Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]([CH3:24])=[CH:11][C:10]=1[F:25])=[O:7].FC(F)(F)S(O[C:34]1[C:45]([CH3:46])=[N:44][C:37]2[N:38]=[C:39]([S:42][CH3:43])[N:40]=[CH:41][C:36]=2[CH:35]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>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>[CH3:27][C:2]([CH3:1])([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:34]2[C:45]([CH3:46])=[N:44][C:37]3[N:38]=[C:39]([S:42][CH3:43])[N:40]=[CH:41][C:36]=3[CH:35]=2)[C:12]([CH3:24])=[CH:11][C:10]=1[F:25])=[O:7]
Reactant: Cc1cc(F)c(NC(=O)NCCC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
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
Solvent: O
Product: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3C)c(C)nc2n1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
Combine 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.669 g, 1.768 mmol), 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (0.6 g, 1.768 mmol), K2CO3 (0.733 g, 5.30 mmol) and Pd(PPh3)4 (0.102 g, 0.088 mmol) in dioxane (8 mL) and water (2 mL) in a pressure tube, sparge with argon, seal and heat at 100° C. overnight. Cool the mixture to RT, treat with saturated aqueous. NaHCO3 and extract with EtOAc (3×). Dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (5-100% EtOAc/Hexanes) to afford the title compound (440 mg, 56%). MS (m/z): 442.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15]C.[CH:32]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(C)=C(C3C=CC(Cl)=CC=3Cl)N=2)CC1>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])=[N:13][C:14]([CH3:15])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:32][CH2:31]1
Reactant: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.87-1.07, 1.18-1.23, 1.82, 2.27, 3.10-3.16, 3.47-3.57, 3.66-3.76, 4.40, 5.83, 5.98, 7.25-7.50; MS (ESI+) for C25H25Cl2N3O m/z 454 (M+H)+.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:21]([C:24]4([C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)[CH2:26][CH2:25]4)=[CH:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1>>[N:23]1[CH:3]=[C:1]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([C:21]([C:24]5([C:27]6[CH:28]=[C:29]7[C:34](=[CH:35][CH:36]=6)[N:33]=[CH:32][CH:31]=[CH:30]7)[CH2:25][CH2:26]5)=[CH:22][N:23]=4)[N:20]=3)=[CH:11][CH:10]=2)[CH:16]=[N:17][CH:18]=1
Reactant: Brc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Reactant: O=C(O)C(F)(F)F
Product: c1cnc2ccc(C3(c4cnc5ncc(-c6ccc(-c7cncnc7)cc6)nn45)CC3)cc2c1

Procedure:
This compound was prepared as a TFA salt starting from 6-{1-[2-(4-bromophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline using procedures analogous to those for Example 94. LCMS: (M+H)=442.1.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([I:15])[N:6]=2)[CH2:4][CH2:3][CH2:2]1.ClC1[C:18]2[N:19](C(C3CC(N(C)C)C3)=NC=2I)[CH:20]=CN=1>>[CH3:18][N:19]([CH3:20])[CH:3]1[CH2:2][CH:1]([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([I:15])[N:6]=2)[CH2:4]1
Reactant: CN(C)C1CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Product: CN(C)C1CC(c2nc(I)c3c(N)nccn23)C1

Procedure:
Prepared according to the procedure described above for 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine, except using [3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-dimethyl-amine. 1H NMR (400 MHz, CDCl3): δ 2.25 (br.s, 6H), 2.47 (br.s, 2H), 2.63 (q, J=8.17 Hz, 2H), 2.93 (br.s, 1H), 3.30-3.41 (m, 1H), 5.64 (br.s, 2H), 7.03 (d, J=4.80 Hz, 1H), 7.22 (d, J=4.80 Hz, 1H). HPLC: tR=0.36 min. (Open Lynx polar—5 min.). MS (ES+): m/z 357.73 (100) [MH+].
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[CH:29]1[O:31][CH2:30]1>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=2)[CH2:30][CH:29]([OH:31])[C:28]([F:33])([F:32])[F:27])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C1CO1
Reactant: CC(C)(C)Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CC(C)(C)Oc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: 45 °C
Reaction time: 24 h
Yield: 41.9 %

Procedure:
The N-(3-phenoxyphenyl)[[3-(1,1-dimethylethoxy)phenyl]methyl]amine (0.270 g, 0.78 mmol) product from EX-654B was dissolved in 2 mL of acetonitrile. Ytterbium triflate (16 mg, 0.026 mmol) was added in 0.5 mL of acetonitrile, and the mixture was stirred under nitrogen. 1,1,1-Trifluoro-2,3-epoxypropane (0.105 g, 0.94 mmol) was added, the vial was sealed and heated to 45° C. After 24 h, TLC analysis showed 50% conversion, so additional 1,1,1-trifluoro-2,3-epoxypropane (88.6 mg, 0.79 mmol) was added and heating continued for an additional 24 h. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (1.5-7% ethyl acetate). Fractions were pooled based on TLC analysis to give 150 mg (42%) of the desired 3-[(3-phenoxy-phenyl)[[3-(1,1-dimethylethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a clear, colorless oil, and an additional 60 mg (17%) was obtained as an amber oil. HRMS calcd. for C26H28F3NO3: 460.2100 [M+H]+, found: 460.2103. 1H NMR (C6D6) δ6.78-7.08 (m, 9H), 6.68 (d, 1H), 6.55 (t, 1H), 6.43 (dd, 1H), 6.34 (dd, 1H), 4.23 (s, 2H), 3.81 (m, 1H), 3.48 (dd, 1H), 3.24 (m, 1H), 2.25 (br s, 1H), 1.07 (s, 9H). 19F NMR (C6D6) δ−78.92 (d, 3F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH2:14])=[N:12][C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:10]1.[Cu][C:29]#[N:30].O>CN(P(N(C)C)(N(C)C)=O)C>[NH2:14][C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([C:29]#[N:30])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=1
Reactant: N#C[Cu]
Reactant: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1ccc(I)cc1F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: N#Cc1ccc(-n2nc(Nc3ccc(N4CCOCC4)cc3)nc2N)c(F)c1
Temperature: 55 °C
Yield: 10.6 %

Procedure:
A mixture of 1-(2-fluoro-4-iodo-phenyl)-N3-(4-morpholino-phenyl)-1H-[1,2,4]triazole-3,5-diamine (0.48 g, 0.99 mmol) and copper (I) cyanide (0.09 g, 0.99 mmol) in HMPA (3 mL) was heated at 55° C. for 2 h, then poured into water (75 mL) and filtered, washing with water. The filter cake was suspended in chloroform (100 mL) and methanol (5 mL), was refluxed for 2 h, cooled, filtered and evaporated. Purification by semi-preparative HPLC provided the title compound (0.04 g, 9% yield) as a pale tan lyophilate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 548.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24](O)=[O:25])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:33][CH:34]=1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([N:38]2[CH2:39][CH2:40][N:35]([C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:42])([F:27])[F:41])=[CH:34][N:33]=4)[CH2:36][CH2:37]2)=[O:25])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.134 mmol) with 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine in the presence of triethylamine (34 mg, 0.337 mmol) in dichloromethane (5 mL) gave 46 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.25-0.29 (m, 2H), 0.52-0.58 (m, 2H), 1.25-1.28 (m, 1H), 3.72-3.74 (m, 4H), 3.78-3.82 (m, 6H), 3.83 (s, 3H), 6.61 (d, J=9.0 Hz, 1H), 6.79-6.82 (m, 1H), 6.87-6.88 (m, 1H), 7.00 (t, J=7.8 Hz, 1H), 7.09-7.12 (m, 1H), 7.19-7.22 (m, 1H), 7.61-7.63 (m, 1H), 7.74 (d, J=3.9 Hz, 1H), 7.80 (d, J=15.9 Hz, 1H), 8.36 (br s, 1H); ESI-MS (m/z) 584.35 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([S:29][CH2:30][CH2:31][OH:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([O:32][CH2:31][CH2:30][S:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: OCCSCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)OCCSCc1ccccc1
Yield: 94 %

Procedure:
A solution of 34.7 g of 2-[4-(3,5-dichloro-2-pyridyloxy)-phenoxy]-propionyl chloride in 80 ml of toluene was added dropwise at 0° to 10° C. to a solution of 16.8 g of 2-benzylthioethanol and 10.1 g of triethylamine in 100 ml of toluene whilst stirring. After the addition was completed, the mixture was stirred further at 30° to 40° C. for 1 hour. The mixture was washed successively with a 1% aqueous solution of sodium hydroxide and water, and dried. Upon distilling off the toluene under reduced pressure, there were obtained 44.9 g of 2-benzylthioethyl 2-[4-(3,5-dichloro-2-pyridyloxy)-phenoxy]-propionate in the form of a colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: O=C1CNCCN1
Product: O=C1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CCN1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazin-2-one according to conditions described in general procedure C. Mp: 108-110° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.14-3.35(m, 8 H), 3.73-3.78(m, 6 H), 6.37(d, J=5.5 Hz, 1 H), 7.03-7.06(m, 2 H), 7.26(d, J=8.5 Hz, 1 H), 7.44-7.63(m, 4 H), 7.84-7.86(m, 1 H), 8.00-8.04(m, 2H), 8.35(d, J=5.1 Hz, 1 H), 10.51(s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([CH3:22])[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[C:11]([CH3:22])[CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: Cc1cc(C#N)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C#N)cc2c1NC(c1cccc(NC(C)(C)C(=O)O)c1)CC2(C)C
Temperature: 25 °C
Yield: 23 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (355.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyano-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (86.7 mg, 23%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 378.1.
Reaction SMILES: CS(C)=O.F[C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[CH:27]=[CH:26][C:15]([O:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[NH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[NH2:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=1)[O:37][C:28]1[CH:29]=[CH:6][CH:7]=[CH:8][C:9]=1[C:10]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=1)=[O:11]
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccccc2C(=O)c2ccc(Oc3cccc(C(=O)O)c3)cc2)c1

Procedure:
As shown by reaction (1), 4,-4-difluorobenzophenone is reacted with 3-hydroxybenzoic acid to obtain 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid. The reaction is carried out in a suitable aprotic solvent, such as dimethylsulfoxide or N,N-dimethylformamide, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. The 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid (A) is then reacted with 3-aminophenol, as shown by reaction (2) to obtain 3-[4-(3-aminophenoxybenzoyl)phenoxy]benzoic acid (B). This reaction is carried out in a suitable aprotic solvent, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. At the end of the reaction period, the reaction mixture is cooled, then poured into water, which is then neutralized to precipitate the monomer (B). If desired, the crude monomer can be purified by recrystallization or by dissolving it in a suitable solvent and precipitating it from solution into a suitable non-solvent.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[C:3](O)=[O:4].O.[NH2:15][NH2:16]>CO.S(=O)(=O)(O)O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[C:3]([NH:15][NH2:16])=[O:4]
Reactant: COc1ccc(C(O)C(=O)O)cc1
Reactant: NN
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COc1ccc(C(O)C(=O)NN)cc1
Reaction time: 1 h

Procedure:
To a solution of hydroxy-(4-methoxy-phenyl)-acetic acid (45 g, 0.25 mol) in 300 ml of methanol are added 30 drops of concentrated sulfuric acid at room temperature and the resulting mixture is heated to reflux for 4 hours. Subsequently the mixture is cooled and evaporated in vacuo. The remainder is taken up in water and extracted with ethyl acetate. The combined organic layer isn washed with brine, dried over magnesium sulfate and evaporated. The residue, which is hydroxy-(4-methoxy-phenyl)-acetic acid methyl ester, is dissolved in 350 ml of diethyl ether. Hydrazine monohydrate (47 ml, 0.95 mol) is added dropwise at room temperature and the mixture is stirred for 1 hour. The reaction mixture is poured on water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated, the remaining hydroxy-(4-methoxy-phenyl)-acetic acid hydrazide is sufficiently pure to be used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](OC)=[O:11])[C:5]([N+:16]([O-])=O)=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:16][C:10](=[O:11])[C:9]([CH3:15])([CH3:14])[NH:8]2
Reactant: COC(=O)C(C)(C)Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC1(C)Nc2nc(Cl)ccc2NC1=O
Yield: 61.2 %

Procedure:
Methyl N-(6-chloro-3-nitro-2-pyridyl)-2-aminoisobutyrate (4.0 g, 14.6 mmol) was hydrogenated in 250 ml of methanol with Raney nickel catalysis under 1 atm of hydrogen. After hydrogen uptake ceased, the catalyst was filtered off with suction, and the filtrate was concentrated and chromatographed on silica gel (ethyl acetate/heptane=1:2). 1.89 g (61%) of the compound of Example 15, of melting point 229° C., were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].C[Si](Cl)(C)C.[C:14]1([C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[OH:1][CH2:2][CH2:3][N:4]([S:21][C:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:5][CH2:6][CH2:7][OH:8]
Reactant: ClSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCNCCO
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: OCCCN(CCO)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-Hydroxyethyl)-3-amino-1-propanol (5.0 g, 41.9 mmol) is coevaporated several times with pyridine (20 mL) and then dissolved in pyridine (100 mL). The reaction flask is flushed with Argon and trimethylsilylchloride (2.47 g, 209.5 mmol) is added dropwise. The reaction mixture is stirred for 1 hour. Triphenyl methanesulfenyl chloride (14.32 g, 46.09 mmol) is dissolved in CH2Cl2and added via dropping funnel to the cooled reaction mixture. The reaction mixture is warmed to room temperature and stirred for 18 hours. The reaction mixture is concentrated in vacuo and the resultant residue is partitioned between H2O and EtOAc (100 ml, 1:1). The H2O layer is separated and extracted with EtOAc (3×50 ml). The EtOAc extracts are pooled, dried (MgSO4) and filtered. The filtrate is concentrated in vacuo and the residue is purified by silica gel flash column chromatography with EtOAc/hexanes as the eluent. The appropriate fractions are pooled and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[O:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[O:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)o1
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a mixture of ethyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-furancarboxylate (0.70 g), tetraethyl methylenediphosphonate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature, and the mixture was stirred at the same temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-furancarboxylate as colorless crystals (0.41 g, yield 46%) from a fraction eluted with acetate-hexane (9:1, v/v). Recrystallization from ethyl ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.