solution of isonipecotamide (2.0 g, 15.6 mmol), 1-iodopropane (1.52 mL, 15.6 mmol), and potassium carbonate (2.15 g, 15.6 mmol) was heated at reflux in 100 mL of 2-butanone. The solids were filtered and the filtrate concentrated in vacuo to give crude product. Purification by flash chromatography (CH2Cl2—CH3OH, 12:1 ) afforded 1.25 9 of the product as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:17][O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=1[F:28].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:29])=[C:22]([F:28])[CH:23]=2)[CH:9]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: C#Cc1cccc(C(C)(C)C(=O)OCC)c1
Reactant: COC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)c1cccc(C#Cc2ccc(CC(=O)OC)c(F)c2)c1

Procedure:
Following General Procedure B and using 2-(3-ethynyl-phenyl)-2-methyl-propionic acid ethyl ester (Intermediate 132, 0.10 g, 0.46 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (0.136 g, 0.46 mmol), triethyl amine (8 mL), copper(I)iodide (0.01 g, 0.05 mmol) and dichlorobis(triphenylphosphine)-palladium(11) (0.035 g, 0.05 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.15 g, 85%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:16][C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[OH:8])=[CH:23][CH:22]=1
Reactant: COc1ccc(C(O)c2ccc(F)cc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cc2ccc(F)cc2O)cc1
Reaction time: 16 h
Yield: 34 %

Procedure:
To a solution of (2-benzyloxy-4-fluorophenyl)-(4-methoxyphenyl)-methanol (2.095 g, 6.19 mmol) in methanol (20 mL), a 20% palladium hydroxide catalyst (200 mg) was added and furthermore 2N—HCl (0.3 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 16 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (489 mg, 34%).
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH:12]=[N:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH2:24][NH2:25])[CH:21]=[CH:22][CH:23]=3)=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:38]=[C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[C:41]([C:49](OCC)=[O:50])[NH:40]1.C(N(CC)C(C)C)(C)C>CCO>[O:38]=[C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[C:41]([C:49]([NH:25][CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]3[N:11]=[CH:12][N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:9]=3)[CH:19]=2)=[O:50])[NH:40]1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Reactant: NCc1cccc(OCCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(NCc1cccc(OCCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Yield: 78 %

Procedure:
A suspension of 1-{3-[(3-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}propyl)oxy]phenyl}methanamine obtained in Reference Example 85 (0.300 g, 0.611 mmol), ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (0.133 g, 0.611 mmol) and N,N-diisopropylethylamine (0.213 mL, 1.22 mmol) in EtOH (4.5 mL) was stirred under microwave irradiation at 100° C. for 1.5 hr (Discover (trademark; CEM Corp), 50 W, run time: 5 min, hold time: 1.5 hr). After the reaction mixture was allowed to cool to room temperature, the precipitated solid was collected by filtration, and washed with EtOH to give the title compound as a white powder (0.315 g, 78%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([NH2:9])[O:6][N:5]=2)[CH2:3][CH2:2]1.[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH:1]1([C:4]2[N:8]=[C:7]([NH:9][C:24]([CH:22]3[C:23]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[O:15][C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:25])[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1nc(C2CC2)no1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: O=C(Nc1nc(C2CC2)no1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 275° C. and MS: m/e=333 (M+) was prepared in accordance with the general method of example 44a from 3-cyclopropyl-[1,2,4]oxadiazol-5-ylamine and 9H-xanthene-carboxylic acid chloride.
Reaction SMILES: C[O:2][C:3](=[O:11])[CH2:4][P:5]([O:9][CH3:10])([O:7][CH3:8])=[O:6].[OH-].[Na+]>>[CH3:8][O:7][P:5]([CH2:4][C:3]([OH:11])=[O:2])([O:9][CH3:10])=[O:6]
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Na+]
Agent: [OH-]
Product: COP(=O)(CC(=O)O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl(dimethoxyphosphinyl)acetate (18.2 g., 0.1 mole) and 1 N sodium hydroxide (100 ml., 0.1 mole) are combined and stirred at room temperature overnight. The reaction mixture is poured onto AG50W-X2 cation exchange resin (200 ml.) and eluted with double distilled water. The acidic fractions are combined and concentrated in vacuo. The residue is dissolved in dichloromethane, dried over magnesium sulfate and concentrated in vacuo to yield 16.8 g. of product, (dimethoxyphosphinyl)acetic acid, yield quantitative.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]>>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25])=[O:13]
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1c(Br)sc2c1CCCC2
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccccc1S)c1c(Br)sc2c1CCCC2

Procedure:
In the same manner as in Starting Material Synthesis Example 60 and using 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid, thionyl chloride, 2-aminothiophenol, 2-bromo-4,5,6,7-tetrahydro-N-(2-mercaptophenyl)-benzo[b]thiophene-3-carboxamide is obtained.
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].Cl[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:17]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([F:22])[CH:21]=2)=[CH:11][CH:10]=1)[CH3:8]>>[F:22][C:20]1[CH:19]=[C:18]([C:23]2([O:29][CH3:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=[C:16]([S:15][C:12]2[CH:11]=[CH:10][C:9]([CH:7]([CH3:8])[O:1][NH:2][C:3]([NH2:5])=[O:4])=[CH:14][CH:13]=2)[CH:21]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Reactant: NC(=O)NO
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ONC(N)=O)cc3)c2)CCOCC1
Temperature: 60 °C
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C. for 2 hours, hydroxyurea was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give N-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyloxy}urea in 32% yield, m.p. 84°-85° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OB(O)c1ccc(F)cc1
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: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1-c1ccc(F)cc1
Reaction time: 24 h
Yield: 42.7 %

Procedure:
4-Chloro-3-nitropyridine (3 g, 18.9 mmol) prepared in Step 1 of Preparation 1, 4-fluorophenylboronic acid (2.9 g, 20.79 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.89 mmol), and potassium carbonate (7.8 g, 56.7 mmol) were suspended in 120 ml of 1,4-dioxane. The resulting suspension was refluxed under stirring for 24 hours, filtered with Celite, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 1.76 g of the titled compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:12][C:11]1[C:2]([NH:1][C:16]2[C:17]([Cl:21])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)c1cccc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(Br)c1Nc1nc(Cl)ncc1Cl
Temperature: 85 °C
Yield: 7.3 %

Procedure:
A mixture of 2-amino-3-bromo-N-methyl-benzamide (420 mg), 2,4,5-trichloropyrimidine (540 mg) and K2CO3 (47 mg) in DMF was heated at 85° C. overnight. The reaction mixture was loaded on silica gel, dried in vacuo, and purified by silica gel chromatography to provide 50 mg of 3-bromo-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 8.4 (bs, 1H), 8.3 (s, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.3 (t, 1H), 6.3 (bs, 1H, NH), 3.0 (d, 3H).