Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=2[N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22]C(=O)OC(C)(C)C)[CH2:17]2)[NH:9][CH:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]>C(O)(C(F)(F)F)=O>[NH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:14]2[C:13]([Cl:30])=[CH:12][N:11]=[C:10]3[NH:9][CH:8]=[C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:15]=23)[CH2:17]1
Reactant: CCCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N)C3)c12
Yield: 89.9 %

Procedure:
(R)-tert-Butyl 1-(3-butyramido-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (221 mg, 0.507 mmol) was stirred in TFA (3 mL) at room temperature for 1.5 hours. The solvent was evaporated in vacuo, and the residue purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 2-50% CH3CN/water, 16CV). The isolated product was taken up in a minimal volume of methanol and added to a stirred solution of 2N HCl-Et2O. The salt formed was collected by filtration, washed with acetonitrile and dried under vacuum to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)butyramide (153 mg, 74% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.83 (br s, 1H), 9.32 (s, 1H), 8.35 (br s, 2H), 8.13 (s, 1H), 7.57 (s, 1H), 3.54-3.46 (m, 1H), 3.45-3.30 (m, 2H), 3.27-3.04 (m, 2H), 2.41-2.34 (m, 2H), 2.18-2.09 (m, 1H), 1.91-1.79 (m, 1H), 1.72-1.59 (m, 3H), 1.59-1.39 (m, 1H), 0.96 (t, 3H). LCMS (APCI+) m/z 336.1, 338.1 (M+H)+, Retention time=2.38 minutes.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)=[O:5].[CH2:16]([Mg]Br)[CH3:17]>CCOCC>[O:13]1[C:9]2[CH:8]=[CH:7][C:6]([C:4](=[O:5])[CH2:16][CH3:17])=[CH:14][C:10]=2[CH:11]=[CH:12]1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc2occc2c1
Solvent: CCOCC
Product: CCC(=O)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An ice-cooled mixture comprising N-methoxy-N-methylbenzofuran-5-carboxamide (1 g, 4.87 mmol) in dry ether (20 ml) under N2 is treated dropwise with ethylmagnesium bromide (2.437 ml, 7.31 mmol). After stirring for 30 mins the mixture is allowed to warm to RT. The reaction is quenched by careful addition of NH4Cl followed by 1M HCl and the contents are transferred to a separating funnel. The mixture is extracted with EtOAc and the organic portion is washed with 1M NaOH, brine, dried (MgSO4), evaporated down to give a light brown oil, which began to crystallise on standing. Purification by chromatography on silica eluting with 25% EtOAc/iso-Hex affords the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 8.2 (d, 1H), 7.9 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 6.8 (d, 1H), 3.0 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:12][S:13]([C:16]1[CH:30]=[CH:29][C:19]2[N:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:21]=[N:22][C:18]=2[CH:17]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][S:13]([C:16]1[CH:30]=[CH:29][C:19]2[N:20]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][C:4]([C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:5])[CH2:27][CH2:28]3)[CH:21]=[N:22][C:18]=2[CH:17]=1)(=[O:15])=[O:14]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(=O)c2ccccc2)CC1
Reaction time: 48 h

Procedure:
3-Chloropropiophenone (860 mg) was added to a mixture of 5-(methylsulfonyl)-1-piperidin-4-yl-1H-benzimidazole (1.395 g) and potassium carbonate (1.38 g) in DMF (30 ml) and stirred for 2 days. The reaction mixture was evaporated to dryness and the residue was dissolved in dichloromethane (20 ml), washed with water (15 ml) and brine (15 ml), dried and evaporated to dryness to give the title compound, yield 2.07 g, M+H 412, NMR (CDCl3) 2.2 (m, 4H) 2.3-2.4 (m, 2H) 2.9 (m, 2H) 3.1 (s, 3H) 3.2-3.3 (m, 4H) 4.3 (m, 1H) 7.5 (m, 2H) 7.6 (m, 2H) 7.9 (m, 2H) 8.0 (m, 1H) 8.2 (s, 1H) 8.4 (s, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:11]=2N=N1.[C:28]([O:32][C:33]([N:35]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C:36]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]([C:51]3[CH:56]=[CH:55][C:54]([C@@H:57]([CH3:79])[CH2:58][O:59][C:60](=[O:78])[NH:61][C:62]4[CH:67]=[C:66]([CH2:68][NH:69][CH3:70])[C:65]([O:71][C@H:72]5[CH2:76][CH2:75][O:74][CH2:73]5)=[C:64]([F:77])[CH:63]=4)=[C:53](C)[CH:52]=3)[C:48]([OH:50])=O)=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[C:28]([O:32][C:33]([N:35]([C:36]1[C:45]2[C:44](=[CH:43][C:42]([NH:46][CH:47]3[C:48](=[O:50])[N:69]([CH3:70])[CH2:68][C:66]4[CH:67]=[C:62]([CH:63]=[C:64]([F:77])[C:65]=4[O:71][C@H:72]4[CH2:76][CH2:75][O:74][CH2:73]4)[NH:61][C:60](=[O:78])[O:59][CH2:58][C@H:57]([CH3:79])[C:54]4[C:53]([CH3:11])=[CH:52][C:51]3=[CH:56][CH:55]=4)=[CH:41][CH:40]=2)[CH:39]=[CH:38][N:37]=1)[C:81](=[O:82])[O:83][C:84]([CH3:85])([CH3:87])[CH3:86])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1O[C@H]1CCOC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@H]3CCOC3)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To BOP (317 mg, 0.716 mmol), 4-dimethylaminopyridine (219 mg, 1.791 mmol) in CH2Cl2 (40 mL), was added a solution of 39E (298 mg, 0.358 mmol) in DMF (10 mL) via a syringe pump over 6 h. The mixture was stirred rt for 16 h, then concentrated and purified by prep HPLC to give 39F (180 mg, 61.7% yield). MS (ESI) m/z: 814.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](OCC)=O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][CH3:19])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
13.0 g (31.3 mmol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-ethoxycarbonylaminopiperidine were dissolved in 60 ml of absolute tetrahydrofuran, the solution was added dropwise to a suspension of 1.82 g (46.9 mmol) of LiAlH4 in 60 ml of absolute tetrahydrofuran and the mixture was stirred at room temperature for 1 hour and at 40° C. for 1 hour. 1.8 ml of H2O, 1.8 ml of 2N NaOH and a further 9 ml of H2O were added dropwise in succession, with cooling; the precipitate formed was then filtered off with suction and rinsed with a little tetrahydrofuran and the filtrate was dried and concentrated.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[OH:5].[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:26](=[O:37])[C:27]3[CH:34]=[C:33]([CH2:35]Cl)[O:32][C:28]=3[N:29]([CH3:31])[CH:30]=2)=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:26](=[O:37])[C:27]3[CH:34]=[C:33]([CH2:35][N:2]([CH2:3][CH:4]([OH:5])[C:6]4[CH:15]=[CH:14][C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]=4)[CH3:1])[O:32][C:28]=3[N:29]([CH3:31])[CH:30]=2)=[O:24])=[CH:19][CH:18]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1ccc2ccccc2n1
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccc2ccccc2n1
Temperature: 90 °C
Yield: 48.6 %

Procedure:
N,N-biisopropylethylamine (0.11 mL) and rac-2-(methylamino)-1-quinolin-2-ylethanol (Preparation 47, 0.125 g) were added to a suspension of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The reaction mixture was allowed to cool to room temperature, poured into water (25 mL), and was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2, 97/3, 9515). The product was then recrystallized from ethyl acetate and then methanol to yield 0.106 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 154-159° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.64, 8.48, 8.29-8.27, 7.94-7.87, 7.70-7.66, 7.62-7.60, 7.57-7.52, 7.41-7.33, 6.85, 5.53, 4.95-4.91, 4.55, 3.74, 3.74-3.72, 2.89-2.85, 2.79-2.74, 2.36; MS (ESI+) m/z 531 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:21][CH2:20][S:19][C@H:18]2[C:22]([O:24][C@H:25]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)[CH:37]=2)[CH2:26][C:27]2[C:32]([Cl:33])=[CH:31][N+:30]([O-:34])=[CH:29][C:28]=2[Cl:35])=[O:23])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:7].[CH:51]([C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56](O)=[O:57])=[O:52].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:35][C:28]1[CH:29]=[N+:30]([O-:34])[CH:31]=[C:32]([Cl:33])[C:27]=1[CH2:26][C@@H:25]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[O:24][C:22]([C@H:18]1[N:17]([S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][NH:2][C:56](=[O:57])[C:55]3[CH:59]=[CH:60][CH:61]=[C:53]([CH:51]=[O:52])[CH:54]=3)[CH:9]=2)(=[O:15])=[O:16])[CH2:21][CH2:20][S:19]1)=[O:23]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=Cc1cccc(C(=O)NCCNC(=O)c2cccc(S(=O)(=O)N3CCS[C@H]3C(=O)O[C@@H](Cc3c(Cl)c[n+]([O-])cc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
4-((S)-2-((S)-3-(3-(2-Aminoethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide hydrochloride (195 mg, 0.244 mmol), 3-formylbenzoic acid (110 mg, 0.733 mmol), DMAP (5.97 mg, 0.049 mmol) and EDC (141 mg, 0.733 mmol) were dissolved in DMF. The reaction was stirred at RT overnight to achieve completion. The reaction mixture was diluted with water, and the precipitate was washed with water, dissolved in DCM and extracted with water. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-(2-(3-formylbenzamido)ethylcarbamoyl)-phenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (100 mg, 0.112 mmol, 45.8% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[N:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:31][C:32]1[C:33]([CH3:41])=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>ClCCl>[N:19]1[N:11]2[C:10]([CH2:9][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([F:31])[C:33]=4[CH3:41])=[CH:23][CH:22]=3)=[O:7])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12]2)=[CH:21][CH:20]=1
Reactant: Cc1c(F)cccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
To a solution of 0.25 g of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 0.0914 g of triethylamine in 6 ml of dichloromethane under argon is added a solution of 0.156 g of 3-fluoro-2-methylbenzoyl chloride in 1.5 ml of dichloromethane. The mixture is stirred overnight at room temperature and is washed with H2O and saturated NaHCO3. The organic layer is treated with activated carbon and filtered through magnesium sulfate. The filtrate is evaporated, ethyl acetate added and the solvent removed to give 0.38 g of white crystals, m.p. 245°-250° C.: Exact mass by mass spectrometry--441.1720(M+H).
Reaction SMILES: C[O:2][P:3]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[C@@H:22]([CH2:23][CH2:24][C@H:25]([O:33][Si](C(C)(C)C)(C)C)[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:21](=[O:41])[N:20]3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:15]([OH:48])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:6])[O:4]C.Br[Si](C)(C)C.CO>ClCCl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@@H:25]([OH:33])[CH2:24][CH2:23][C@H:22]2[C:21](=[O:41])[N:20]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@@H:19]2[C:16]2[CH:17]=[CH:18][C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([P:3](=[O:2])([OH:4])[OH:6])[CH:8]=3)=[CH:14][C:15]=2[OH:48])=[CH:27][CH:28]=1
Reactant: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)c(O)c2)c1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(P(=O)(O)O)c3)cc2O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.3 %

Procedure:
A solution of dimethyl(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonate (0.041 g, 0.059 mmol) in dry dichloromethane (5 mL) under nitrogen was cooled in ice and bromotrimethylsilane (0.030 mL, 0.30 mmol) was dripped in over 5 min. The reaction mixture was stirred at room temperature for 3 h, then methanol (1 mL) was added and the reaction was partitioned between water and ethyl acetate. The organic solution was washed successively with water (2×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 59% acetonitrile-0.1% trifluoroacetic acid in water) to afford (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid as a white powder (0.014 g, 44%); 1H NMR (300 MHz, CD3OD) δ 8.0 (d, J=13.6 Hz, 1H), 6.9-7.8 (m, 15H), 5.17 (d, J=2.1 Hz, 1H), 4.63 (d, J=5.2 Hz, 1H), 3.15-3.25 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M−H]+ 546, [2M−H]+ 1093.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[N:5]=[C:4]2[N:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[C:20](=[O:23])[NH:21][CH2:22][C:3]=12.O.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:64])[C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=2)=[CH:42][CH:41]=1>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:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[N:19]1[C:4]2[N:5]=[C:6]([N:8]3[CH2:9][CH2:10][CH:11]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[CH2:12][CH2:13]3)[N:7]=[C:2]([C:50]3[CH:49]=[C:48]([CH:53]=[CH:52][C:51]=3[CH3:54])[C:47]([NH:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)=[O:64])[C:3]=2[CH2:22][NH:21][C:20]1=[O:23]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1NCc2c(Cl)nc(N3CCC(N4CCCC4)CC3)nc2N1c1c(F)cccc1F
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: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(N3CCCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 54.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-[4-(1-pyrrolidinyl)-1-piperidinyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (18 mg, 0.04 mmol) in dioxane (1.5 mL)/water (0.5 mL) were added potassium carbonate (34 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002 mmol) and N-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (22 mg, 0.062 mmol). The reaction mixture was bubbled with N2 for 5 mins, then microwaved at about 150° C. for about 30 mins. The reaction mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (14 mg, 54%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([N:16]1[CH2:21][C@H:20]([CH3:22])[NH:19][C@H:18]([CH3:23])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CCCC)CCCC)CCC.C1(OC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:9]([N:16]1[CH2:17][C@@H:18]([CH3:23])[N:19]([C:2]2[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=2)[C@@H:20]([CH3:22])[CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Reactant: Clc1nccnc1Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1c1nccnc1Cl
Temperature: 220 °C

Procedure:
A mixture of 2,3-dichloropyrazine (4.9 g, 32.9 mmol), 1-benzyl-cis-3,5-dimethylpiperazine (5.9 g, 29.0 mmol), tributylamine (5.9 g, 32 mmol) and diphenyl ether (70 mL) was heated in a sealed tube at 220° C. for 3 days. The reaction mixture was cooled to ambient temperature and EtOAc (200 mL) and toluene (100 mL) were added. The organic phase was extracted with 5 M aqueous HCl (×3) and the combined aqueous phases were extracted with CHCl3 (×3). The combined organic layers, which contained the product, were washed with aqueous NaOH (5 M), dried (MgSO4), and the solvent was evaporated. The crude product (0.96 g), about 80% pure based on GC, was used in the next step without further purification.
Reaction SMILES: O[CH:2]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[N:6][C:5]1=[O:27].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCCl>[CH:24]([C:21]1[CH:22]=[CH:23][C:18]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]#[CH:17])[CH:9]=3)[N:4](/[CH:3]=[CH:2]/[C:28]3[C:29]([CH3:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=3[CH3:34])[C:5](=[O:27])[N:6]=2)=[CH:19][CH:20]=1)([CH3:25])[CH3:26]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CC(O)c1c(C)cc(C)cc1C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2/C=C/c1c(C)cc(C)cc1C

Procedure:
A solution of 50 mg (0.104 mmol) 1-[2-hydroxy-2-(2,4,6-trimethyl-phenyl)-ethyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one and 34.3 μl (0.208 mmol) trifluoromethane sulphonic anhydride in 0.5 ml 1,2 dichloroethane is heated to 80° C. for 15 min. Extraction with dichloromethane/aqueous NaHCO3 followed by preparative reversed phase HPLC yielded the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[CH2:8]([CH:10]1[O:12][CH2:11]1)Cl.[Na+].[Cl-]>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH:10]2[CH2:11][O:12]2)[N:3]=1
Reactant: ClCC1CO1
Reactant: Cc1cc(C)[nH]n1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cc(C)n(CC2CO2)n1

Procedure:
General Synthesis of 1-Dialkylamino-3-(3,5-dimethyl-pyrazol-1-yl)-propan-2-ols NaOH pellets (7.50 g, 0.188 mol) were added into a slightly heterogeneous mixture of 3,5-dimethylpyrazole (15.0 g, 0.156 mol) and epichlorohydrin (250 ml, 3.19 mol). After stirring for several minutes, NaCl began to precipitate and the reaction mixture was stirred at room temperature for 24 h. The resulting suspension was then filtered and the filtrate was evaporated under reduced pressure to give 3,5-dimethyl-1-oxiranylmethyl-1H-pyrazole as a viscous oil. This crude product, which contained 5-10% (by GC-MS) of 1,3-bis(3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ol, was used in the preparation of the following compounds without purification.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C([O-])([O-])=O.[K+].[K+]>CO.CCCCC>[CH2:13]([O:12][C:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[C:4]#[CH:3])[CH3:14]
Reactant: CCOC(C#C[Si](C)(C)C)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: CO
Product: C#CC(OCC)(OCC)OCC
Temperature: 23 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A solution of trimethyl(3,3,3-triethoxyprop-1-ynyl)silane (25 g, 102 mmol) in MeOH (400 mL) was treated with K2CO3 (14 g, 102 mmol). The reaction was stirred at 23° C. After 15 hours, the reaction was diluted with pentane (500 mL). The pentane layer was separated, and the MeOH layer was extracted with pentane (2×250 mL). The combined pentane layers were washed with water (200 mL), dried over MgSO4, and concentrated (at 220 torr on rotary evaporator). The crude product was filtered through a silica gel plug using 10% diethyl ether/pentane as the eluant. The filtrate was then concentrated (at 220 torr on rotary evaporator) affording 13.25 g of 3,3,3-triethoxyprop-1-yne.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH2:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH:38]=[CH2:39]>ClCCl>[CH2:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:42][CH2:41]1)[CH:38]=[CH2:39]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: C=CCN1CCNCC1
Solvent: ClCCl
Product: C=CCN1CCN(Cc2cc3c(cn2)ncn3-c2cc(O[C@H](C)c3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 126.2 mg of 1-allylpiperazin in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH:5]=O.ClC1C=CC(OC(F)F)=C(C=1)C=O.[C:28]([OH:34])([C:30](F)(F)F)=[O:29]>>[Cl:1][C:2]1[C:3]([F:14])=[C:4](/[CH:5]=[CH:30]/[C:28]([OH:34])=[O:29])[C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=Cc1c(C(F)(F)F)ccc(Cl)c1F
Agent: O=Cc1cc(Cl)ccc1OC(F)F
Product: O=C(O)/C=C/c1c(C(F)(F)F)ccc(Cl)c1F

Procedure:
Intermediate 16 was made in a similar manner as Intermediate 15 substituting 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde for 5-chloro-2-(difluoromethoxy) benzaldehyde followed by TFA deprotection. MS (ESI) m/z: 292 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ 7.87 (1H, dd, J=16.17, 2.02 Hz), 7.49-7.62 (2H, m), 6.67 (1H, dd, J=16.30, 1.39 Hz) ppm.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(OC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(CC(=O)O)cc1
Yield: 95.5 %

Procedure:
Methyl 2-(4-isopropoxyphenyl)acetate (10 g, 48.0 mmol), and NaOH (5.76 g, 144 mmol) were heated in methanol (50 mL)/Water (50 mL) solution at reflux for 2 h. Most of the MeOH was removed under vacuum and the remaining aqueous solution was acidified with 1 N HCl. The solid that precipitated from the solution was extracted into EtOAc solution. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum to give 2-(4-isopropoxyphenyl)acetic acid (8.9 g, 95% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.16 (m, 2H), 6.88-6.83 (m, 2H), 4.53 (spt, J=6.1 Hz, 1H), 3.59 (s, 2H), 1.34 (d, J=6.0 Hz, 6H).