Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:11]([CH:35]([CH3:37])[CH3:36])[CH2:12][C:13]([C:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:16]=1)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH2:4]([N:11]([CH:35]([CH3:37])[CH3:36])[CH2:12][C:13]([C:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:16]=1)([OH:14])[CH3:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1c(C(=O)CN(Cc2ccccc2)C(C)C)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1c(C(C)(O)CN(Cc2ccccc2)C(C)C)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Methyl magnesium bromide (0.1 ml, 0.144 mmol) was added dropwise into the solution of 2-(benzyl-isopropyl-amino)-1-[5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-methyl-1H-pyrazol-3-yl]-ethanone (61 mg, 0.12 mmol) in 0.5 ml THF at room temperature. After 2 h, the reaction mixture was then partitioned with ethyl acetate and saturated NH4Cl. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 30% ethyl acetate/hexanes) to give the title compound 4A-1 as a white waxy solid (24 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[CH3:33])(=[O:25])=[O:24].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:41][CH2:40][C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[CH3:33])(=[O:25])=[O:24]
Reactant: NCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c(C)c1
Yield: 23.7 %

Procedure:
Reaction of oxalyl chloride (31 λL, 0.35 mmol) and benzoic acid 44 (92 mg, 0.24 mmol) with subsequent coupling to 3-pyridinylmethylamine (27 λL, 0.26 mmol) gave benzamide 45 (27 mg, 24%) as a clear gum: 1H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.5 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 8.00 (d, J=8.4 Hz, 2H, H-2, H-6), 7.88 (d, J=8.4 Hz, 2H, H-3, H-5), 7.74 (br d, J=7.8 Hz, 1H, H-4′), 7.57 (d, J=8.1 Hz, 1H, H-5″) 7.37 (dd, J=7.8, 4.7 Hz, 1H, H-5′), 7.27 (br s, 1H, H-3″), 7.18 (d, J=8.1 Hz, 1H, H-6″), 4.61 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2N), 2.55 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.15 (s, 3H, CH3); MS m/z 476.6 (MH+, 100%). Anal. calcd for C26H25N3O4S.½CH3CO2CH2CH3: C, 64.72; H, 5.63; N, 8.09. Found: C, 64.72; H, 5.60; N, 7.75%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: Clc1ccc(CBr)cc1Cl
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(Cl)c(Cl)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 59.3 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3,4-dichloro-benzyl bromide (116 mg, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(3,4-dichloro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (104 mg, 59%) as a light yellow solid. APCI-MS (M+H) 365.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:32]=2[N:33]2[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:34]2)=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (632.0 mg, 1.575 mmol), benzyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (559.9 mg, 1.715 mmol) and HATU (1822 mg, 4.792 mmol), DMF (15.0 mL) was added, followed by DIPEA (1854 mg, 14.34 mmol). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to afford the sub-title compound (912.7 mg, 82%). LCMS calc. for C36H34BrN6O5(M+H)+: m/z=709.2. found 709.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([S:12]([OH:15])(=[O:14])=[O:13])([CH2:8][C:9]([O-:11])=[O:10])[C:5]([O-:7])=[O:6])[CH3:2].[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]OS([O-])(=O)=O.[Na+:33]>>[CH2:1]([O:3][C:4]([S:12]([OH:15])(=[O:13])=[O:14])([CH2:8][C:9]([O-:11])=[O:10])[C:5]([O:7][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[O:6])[CH3:2].[Na+:33]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: CCOC(CC(=O)[O-])(C(=O)[O-])S(=O)(=O)O
Agent: [Na+]
Product: CCCCCCCCCCCCOC(=O)C(CC(=O)[O-])(OCC)S(=O)(=O)O

Procedure:
coconut monoethanolamide ethoxysulphosuccinate, (e.g. EMPICOL SGG)
Reaction SMILES: [OH:1][C:2](=[CH:8][CH:9]=[C:10]([S:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>C(O)C>[OH:1][C:2](=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)=CC=C(Sc1ccc2ccccc2c1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(O)C(=O)O)Sc1ccc2ccccc2c1
Yield: 81.1 %

Procedure:
The procedure is as in Example 39, starting with diethyl 2-hydroxy-5-(2-naphthylthio)-2,4-hexadienedioate, (2 g), 1N aqueous sodium hydroxide solution (80 cc) and ethanol (100 cc). 2-Hydroxy-5-ethoxycarbonyl-5-(2-naphthylthio)-2,4-pentadienoic acid (1.5 g), m.p. 182° C., is obtained by precipitation in ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[O:53][CH2:52][N:43]3[C:44]4[CH:45]=[CH:46][CH:47]=[C:48]([F:51])[C:49]=4[CH:50]=[C:42]3[C:41]=2[N:54]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:51][C:48]1[C:49]2[CH:50]=[C:42]3[C:41]4[N:54]=[C:37]([C:18]5[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][C:10]6[O:9][C:8]([C:5]7[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=7)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=6[CH:17]=5)[CH:38]=[CH:39][C:40]=4[O:53][CH2:52][N:43]3[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 80 °C
Yield: 49.1 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.199 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (56 mg, 0.199 mmol) and K3PO4.3H2O (159 mg, 0.597 mmol) in dioxane/H2O (0.8 mL/0.2 mL) was added Pd2(dba)3 (9 mg, 0.01 mmol) and X-Phos (9 mg, 0.02 mmol) under N2. The mixture was heated at 80° C. for 1 hour. The mixture was then diluted with water (30 mL) and extracted with EtOAc (15 mL×3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether/EtOAc=1:1.5) to provide the pure product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, 48.8%). 1H-NMR (CDCl3, 400 MHz) δ: 7.99 (s, 1H), 7.93˜7.96 (m, 2H), 7.65 (s, 1H), 7.45˜7.50 (m, 2H), 7.17˜7.21 (m, 4H), 7.10 (d, J=8.0 Hz, 1H), 6.81˜6.85 (m, 1H), 5.98 (s, 3H), 3.35 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 615.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[CH2:6][C:7]1=[O:14])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Product: COc1cc2c(cc1OC)N(C(C)=O)C(=O)C2
Temperature: 130 °C

Procedure:
16.0 g of 5,6-dimethoxy-2-indolinone (according to Hahn; Tulus; Chem. Ber. 74, 500 (1941)) are dissolved in 170 ml of acetic anhydride and stirred for more than 3 hours at 130° C. After cooling the residue is filtered off, washed with ether and dried in vacuo at 100° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]1([CH3:21])[CH3:20].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:20][C:13]1([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([CH3:18])([CH3:19])[N:12]1[O:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1ccccc1CON1C(C)(C)CCCC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCCC(C)(C)N1OCc1ccccc1C(=O)O
Reaction time: 24 h
Yield: 77.2 %

Procedure:
2-(2,2,6,6-Tetramethylpiperidin-1-yloxymethyl)-benzoic acid methyl ester (946 mg, 3.1 mmol) was diluted in THF/methanol (1:1, 10 mL). To the solution was added 25% NaOH (aq) (5 mL) at room temperature. After 24 h, the reaction was acidified with 10% HCl and extracted with CH2Cl2 (×3). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (Hex/EtOAc=1:1) to give 2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)-benzoic acid as a white solid (697 mg, 77%). Rf=0.6 (Hex:EtOAc=1:1); 1H NMR (300 MHz, CDCl3): δ 8.01 (d. J=7.8 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 5.27 (s, 2H), 1.69-1.46 (br m, 6H), 1.22 (s, 12H): 2-(2,2,6,6-Tetramethylpiperidin-1-yloxymethyl)-benzoic acid (697 mg, 2.39 mmol) and Nhydroxysuccinimid (330 mg, 2.87 mmol) were dissolved in dry CH2Cl2 (10 mL) under argon atmosphere. A solution of N,N′-dicyclohexylcarbodiimide (DCC) (592 mg, 2.87 mmol) was slowly added to the solution at 0° C. After 10 h of stirring, the reaction mixture was filtered through a short pad of silica gel with CH2Cl2 and the filtrate was concentrated to give a crude product. Purification of the crude product by column chromatography on silica gel (Hex:EtOAc=2:1) gave the final product as a white solid (680 mg, 73%). mp=145° C.; Rf=0.5 (Hex:EtOAc=2:1); 1H NMR (500 MHz, CDCl3): δ 8.17 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 5.22 (s, 2H), 2.90 (s, 4H), 1.48 (br s, 4H), 1.36 (br s, 1H), 1.32 (br s. 1H), 1.19 (s, 6H), 1.17 (s, 6H); 13C NMR (125 MHz, CDCl3) 169.48, 161.45, 143.56, 134.61, 131.29, 127.39, 126.78, 121.73, 76.07, 60.14, 39.86, 33.07, 25.86, 20.64, 17.29; IR (neat): 2932 (w), 1767 (m), 1741 (s), 1468 (w), 1375 (w), 1229 (m), 1207 (s), 1132 (w), 1071 (m), 983 (S), 843 (w), 737 (s), 647 (m) cm-1; Anal. Calcd for C21H28N2O5: C. 64.93; H, 7.27; N, 7.21, Found; C. 64.95; H, 7.15; N, 7.10.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:19](S(C)(=O)=O)=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1.O>C1COCC1>[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]3[N:20]4[CH2:21][CH2:22][CH2:23][N:24]([C:25]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[C:19]4=[N:18][C:13]=3[CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(S(C)(=O)=O)nc2cnc3cc(Br)ccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCn2c1nc1cnc3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
Under a nitrogen atmosphere, potassium tert-butoxide (6 mL of a 1 M solution in THF) was added to a solution of tert-butyl 3-(7-bromo-2-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (2.3 g, 4.8 mmol) in THF (50 mL). The reaction was stirred overnight at room temperature, and an analysis by LC/MS indicated the presence of starting material. Additional potassium tert-butoxide solution (4 mL) was added, and the reaction was stirred for an additional 30 minutes at room temperature. The reaction was poured into water. A solid was present and was washed with water and dried for three days in a vacuum oven to provide 0.95 g of tert-butyl 3-bromo-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:20].[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:37])[F:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2nc(NCC(F)(F)F)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCC(F)(F)F)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (116 mg, 0.47 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41062 (160 mg, 0.47 mmol) at RT followed by a 2 N aq. solution of LiOH (0.47 mL, 0.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 30 mg of 6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to give 6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride SLA 41064 as a yellow solid (31 mg, 11% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([NH2:22])=[O:21])=[CH:14][CH:13]=1)([O-])=O.C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO.CN(C=O)C.O>[N:10]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:1][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([NH2:22])=[O:21])=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccccc1-c1ccc(CNc2ccccc2[N+](=O)[O-])cc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1-c1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-[(2-nitro-phenylamino)-methyl]-phenylbenzamide (14) (74.9 mmol) in anhydrous EtOH and anhydrous DMF (75 mL) was slowly added sodium methoxide (30% w/w) (375 mmol) at room temperature under argon atmosphere, followed by heating to 60° C. for 2 h. After cooling to ambient termperature, the solution was diluted with water (700 mL) and then acidified with saturated citric acid. The resulting precipitate was collected on a sintered funnel while rinsing with water. The crude product was recrystallized in hot EtOH.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:18][C@@H:17]4[CH2:19][C@H:14]3[C:15](=[O:20])[O:16]4)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:22][C:23]1([C:26]#[N:27])[CH2:25][CH2:24]1.C(C(CCCC)C([O-])=O)C.[Na+].Cl.[Cl-].[Na+]>O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:13]3[CH2:18][C@@H:17]([OH:16])[CH2:19][C@H:14]3[C:15]([NH:22][C:23]3([C:26]#[N:27])[CH2:25][CH2:24]3)=[O:20])=[O:12])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: N#CC1(N)CC1
Reactant: O=C1O[C@H]2C[C@@H]1N(C(=O)C1(c3ccc(Cl)cc3)CC1)C2
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(NC(=O)[C@@H]2C[C@H](O)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1
Temperature: 53 °C
Reaction time: 20 h
Yield: 88.1 %

Procedure:
A mixture of (1S,4S)-5-(1-(4-chlorophenyl)cyclopropanecarbonyl)-2-oxa-5-azabicyclo[2.2.1]heptan-3-one (Example 457a; 10.578 g), 1-aminocyclopropanecarbonitrile hydrochloride (5.94 g), sodium 2-ethylhexanoate (9.44 g) in water (54 mL) was stirred at 52-54° C. for 20 hr. The reaction mixture was diluted with 36 mL tetrahydrofuran. Concentrated hydrochloric acid (1.9 mL) and sodium chloride (18.09 g) were added. The reaction mixture was stirred for 15 min, then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was crystallized in a mixture of ethyl acetate and heptane to yield 11.94 g (88%) of the title compound as a white solid. MS (ESI): m/z=374.12 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.I[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:29][N:28]=2)[CH3:26])=[O:23])=[CH:17][CH:16]=1.ON1C2N=CC=CC=2N=N1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([NH:24][C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:38])([F:36])[F:37])=[CH:29][N:28]=2)[CH3:26])=[O:23])=[CH:19][CH:20]=1
Reactant: C[C@@H](NC(=O)Cc1ccc(I)cc1)c1ccc(OCC(F)(F)F)cn1
Reactant: Cn1c(B(O)O)cc2ccccc21
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)Cc1ccc(-c2cc3ccccc3n2C)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 150 °C
Yield: 79.2 %

Procedure:
To a mixture of (1-methyl-1H-indol-2-yl)boronic acid (37.7 mg mg, 0.215 mmol), 2-(4-iodophenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (50.0 mg, 0.108 mmol), tricyclohexylphosphine (0.7 mg, 0.003 mmol), 1-hydroxy-7-azabenzotriazole (101 mg, 0.744 mmol) and Pd2(dba)3 (1 mg, 0.001 mmol) were added dioxane (0.4 mL) and a solution of K3PO4 in H2O (0.2 mL, 1.27 M). The resulting solution was heated in microwave at 150° C. for 0.5 hr. The reaction was completed and diluted with EtOAc. The water later was removed. The remaining organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase HPLC to give the product as a TFA salt (40 mg, 79%). 1H NMR (CDCl3, 400 MHz) δ 8.22 (dd, J=0.8, 2.8 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.49 (dd, J=2.0, 6.4 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.37 (d, J=6.4, 1H), 7.27-7.19 (m, 2H), 7.14 (t, J=8.0 Hz, 1H), 6.80 (d, J=7.2 Hz, 1H), 6.56 (s, 1H), 5.14 (quintet, J=7.2 Hz, 1H), 4.38 (q, J=8.0 Hz, 2H), 3.75 (s, 3H), 3.65 (s, 2H), 1.44 (d, J=6.8 Hz, 3H); HRMS (ES) [M+1]+ calcd for C26H25F3N3O2: 468.1893, Found: 468.1889. FLIPR alpha1I IP=36 nM.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:10]1)C1C=CC=CC=1.[ClH:23].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:23].[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C@H:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc([C@H]2CCC[C@H](NCc3ccccc3)C2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cccc([C@H]2CCC[C@H](N)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(trans)-N-Benzyl-N-[3-(3-methoxyphenyl)cyclohexyl]amine (6.59 g) was dissolved in ethyl acetate (20 ml), and then 4 N HCl-ethyl acetate solution (20 ml) was added while cooling on ice, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, 10% palladium-carbon (1.3 g) and acetic acid (60 ml) were added for hydrogen addition at an external temperature of 80° C. for 8 hours. After filtering off the solvent from the reaction solution, the solvent was concentrated under reduced pressure (repeated azeotropy with ethanol and toluene) to give 5.40 g of (trans)-3-(3-methoxyphenyl)cyclohexylamine hydrochloride (quantitative yield).
Reaction SMILES: FC(F)(F)S(O[C@@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])(=O)=O.[N-:17]=[N+:18]=[N-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOCC>[N:17]([C@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)COC(=O)[C@@H]1OS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(C)COC(=O)[C@H]1N=[N+]=[N-]
Reaction time: 5 h

Procedure:
To a solution containing the product from Example 174A (4.6 g, 17.56 mmol) in toluene (80.0 mL) was added tetra-n-butylammonium azide (5.0 g, 17.57 mmol) at room temperature, and the mixture was stirred for 5 hours. The reaction was diluted with ether and washed with water, dilute NaHCO3, 10% citric acid and brine. The organic layer was dried over MgSO4, filtered and concentrated to give the crude product, which was used without further purification (2.79 g).