Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][CH:15]([C:17](O)=[O:18])[CH2:14][N:13]([CH2:20][CH:21]([F:23])[F:22])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28](=[O:31])[CH2:29][CH3:30].C(N(CC)CC)C>CC1CCCO1>[F:22][CH:21]([F:23])[CH2:20][N:13]1[CH2:12][C:11]2([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:25][CH2:24]2)[O:16][CH:15]([C:17](=[O:18])[NH:26][CH2:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)O)O2
Reactant: CCC(=O)CN
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: CCC(=O)CNC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 40 °C
Yield: 60.2 %

Procedure:
To 9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (418 mg, 1.15 mmol), 1-aminobutan-2-one (156 mg, 1.26 mmol) and propane phosphonic acid anhydride (T3P) (1.095 g, 1.0 mL of 50% w/w, 1.72 mmol) in 2-methyltetrahydrofuran (3.1 mL) was added triethylamine (640 μL, 4.59 mmol) at room temperature. The reaction mixture was then heated at 40° C. for 5 hours. The reaction mixture was cooled quenched with sat. aq. NaHCO3 and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo, then purified by silica gel column chromatography using 0-50% EtOAc in DCM to yield tert-butyl 4-(2,2-difluoroethyl)-2-((2-oxobutyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (300 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 1H), 6.09-5.64 (m, 1H), 4.31 (dd, J=11.0, 3.0 Hz, 1H), 4.21-4.05 (m, 2H), 3.77 (ddt, J=10.9, 7.5, 6.3 Hz, 2H), 3.39-3.17 (m, 2H), 3.14-2.95 (m, 1H), 2.80-2.63 (m, 3H), 2.50 (q, J=7.3 Hz, 2H), 2.41-2.27 (m, 1H), 2.25-2.11 (m, 2H), 1.67-1.51 (m, 3H), 1.46 (s, 9H), 1.13 (t, J=7.4 Hz, 3H). ESI-MS m/z calc. 433.2. found 434.5 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]([F:26])([F:25])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:13][C:12]([F:26])([F:25])[F:11])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)CSc1ccc(Br)cc1
Temperature: 0 °C
Yield: 44.5 %

Procedure:
Dissolve 4-bromo-benzenethiol (1.0 g, 5.3 mmol) in dry dimethylformamide (50 mL) and cool to 0° C. under nitrogen. Add dry sodium hydride (152 mg, 6.4 mmol), portionwise. After the vigorous gas evolution stops, add toluene-4-sulfonic acid 2,2,2-trifluoro-ethyl ester (2.0 g, 8.0 mmol) and stir the reaction overnight at room temperature. Slowly pour the reaction into water (400 mL) and extract with ethyl acetate (2×50 mL). Wash the combined organic layers with water (100 mL) and brine (100 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the resultant residue on a SiO2 column with hexanes to yield 640 mg of 1-bromo-4-(2,2,2-trifluoro-ethylsulfanyl)-benzene (45%).
Reaction SMILES: Cl.Cl.[O:3]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[O:17])=[C:13]([NH:26][C:27]([C@H:29]3[CH2:34][CH2:33][C@H:32]([N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])[CH2:31][CH2:30]3)=[O:28])[C:12]=2[CH:41]=1)N.C(N(CC)C(C)C)(C)C.[C:51]([O:55][C:56]([NH:58][C:59]([N:68]1C=CC=N1)=[N:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:57])([CH3:54])([CH3:53])[CH3:52]>CN(C)C=O>[C:64]([O:63][C:61]([N:60]([O:3][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[O:17])=[C:13]([NH:26][C:27]([C@H:29]3[CH2:30][CH2:31][C@H:32]([N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])[CH2:33][CH2:34]3)=[O:28])[C:12]=2[CH:41]=1)[C:59]([NH:58][C:56]([O:55][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:57])=[NH:68])=[O:62])([CH3:65])([CH3:66])[CH3:67]
Reactant: NOCCOc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(=N)N(OCCOc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-5-(2-aminoxyethoxy)-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (90 mg) obtained in Example 183 is dissolved in N,N-dimethyl formamide (3 ml), and thereto are added N,N-diisopropylethylamine (38 μl) and N,N′-bis(t-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (57 mg), and the mixture is stirred at room temperature for one day. The reaction solution is concentrated under reduced pressure, and the residue is poured into water, and extracted with chloroform. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then ethyl acetate) to give trans-5-{2-[N,N′-bis(t-butoxycarbonyl)-guanidinoxy]ethoxy}-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (82 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([C:23](OC)=[O:24])[CH2:14]1>>[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([C:23]([O:1][CH2:2][CH2:3][CH2:4][C:5]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:24])[CH2:14]1
Reactant: OCCCC1(O)CCCC1
Reactant: COC(=O)C1CC2CC1C1C3C=CC(C3)C21
Product: O=C(OCCCC1(O)CCCC1)C1CC2CC1C1C3C=CC(C3)C21
Yield: 88 %

Procedure:
By following the procedure of Synthesis Example 2 except that 1-(3-hydroxypropyl)cyclopentanol was used instead of 4-methyl-1,4-pentanediol and methyl 8-tetracyclo-[4.4.0.12,5.17,10]dodecene-3-carboxylate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 3-(1-hydroxycyclopentyl)propyl 8-tetracyclo[4.4.0.12,5.17,10]-dodecene-3-carboxylate. Yield 88%.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:15][C:16]([F:21])([F:20])[C:17](O)=O>>[F:15][C:16]([F:21])([F:20])[C:17]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3
Reactant: COc1ccc2c(NN)nccc2c1
Reactant: O=C(O)C(F)(F)F
Product: COc1ccc2c(ccn3c(C(F)(F)F)nnc23)c1
Yield: 20 %

Procedure:
A solution of 1-hydrazino-6-methoxyisoquinoline and excess trifluoroacetic acid was held at reflux for four hours. After removal of the excess acid, the residue was treated with potassium bicarbonate solution until neutral and filtered. The filter cake was recrystallized from ethanol to provide the product in a yield of 20%; m.p. 214°-215°C.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[O:87]=[C:88]1[CH2:92][CH2:91][CH2:90][N:89]1[CH2:93][C:94](O)=[O:95]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:94](=[O:95])[CH2:93][N:89]1[CH2:90][CH2:91][CH2:92][C:88]1=[O:87])[CH2:19][CH2:18]2
Reactant: O=C(O)CN1CCCC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(2-oxopyrrolidin-1-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 655.5 (M+H)+, 1.99 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=7.9 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 6.77 (s, 1H), 5.29 (d, J=4.7 Hz, 1H), 4.75 (d, J=1.3 Hz, 1H), 4.63 (s, 1H), 3.97-3.85 (m, 2H), 3.58-3.51 (m, 2H), 2.65-2.54 (m, 2H), 2.47 (t, J=8.0 Hz, 2H), 2.38 (dd, J=8.4, 12.5 Hz, 1H), 2.17-2.07 (m, 3H), 1.95-1.85 (m, 1H), 1.83-1.74 (m, 2H), 1.73 (br. s., 1H), 1.70 (s, 3H), 1.68-1.62 (m, 1H), 1.60-1.43 (m, 8H), 1.42-1.22 (m, 6H), 1.13 (br. s., 1H), 1.09 (s, 3H), 1.01 (s, 6H), 0.94 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].Cl.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH2:25][C@H:24]([NH2:27])[C:23]2=[O:28])=[CH:18][CH:17]=1)#[N:15].C(O)(=O)[C@@H](C1C=CC=CC=1)O.N[C@H](C)[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].CCOC(C)=O>N1C=CC=CC=1.CN(C=O)C>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:26][CH2:25][C@H:24]([NH:27][C:1]([NH:8][C@H:12]([CH3:11])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:2])[C:23]2=[O:28])=[CH:20][CH:21]=1)#[N:15]
Reactant: CCOC(=O)C[C@@H](C)N
Reactant: N#Cc1ccc(N2CC[C@H](N)C2=O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](C)NC(=O)N[C@H]1CCN(c2ccc(C#N)cc2)C1=O
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a suspension of 1,1'-carbonyldiimidazole (178 mg, 1.1 mmol) in pyridine (2.5 mL) at 5° C. under nitrogen was added the product of example 4 (260 mg, 1.1 mmol). The resulting solution was stirred at 5° C. for 15 minutes, diluted with 2.5 mL of DMF and removed from the ice bath. The product of example 8 (375 mg, 1.32 mmol) was added all at once and the reaction mixture stirred at 75°-80° C. for 2 hours. After cooling to room temperature, the resulting solution was diluted EtOAc and washed with 1N HCl, saturated NaHCO3 and dried (MgSO4). Evaporation of the solvent afforded 295 mg (73%) of product (m.p. 177.5°-179° C.). 1H-NMR (300 MHz, CDCl3) δ 1.20-1.30 (m, 6H), 2.05 (m, 1H), 2.53 (m, 2H), 2.83 (m, 1H), 3.83 (m, 2H), 4.15 (q, J=7Hz, 2H), 4.19 (m, 1H), 4.48 (m, 1H), 7.68 (d, J=8Hz, 2H), 7.82 (d, J=8Hz, 2H).
Reaction SMILES: [C:1]1([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.CC#N>[NH:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][N:2]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2nccc3ccccc23)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC#N
Product: c1ccc2c(O[C@@H]3CCCNC3)nccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 53 was treated with 4N HCl in dioxane (40 mL) at RT for 3 h. The mixture was concentrated in vacuo to give a viscous oil which was dissolved in MeCN (200 mL). To the solution was added NaHCO3 powder (2.0 g). The mixture was stirred at RT overnight. The mixture was filtered and the filtrate was concentrated. The residue was subjected to flash column chromatography with 0%-100% EtOAc in DCM and then 0%-9% MeOH in DCM to isolate (R)-1-(piperidin-3-yloxy)isoquinoline (54).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:8]2)=[CH:2]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:33][C:29]4[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=4)[C:26]([OH:35])=[O:25])[CH2:20][CH2:19]3)=[CH:8]2)=[CH:2]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Product: COc1ccc2c(c1)c(C1CCN(Cc3cccc(C(=O)O)c3)CC1)cn2Cc1ccoc1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3.7 g (11.9 mmol) of 1-furan-3-ylmethyl-5-methoxy-3-piperidin-4-yl-1H-indole (example 92, part B) and 3 g (13 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up, 2.4 g (45% of yield) of the expected acid were obtained. In this case a p-tolensulfonate derivative salt was prepared affording 2.9 g of white solid.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17](Cl)=[O:18])([CH2:10]3)[CH2:8]1)[CH2:14]2)=[O:6].CO.[Cl-].[NH4+]>[Cu]I.CCOCC>[C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([C:5]([O:4][CH3:3])=[O:6])([CH2:14]3)[CH2:8]1)[CH2:10]2)(=[O:18])[CH3:1]
Reactant: COC(=O)C12CC3CC(CC(C(=O)Cl)(C3)C1)C2
Reactant: [Li]C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C12CC3CC(CC(C(C)=O)(C3)C1)C2
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Under nitrogen, a chilled (0° C.) diethyl ether suspension of copper (1) iodide (3.0 eq) was treated with methyl lithium (6.0 eq, 1.4 M in ethyl ether). The resulting solution was chilled to −78° C. and after ten minutes a chilled (−30° C.) diethyl ether solution of 3-methoxycarbonyladamantane-1-carboxylic acid chloride was added dropwise over a five minute period. The reaction was stirred for 45 minutes at −78° C. and then quenched with MeOH (11.0 eq) and allowed to warm to room temperature. After addition of Et2O and saturated aqueous ammonium chloride solution, the mixture was stirred for ten minutes and then the organic phase was washed with saturated NH4Cl, saturated NaHCO3, brine, dried (MgSO4), filtered and concentrated to a volatile oil, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[N:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].P(Br)(Br)[Br:20].O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Br:20])=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1Br
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A suspension of 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately RT—may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[N:30]([CH2:33][CH3:34])=[C:31]=[O:32].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:31]([NH:30][CH2:33][CH3:34])=[O:32])[CH2:27][CH2:28]2)=[O:21])[CH2:17][CH2:18]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (0.35 g, 0.79 mmol), isocyanatoethane (72.5 mg, 1.02 mmol) and triethylamine (329 μL, 2.36 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.34 g, 99%) as a white solid.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])=[O:3]
Reactant: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)O
Reactant: CN
Product: CNC(=O)C(C)Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
Three g of the product of Example 65 was reacted with 2 ml of aqueous methylamine, substantially as shown in Example 60, to obtain 2.3 g of the desired product, m.p. 157°-158°.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][Si:13](C)([CH3:23])[CH2:14]C(C1C=CC=CC=1)=C.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.CCN(CC)CC.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCl>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]([O:11][Si:13]([CH3:23])([CH3:14])[CH3:12])=[CH:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: C=C(C[Si](C)(C)C)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CC=C(O[Si](C)(C)C)CC1
Yield: 90 %

Procedure:
A solution (2.0 ml) of the mixture of 4-tert-butylcyclohexanone (1b) (77.1 mg, 0.500 mmol, 0.250 M) and trimethyl(2-phenylallyl)silane (2d) (85.2 mg, 0.500 mmol, 0.250 M) in toluene/dichloromethane (1:1, volume ratio), solution (2.0 ml) of Tf2NH (1.41 mg, 5.00 μmol, 2.50 mM) in toluene/dichloromethane (1:1, volume ratio), and a solution (5.0 ml) of NEt3 (2.53 mg, 25.0 μmol, 5.00 mM) in toluene/dichloromethane (1:1, volume ratio) were used as solution A, solution B and solution C, respectively. The three kinds of solutions were each loaded in a gas tight syringe, and set on a syringe pump as shown in the above-mentioned schematic diagram. Using a microreactor (manufactured by Techno Applications Co., Ltd., COMET-X01) at room temperature, solution A and solution B were continuously supplied at a flow rate of 150 μl/min, and solution C was supplied at a flow rate of 300 μl/min. A micromixer was set at a place where solution A and solution B were mixed, and a micromixer was also set at a place where mixture A-B and solution C were mixed. A flask containing ice-cooled aqueous sodium hydrogen carbonate solution was set at the outlet of the reaction mixture, and the mixture of A, B and C was collected there. After completion of the reaction, the recovered product was extracted with hexane and the organic layer was dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the object product, 4-tert-butyl-1-trimethylsilyloxy-1-cyclohexene (3b) (yield 90%). The time necessary for mixing solution A and solution B (calculated from distance between the two micromixers and flow rate) was 145 sec, and the time necessary for mixing mixture A-B and solution C (calculated from distance from the second micromixer to reaction mixture outlet and flow rate) was 40 sec.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9]([O:11][CH3:12])=[O:10].[I:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)([CH3:30])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1>CN(C=O)C>[I:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:9]([O:11][CH3:12])=[O:10])=[CH:35][CH:36]=2)([CH3:30])[CH:27]([CH3:28])[CH3:29])=[CH:24][CH:25]=1
Reactant: COC(=O)C(Br)c1ccccn1
Reactant: CC(C)C(C)(c1ccc(O)cc1)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(C(C)(c2ccc(I)cc2)C(C)C)cc1)c1ccccn1

Procedure:
Cesium carbonate (1.5 equiv.) followed by methyl bromo(pyridin-2-yl)acetate (5i) (1 equiv.) are added to a stirred solution of 5b (1 equiv.) in DMF at room temperature. After completion of reaction, the reaction mixture is quenched with saturated aqueous ammonium chloride, poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts are washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound 5c.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][Cl:32].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:29][CH2:30][CH2:31][Cl:32])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCCl
Temperature: 40 °C
Reaction time: 8 h
Yield: 91.02 %

Procedure:
To a suspension of 4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (1.83 g), K2CO3 (2.21 g), in DMF (20 mL) was added 1-bromo-3-chloropropane (1.90 mL) at rt, the mixture was stirred at 40° C. overnight. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (2.11 g, 91.02%).