Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]1[O:21][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Ni].O1CCOCC1>[OH:21][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: [H][H]
Reactant: CCOC(=O)C1OC1c1ccc(OCc2ccccc2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
A mixture of ethyl-2,3-epoxy-3-(4-benzyloxyphenyl)propionate of the formula (9) (125 g) obtained according to the procedure described in step (ii) above. Railey Nickel (12.5 g) and 1,4-dioxane (750 ml) was hydrogenated at room temperature at 30–40 psi of hydrogen pressure for a period of 8–10 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the solvent was removed under reduced pressure to afford the title compound of the formula (10) (100–105 g. 80–83%).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:38][C:39]([Si:42]([CH3:78])([CH3:77])[O:43][C@H:44]([C@@H:55]([CH3:76])[CH2:56]/[C:57](/[CH3:75])=[CH:58]\[C@H:59]([CH3:74])[C@@H:60]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C@@H:61]([CH3:65])[CH2:62][NH:63][CH3:64])[C@H:45]([CH3:54])[C@@H:46]([OH:53])[C@@H:47]([CH3:52])/[CH:48]=[CH:49]\[CH:50]=[CH2:51])([CH3:41])[CH3:40].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:71][C:70]([Si:67]([CH3:68])([CH3:69])[O:66][C@H:60]([C@@H:59]([CH3:74])/[CH:58]=[C:57](/[CH3:75])\[CH2:56][C@H:55]([CH3:76])[C@@H:44]([O:43][Si:42]([C:39]([CH3:41])([CH3:40])[CH3:38])([CH3:78])[CH3:77])[C@H:45]([CH3:54])[C@@H:46]([OH:53])[C@@H:47]([CH3:52])/[CH:48]=[CH:49]\[CH:50]=[CH2:51])[C@@H:61]([CH3:65])[CH2:62][N:63]([CH3:64])[C:8](=[O:10])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH3:73])[CH3:72]
Reactant: O=C(O)CC1CCCCC1
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN(C)C(=O)CC1CCCCC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A DMF (2 mL) solution of cyclohexaneacetic acid (30.2 mg, 0.222 mmol) and BOP (131 mg, 0.296 mmol) is added to the stirred DMF (3 mL) solution of (3Z,5S,6S,7R,8R,9S,11Z,13S,14R,15S)-8,14-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7,9,11,13,15-hexamethyl-16-(methylamino)-1,3,11-hexadecatrien-6-ol (90 mg, 0.148 mmol) and DIEA (77 μL, 0.444 mmol) dropwise at 0° C. The solution is warmed up to 23° C. and stirred for an additional 1 hour. DMF is removed in vacuo and the residue is dissolved in EtOAc (10 mL). The organic solution is washed with H2O (1×10 mL) and brine (1×10 mL). The aqueous layer is extracted with Et2O (3×20 mL) and the combined extracts are dried (Na2SO4) and concentrated. Chromatography (SiO2, 0–30% EtOAc-hexanes gradient elution) provided the desired compound (70 mg, 65%). HRMS: ESI m/z 734.5906 (M+H+), Calcd. 734.5939.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH:13]=[N:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(=O)(=O)(O)O.Cl[CH2:33]Cl.[OH2:35]>CO>[Cl:1][C:2]1[C:3]([CH2:12][CH:13]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:23])([F:24])[F:25])[O:35][CH3:33])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: ClCCl
Reactant: O
Reactant: O=C(N=CCc1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(Cc1ncc(C(F)(F)F)cc1Cl)NC(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
0.16 g of N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethylidene}-2-(trifluoromethyl)benzamide (Int-6) were diluted in 2 mL of methanol. 50 μL of sulfuric acid 99% were added. The reaction mixture was stirred at room temperature for 48 hours. A mixture of dichloromethane (10 mL) and water (5 mL) was added. After separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with 5 mL of water, dried over magnesium sulfate, filtered, concentrated to yield to 0.150 g of crude material, which was purified by chromatography on silica gel to yield 0.107 g (63%) of desired product N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1-methoxyethyl}-2-(trifluoromethyl)benzamide (Ia-111), [M+1]=427.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([NH:22][CH2:23][CH2:24][C:25]1[CH:32]=[CH:31][C:29]([OH:30])=[C:27]([OH:28])[CH:26]=1)=[O:21])[C@@H:10]([CH3:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[C:33]([OH:45])(=O)/[CH:34]=[CH:35]/[C:36]1[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=1>>[C:33]([NH:8][C@H:9]([C:20]([NH:22][CH2:23][CH2:24][C:25]1[CH:32]=[CH:31][C:29]([OH:30])=[C:27]([OH:28])[CH:26]=1)=[O:21])[C@@H:10]([CH3:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:45])/[CH:34]=[CH:35]/[C:36]1[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)c(O)c1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)/C=C/c1ccc(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
The title compound was prepared from N-[Nα-(tert-butoxycarbonyl)-O-benzyl-L-threonyl]dopamine (1.0 g, 2.3 mmol, example 9, step A) as described for example 9 (step B) using caffeic acid (620 mg, 3.4 mmol) instead of 3,4-dihydroxybenzoic acid. The crude material was purified by flash chromatography using 30% EtOAc/CHCl3 and 5% MeOH/CHCl3 as the eluent. The title compound was obtained as yellow crystals (717 mg, 62%).
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([O:21][CH3:22])=[CH:16][C:15]=3[CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:11][CH:12]=2)[N:7](C2CCCCO2)[N:6]=1)=[NH:4].C(OC([N:41]1[CH2:46][CH2:45][C:44](OCC)(OCC)[CH:43]([NH2:53])[CH2:42]1)=O)(C)(C)C.C(O)(=O)C.[ClH:58]>C(O)C>[ClH:58].[ClH:58].[ClH:58].[F:20][C:18]1[C:17]([O:21][CH3:22])=[CH:16][C:15]([CH2:23][C:24]([F:27])([F:26])[F:25])=[C:14]([C:10]2[CH:9]=[C:8]3[C:13]([C:5]([C:3]4[NH:53][C:43]5[CH2:42][NH:41][CH2:46][CH2:45][C:44]=5[N:4]=4)=[N:6][NH:7]3)=[CH:12][CH:11]=2)[CH:19]=1
Reactant: COC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OC)cc3CC(F)(F)F)ccc12
Reactant: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1N
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CNCC5)n[nH]c3c2)cc1F
Temperature: 50 °C
Yield: 96.8 %

Procedure:
To a solution of 6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboximidic acid methyl ester (Preparation 37, 1.64 g, 3.78 mmol) in ethanol (5 mL) was added a solution of 3-amino-4,4-diethoxy-piperidine-1-carboxylic acid tert-butyl ester (US-2004/0229862, 1.15 g, 3.97 mmol) in ethanol (7.5 mL). Acetic acid (430 μL, 7.56 mmol) was added and the reaction mixture was heated at 50° C. for 18 hours and then concentrated in vacuo to give a brown oil. The oil was dissolved in ethanol (15 mL) and the resulting solution was treated with concentrated hydrochloric acid (12M, 4.75 mL, 56.7 mmol) and then heated at 80° C. for 18 hours. The solvent was removed in vacuo to yield the title compound (2.03 g) in a 97% yield.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:22][C:23]([CH3:38])([CH3:37])[CH2:24][CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH2:20][OH:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:22][C:23]([CH3:37])([CH3:38])[CH2:24][CH2:25][O:26][Si:27]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:32])[CH3:33])[CH:34]([CH3:35])[CH3:36])[CH:20]=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)[Si](OCCC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCCC(C)(C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
14.7 ml of dimethylsulfoxide in 200 ml of methylene chloride are added dropwise to a solution of 13.4 ml of oxalyl chloride in 200 ml of methylene chloride at -60° C. After 15 min, a solution of 43.2 g of 2(S)-tert-butoxycarbonylamino-6-triisopropylsilyloxy-4,4-dimethyl-hexan-1-ol in 320 ml of methylene chloride is added dropwise at -60° C. in the course of 40 min, while stirring vigorously. 58 ml of triethylamine are then added and the reaction mixture is stirred at -60° C. for 90 min. It is allowed to warm to -10° C., 200 ml of a 20% potassium hydrogen sulfate solution are added, the mixture is subsequently stirred briefly and the product is extracted with methylene chloride. This gives 43 g of the title compound, which is reacted further without additional purification: Rf (A)=0.62, Rf (D)=0.3; Rt (II)=34.8 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31]CCl.CO.[ClH:36]>C(OCC)C>[ClH:31].[ClH:36].[ClH:31].[N:25]1([CH2:24][CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1cc(OCCCN2CCCCC2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of 4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (D1) (1.576 g, 3.76 mmol) in a (1:1) mixture of dichloromethane and methanol (20 ml) was added a 1M solution of hydrogen chloride in diethyl ether (20 ml) and the reaction stirred for 5 hours at room temperature. The solvent was then evaporated in vacuo and the resulting residue triturated with diethyl ether to afford the title compound (1.5 g, 93%); MS (ES+), m/e 318 [M+H]+.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][C:9]=1[O:19][CH3:20])([O-])=O.C([O-])(O)=O.[Na+]>O>[NH2:5][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][C:9]=1[O:19][CH3:20]
Reactant: COc1cc2c(cc1[N+](=O)[O-])C(=O)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1N)C(=O)CCC2
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of acetic acid (20 mL) in H2O (100 mL), 7-nitro-6-methoxy-1-tetralone (2.21 g, 10.0 mmol) was added. The solution was heated to reflux for 1 hour, and then cooled down to rt. NaHCO3 (60 mL, saturated solution) was added, and the mixture was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated in vacuo to provide a red oil. 7-Amino-6-methoxy-1-tetralone (1.74 g, 9.1 mmol, 91%) was obtained following purification by column chromatography. 1H-NMR (CDCl3, 300 MHz) 2.07 (m, 2H), 2.57 (t, J=6.5 Hz, 2H), 2.86 (t, J=6.0 Hz, 2H), 3.73 (b, 2H), 3.91 (s, 3H), 6.59 (s, 1H), 7.36 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:23]1(=O)[CH:28]=[CH:27][C:26](=[O:29])[CH:25]=[CH:24]1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:15][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=3[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12

Procedure:
The material prepared in Example 1A (250 g, 1.19 mole) was combined with zinc chloride (243.5 g, 1.784 mole) and toluene (3.75 L). The reaction mixture was heated to reflux under a nitrogen atmosphere. Benzoquinone (167 g, 1.546 mole) in tetrahydrofuran (500 mL) was added dropwise to the reaction, and upon completion of the addition, the reaction mixture was heated at reflux for 6 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated in vacuo to a brown solid. The solid was recrystallized from acetonitrile yielding the title compound as a brown solid (125 g, 35%). MS m/z 301 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[OH:32][N:31]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(c2ccc(C=CC(=O)O)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(C=CC(=O)O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-{4-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-acrylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of Z to E isomers (1.7:1) as a colorless oil, MS (ESI+): m/z=401.1859 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH2:15]O)[S:12][N:11]=2)=[CH:6][CH:5]=1.P(Br)(Br)[Br:20].O>C1(C)C=CC=CC=1>[Br:20][CH2:15][C:13]1[S:12][N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:18])([F:17])[F:1])=[CH:5][CH:6]=2)[N:14]=1
Reactant: BrP(Br)Br
Reactant: OCc1nc(-c2ccc(OC(F)(F)F)cc2)ns1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2nsc(CBr)n2)cc1
Temperature: 120 °C
Yield: 90.1 %

Procedure:
To a solution of [3-(4-trifluoromethoxyphenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.10 g, 0.36 mmol) in toluene (5 ml) was added PBr3 (0.050 ml, 0.54 mmol) and the resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.11 g, 89%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[C:22]([O-:25])([O-:24])=O.[Cs+].[Cs+].[O:28](C(OC(C)(C)C)=O)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=O.O>CN(C=O)C>[C:5]([O:24][C:22]([NH:21][S:18]([N:13]1[C:14]2([CH2:16][CH2:15]2)[CH2:17][N:10]([C:4]2[C:5]3[CH:9]=[CH:8][N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:28])[C:6]=3[N:1]=[CH:2][N:3]=2)[CH2:11][CH2:12]1)(=[O:20])=[O:19])=[O:25])([CH3:9])([CH3:6])[CH3:4]
Reactant: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diaza-spiro[2.5]octane-4-sulfonic acid amide (intermediate 1) (1.95 mmol) was dissolved in dry DMF (15 ml), added Cs2CO3 (4.29 mmol), BOC2O (4.29 mmol) and stirred at rt for 16 h. The crude mixture was treated with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][O:26][C:20]=3[CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:25]1[O:26][C:20]2[CH2:19][N:18]([S:15]([C:12]3[CH:13]=[CH:14][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=3)(=[O:16])=[O:17])[CH2:23][CH2:22][C:21]=2[CH:24]=1)[CH3:29]
Reactant: CNC
Reactant: O=C(c1ccccc1)c1ccc(S(=O)(=O)N2CCc3ccoc3C2)cc1
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(S(=O)(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.111 g (0.302 mmol) of 6-(4-benzoylphenylsulfonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 41 mg (0.45 mmol) of 50% aqueous dimethylamine and 37 mg (0.45 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:12]([OH:15])(=O)[CH3:13].C(#[N:18])C>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:18][C:12](=[O:15])[CH3:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC#N
Reactant: CC(C)(O)c1ccc(Cl)nc1
Product: CC(=O)NC(C)(C)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
2-(6-chloropyridin-3-yl)propan-2-ol (637 mg, 3.71 mmol, Eq: 1.00) was dissolved in acetonitrile (5 ml). Acetic acid (2.9 g, 2.76 ml, 48.3 mmol, Eq: 13) was added at room temperature and cooled after the addition to 0° C. Sulfuric acid, concentrated (5.1 g, 2.77 ml, 52.0 mmol, Eq: 14) was added dropwise to the solution, then allowed to warm up to room temperature and stirred over night. The reaction mixture was poured into ice, concentrated NaOH solution was added until pH was basic; extracted with ethyl acetate; org. phase was washed with brine; dried with sodium sulfate; filtered to give a yellow solid. This residue was triturated with ethyl acetate and a little bit hexane. Resulting precipitate was filtered off to give a white solid (338 mg, 1.59 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[C:16]1([C:22]2[CH:23]=[CH:24][C:25](=O)[NH:26][N:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:15][C:2]1([CH3:1])[CH:3]=[C:4]([O:14][C:25]2[N:26]=[N:27][C:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][CH:24]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Product: CC1(C)C=C(Oc2ccc(-c3ccccc3)nn2)c2cc(C#N)ccc2O1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 6-phenyl-2H-pyridazin-3-one as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25](B(O)O)[CH:26]=4)[C:21]([CH3:32])([CH3:31])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH:33]1[C:38](Cl)=[N:37][C:36]([NH2:40])=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:34]5[CH:33]=[CH:38][N:37]=[C:36]([NH2:40])[N:35]=5)[CH:26]=4)[C:21]([CH3:32])([CH3:31])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B(O)O)cc21
Reactant: Nc1nccc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(-c3ccnc(N)n3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (92 mg, 0.215 mmol), PdCl2(PPh3)2 (15.12 mg, 0.021 mmol), 2-amine-4-chloropyrimidine (30.6 mg, 0.236 mmol) and sodium carbonate (68.3 mg, 0.644 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) and heating in the microwave for 1 h at 120° C. After purification 4-(1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-pyrimidinamine was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.68-8.80 (1H, m), 8.49 (1H, d, J=2.0 Hz), 8.26 (1H, d, J=5.5 Hz), 7.72-7.99 (4H, m), 7.41 (1H, ddd, J=7.0, 5.1, 2.0 Hz), 7.29-7.34 (1H, m), 6.93 (1H, d, J=5.1 Hz), 6.77-6.86 (1H, m), 5.16 (2H, br. s.), 3.77-3.95 (2H, m), 2.27-2.44 (3H, m), 1.61-1.68 (3H, m), 1.51-1.60 (3H, m). Mass Spectrum (ESI) m/e=478 (M+1).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:10]1[C:11]([CH3:27])=[C:12]([C@@H:17]2[O:22][CH2:21][C@@H:20]3[CH2:23][NH2+:24][CH2:25][CH2:26][N:19]3[CH2:18]2)[CH:13]=[CH:14][C:15]=1[F:16])#[N:9].CN1CCOCC1.[N:35]1([C:40]2[N:45]=[CH:44][C:43]([CH2:46][C:47](O)=[O:48])=[CH:42][CH:41]=2)[CH:39]=[N:38][N:37]=[N:36]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:16][C:15]1[C:10]([C:8]#[N:9])=[C:11]([CH3:27])[C:12]([C@@H:17]2[O:22][CH2:21][C@@H:20]3[CH2:23][N:24]([C:47](=[O:48])[CH2:46][C:43]4[CH:44]=[N:45][C:40]([N:35]5[CH:39]=[N:38][N:37]=[N:36]5)=[CH:41][CH:42]=4)[CH2:25][CH2:26][N:19]3[CH2:18]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Reactant: Cc1c([C@H]2CN3CC[NH2+]C[C@H]3CO2)ccc(F)c1C#N
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4ccc(-n5cnnn5)nc4)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3S,9aS)-3-(3-Cyano-4-fluoro-2-methylphenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-ium trifluoroacetate (1.44 g, 3.70 mmol) and N-methylmorpholine (1.220 mL, 11.10 mmol) was added to DCM (25 mL). Then [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (0.911 g, 4.44 mmol), HOBT (0.850 g, 5.55 mmol) and EDC (1.418 g, 7.40 mmol) were added in that order. The reaction mixture was stirred at RT for 4 h. The reaction mixture was washed with brine and saturated aq. NaHCO3 solution. The DCM layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by preparative TLC eluting with a 5% (10% NH4OH in Methanol): 95% chloroform solvent system to yield the title compound: 1H-NMR (500 MHz, DMSO): δ ppm 10.17 (s, 1H), 8.48 (s, 1H), 8.22 (t, J=7.35 Hz, 1H), 8.01 (s, 2H), 7.37 (s, 1H), 4.93 (s, 1H), 4.21 (dd, J=13.3, 60.75 Hz, 1H), 3.89-3.99 (m, 3H), 3.57 (dd, J=11, 23.5 Hz, 1H), 3.29 (s, 1H), 3.10-3.24 (m, 2H), 2.80-3.0 (m, 2H), 2.68 (d, J=11 Hz, 1H), 2.53 (s, 3H), 2.23-2.48 (2H).