Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:19][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21]Br.C([O-])([O-])=O.[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH:20]([CH3:21])[CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(O)cc1
Reactant: CCCC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCC(C)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Temperature: 70 °C
Yield: 75.4 %

Procedure:
[(R)-2-Hydroxy-1-(4-hydroxy-phenyl)-ethyl]-carbamic acid t-butyl ester (0.700 g 2.77 mmol), 2-methylpentyl bromide (0.548 g, 3.32 mmol) and Cs2CO3 (1.17 g, 3.59 mmol) were combined in DMF (15 ml). The reaction mixture was heated at 70° C. overnight. Saturated NH4Cl was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine, then dried over MgSO4, filtered and concentrated to give a white crude solid. The crude product was purified via column chromatography on silica gel (0%-50% ethyl acetate in hexanes) to afford the title compound (0.705 g, 76% yield of 2 steps) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 (d, 2H), 6.89 (d, J=8.6 Hz, 2H), 5.18 (d, J=7.1 Hz, 1H), 4.72 (br. s., 1 H), 3.81 (dd, J=9.0, 5.7 Hz, 3H), 3.72 (m, 1H), 3.49 (s, 2H), 2.54 (br. s., 1H), 1.95 (m, 1H), 1.35 (m, 11H), 1.02 (d, J=6.8 Hz, 3H), 0.93 (m, 3H); LCMS (ESI) m/e 338.2 [(M+H), calcd for C19H32NO4 338.5].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC(O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Temperature: -80 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
The reduction was carried out following the procedure described in Example 9. A solution of 180 mg (0.38 mmole) of ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1 H-tetrazol-1-yl)-3-oxo-6,8-nonadienoate in 10 mL of tetrahydrofuran at 0° C. was treated with triethylborane (0.9 mL, 1 M in tetrahydrofuran). After 2 hrs., the solution was cooled to -80° C. and treated with 30 mg of sodium borohydride followed by 200 μL of methanol. The crude product was purified by silica gel chromatography to yield 111.2 mg (62%) of the title compound.
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][CH2:8][NH:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][C:19]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([CH2:36][N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][C:38]4=[O:44])=[C:28]([CH:31](OC)[O:32]C)[N:29]=3)[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:11]=1)([CH3:5])([CH3:4])[CH3:3].C([O-])(O)=O.[Na+]>C1COCC1>[C:2]([O:6][CH2:7][CH2:8][NH:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][C:19]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([CH2:36][N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][C:38]4=[O:44])=[C:28]([CH:31]=[O:32])[N:29]=3)[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2C(=O)Nc1cc(NCCOC(C)(C)C)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc3c(nc2C=O)N(C(=O)Nc2cc(NCCOC(C)(C)C)c(C#N)cn2)CCC3)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrochloric acid (4 M, 10.9 ml) was added to a solution of N-(4-((2-(tert-butoxy)ethyl)amino)-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 120C, 1.3 g, 2.19 mmol) in THF (20 ml) at room temperature. After stirring for 1 h at room temperature, sat. aq. NaHCO3 was added and the mixture extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was triturated with Et2O to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[C:15](=[O:16])[NH:14][N:13]=[C:12]2[N:3]1[C:4]1[CH:5]=[C:6]3[N:19]([C@@:20]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=[CH:17][C:7]3=[CH:8][C:9]=1[O:10][CH2:11]2.C(OC(N1CC[C@](NC2C=C3C(=CC=2Br)OCC2N3[C@H](C)C(=O)NN=2)(C)C1)=O)(C)(C)C>>[CH3:1][C@@H:2]1[C:15](=[O:16])[NH:14][N:13]=[C:12]2[N:3]1[C:4]1[CH:5]=[C:6]3[N:19]([C@:20]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=[CH:17][C:7]3=[CH:8][C:9]=1[O:10][CH2:11]2
Reactant: C[C@H]1C(=O)NN=C2COc3cc4ccn([C@@]5(C)CCNC5)c4cc3N21
Agent: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(N[C@]4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Product: C[C@@H]1C(=O)NN=C2COc3cc4ccn([C@]5(C)CCNC5)c4cc3N21

Procedure:
Using a similar procedure as described in Example #162, Step F-G, (R)-1-methyl-10-((R)-3-methyl-pyrrolidin-3-yl)-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one (SFC (Table 1, Method 52) Rt=4.593 min 0.015 g, 5%) was prepared from (R)-3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (isomer C, SFC (Table 1, Method 54), Rt=1.752 min, 0.45 g, 0.9 mmol). 1H NMR (400 MHz, DMSO-d6) δ 10.71 (brs, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 6.31 (s, 1H), 5.09 (q, J=6.4 Hz, 1H), 4.54 (d, J=14.8 Hz, 2H), 3.11 (m, 4H), 2.45 (m, 2H), 1.57 (s, 3H), 1.32 (d, J=6.4 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.363 min; MS (ESI): m/z 340 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[S:13][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(Cc2ccc([N+](=O)[O-])cc2)n1

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (1.50 g), ethyl bromopyruvate (1.64 g) and ethanol (50 mL) was heated under reflux for 30 min. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 2-(4-nitrobenzyl)-1,3-thiazole-4-carboxylate was obtained as pale-yellow crystals (1.79 g, yield 81%) from a fraction eluted with hexane-ethyl acetate (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 122-123° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1.FC1C=C(C(=O)C)C=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:70]=[N:71][CH:72]=[C:73]([Cl:75])[CH:74]=2)[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[Cl:75][C:73]1[CH:74]=[C:69]([O:68][CH:65]2[CH2:64][CH2:63][N:62]([C:60](=[O:61])[CH2:59][NH:58][C:22]([C:19]3[CH:18]=[C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=4)[O:21][N:20]=3)=[O:24])[CH2:67][CH2:66]2)[CH:70]=[N:71][CH:72]=1
Reactant: NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1
Reactant: O=C(O)c1cc(-c2cccc(F)c2)on1
Agent: CC(=O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1)c1cc(-c2cccc(F)c2)on1
Reaction time: 8 h
Yield: 20.1 %

Procedure:
DIPEA (253 mg, 1.96 mmol) was added to a stirred solution 5-(3-fluoro-phenyl)-isoxazole-3-carboxylic acid (81 mg, 0.39 mmol) (prepared by the method used for the synthesis of Intermediate 25, starting from 3′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (56 mg, 0.41 mmol) and EDCI.HCl (79 mg, 0.41 mmol). After 2 minutes 2-amino-1-[4-(5-Chloro-pyridin-3-yloxy)-piperidin-1-yl]-ethanone hydrochloride (120 mg, 0.38 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from 1% methanol in ethyl acetate to afford 35 mg (19.5% Yield) of 5-(3-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 459, 100%. 1H NMR (300 MHz, DMSO-d6): δ 8.7 (t, 1H), 8.32 (d, 1H), 8.22 (s, 1H), 7.78 (t, 2H), 7.72 (s, 1H), 7.58 (m, 1H), 7.5 (s, 1H), 7.36 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 2H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1CCNC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with pyrrolidine (1.2 equiv) to give 158 (17.7 mg, M+1 367.1)
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][C@@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30].C[O-].[Na+]>COCCO>[C:36]([O:35][C:33]([NH:32][C@H:28]([CH2:27][CH2:26][NH:25][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[C:29]([OH:31])=[O:30])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)N[C@H](CCN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (25 mg, 0.08 mmol), (R)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (crude, 0.47 mmol) and sodium methoxide (24 mg, 0.44 mmol) were suspended in 2-methoxyethanol (5 mL). The resulting mixture was heated to reflux for 2 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 20 mg. MS: (−) m/z 505.35 (M−1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH2:1]([NH:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH2:26][CH2:25][Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CNc2ncnc3nc[nH]c23)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrCCn1cnc2c(NCc3ccccc3)ncnc21
Yield: 82 %

Procedure:
6-Benzylaminopurine (1 g, 4.43 mmol), K2CO3 (2.45 g, 17.8 mmol) and 1,2-dibromoethane (1.15 mL, 13.3 mmol) was stirred for 16 h at room temperature under CaCl2 plug in DMF (30 mL). After removal of the DMF by vacuum evaporation, the resulting material was diluted with water (30 mL) and extracted into ethyl acetate (EtOAc) (3×15 mL). The organic fractions were combined, washed with water (2×10 mL), dried over Na2SO4, purified by carbofiltration and concentrated under vacuum. The pure product was purified by flash chromatography—chloroform:methanol (9:1) was used as an eluent. Yield: 82%.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]([NH:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:30])[C:14]3=[O:40])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[C:14]3=[O:40])=[CH:11][CH:12]=2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetamido)acetate (20.0 mg, 0.0332 mmol) is dissolved in a mixture solvent of DCM (0.4 mL) and TFA (0.4 mL). The reaction mixture is stirred at room temperature for 3 h before removal of the solvent. The residue is purified by reparative LC/MS to provide the title compound; HPLC-MS calculated for C26H21ClF3N3O5 (M+H+) 548.1, found 548.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:22][C:6]2=[N:7][C:8]3[C:9]([CH2:10][CH:11]=[CH:12][C:13]=3[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:5]2[CH2:4][CH2:3]1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:1][C:2]1([CH3:23])[CH2:22][C:6]2=[N:7][C:8]3[C:9]([CH:10]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[CH:12][C:13]=3[O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:5]2[CH2:4][CH2:3]1
Reactant: CC1(C)CCC2=C3CC=CC(OCc4ccccc4)=C3N=C2C1
Reactant: CCCCCCCCBr
Product: CCCCCCCCC1C=CC(OCc2ccccc2)=C2N=C3CC(C)(C)CCC3=C21
Yield: 93.5 %

Procedure:
Using the procedure of Example 9, the alkylation of 4.3 g of 1,2,3,4-tetrahydro-3,3-dimethyl-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole from Example 59 was reacted with 2.92 g of 1-bromooctane to produce 5.5 g (94%) of 1,2,3,4-tetrahydro-3,3-dimethyl-6-phenylmethoxy -9-octyl-9H-dibenzo[b,d]pyrrole as a white solid after chromatographic purification.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([OH:18])=O)[C:13]=3[CH2:14][C:5]=2[N:4]2[CH:19]=[CH:20][N:21]=[C:3]12.Cl.CN(C)CCCN=C=NCC.O[C:35]1[C:43]2N=N[NH:40][C:39]=2[CH:38]=[CH:37][CH:36]=1.NC1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O.Cl.O>[C:39]1([NH:40][C:16](=[O:18])[CH2:15][C:12]2[C:13]3[CH2:14][C:5]4[N:4]5[CH:19]=[CH:20][N:21]=[C:3]5[C:2](=[O:1])[NH:7][C:6]=4[C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:43]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: Nc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12)Nc1ccccc1
Yield: 28.2 %

Procedure:
A solution of 0.56 g of (4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)acetic acid, 0.38 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.27 g of hydroxybenzotriazole and 1.1 ml of aniline in 20 ml of dimethylformamide is stirred under an argon atmosphere for 20 hours at a temperature in the region of 20° C. 20 ml of hydrochloric acid are added to the reaction mixture. The precipitate formed is filtered, washed with water and with isopropyl ether and then dried under reduced pressure (15 mm Hg; 2 kPa) at 20° C. The beige solid obtained is suspended in a solution of 20 ml of water and 84 mg of sodium hydrogencarbonate and then filtered and washed with water. The solid obtained is resuspended in 10 ml of 0.1N hydrochloric acid and then filtered, washed with water and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. 0.2 g of N-phenyl-2-(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)acetamide is obtained in the form of a white solid melting at a temperature greater than 260° C. (Analysis C21H16N402; % Calculated C: 70.77, H: 4.53, N: 15.72; % Found C: 70.74, H: 4.39, N: 15.64).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:13](B(O)O)=[C:12]([CH3:17])[O:11][N:10]=1.Br[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)(O)[O-].[Na+]>CCO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:9]1[C:13]([C:21]2[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=[CH:19][C:20]=2[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:12]([CH3:17])[O:11][N:10]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CCOC(=O)CCc1ccc(OC)cc1Br
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc(OC)cc1-c1c(C)noc1C
Temperature: 95 °C
Yield: 94.2 %

Procedure:
To a 25 mL RB flask fitted with a magnetic stirrer was charged with Toluene (1 mL). To the stirred solvent were added (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid (0.059 g, 0.42 mmol), ethyl 3-(2-bromo-4-methoxyphenyl)propanoate (0.08 g, 0.28 mmol), sodium bicarbonate (0.5 mL, 2M solution) in ethanol (1 mL) under argon atmosphere. After addition, the reaction mixture was purged with argon for 15 minutes. To the reaction mixture was added tetrakis (triphenylphosphine) palladium (0) (0.016 g, 0.01 mmol) and purged with argon for 10 minutes. After addition, the reaction mixture was heated at 95° C. for 5 h under argon atmosphere. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (5 mL) and brine solution (5 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product (0.08 g, yield: 94.10%) was taken for next step with out purification.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[CH3:8][Si:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][OH:12]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[O:6]=[C:5]([O:12][CH2:11][CH2:10][Si:9]([CH3:14])([CH3:13])[CH3:8])[CH2:4][CH2:3][C:2]([OH:7])=[O:1]
Reactant: O=C1CCC(=O)O1
Reactant: C[Si](C)(C)CCO
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)CCC(=O)O
Temperature: 25 °C
Yield: 118 %

Procedure:
Dihydrofuran-2,5-dione (8.0 g, 80 mmol) and 2-(trimethylsilyl)ethanol (5 g, 42.3 mmol) were dissolved in dry toluene (80 mL), followed by addition of DMAP (0.517 g, 4.23 mmol). The mixture was heated to reflux for 14 h. The mixture was cooled to rt, diluted with EtOAc (50 mL) and washed with aq. HCl (1 N, 3×30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford crude product as a white semi-solid (10.9 g, purity 85% as determined by 1H NMR, 100% yield), which is used in next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[Cl:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([Br:21])=[CH:4][N:3]=1.[C:22]([N:30]=[C:31]=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:22]([NH:30][C:31](=[S:32])[NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[Cl:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([Br:21])=[CH:4][N:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(N)ncc2Br)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(NC(=S)NC(=O)c3ccccc3)ncc2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A flask was charged with ethyl 3-(2-amino-5-bromopyridin-4-yloxy)-4-chlorobenzoate (2.76 g, 7.43 mmol), benzoyl isothiocyanate (1.05 ml, 7.80 mmol) and THF (100 mL). The reaction mixture was stirred at ambient temperature overnight and then concentrated. The residue was purified by silica gel column chromatography using 20% ether in hexanes to give the desired product (1.35 g, 34% yield) as light yellow solid.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:20][C@H:21]1[O:26][C@@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1.CC(C)([O-])C.[Na+].O1CCOCC1>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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O>[CH3:27][C@H:25]1[O:26][C@@H:21]([CH3:20])[CH2:22][N:23]([C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ccc3c(c2)OCCN(C(=O)OC(C)(C)C)C3)C[C@H](C)O1
Yield: 135.9 %

Procedure:
A solution of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.609 mmol), cis-2,6-dimethylmorpholine (0.370 ml, 3.00 mmol), X-phos (26.1 mg, 0.0548 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.6 mg, 0.0181 mmol), sodium tert-butoxide (131 mg, 1.37 mmol) and dioxane (6 ml) was stirred under an argon atmosphere for 2 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (300 mg, 90.4%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1
Reactant: Oc1cc(-c2ccccc2)nc2ccc(Cl)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(-c3ccccc3)cc(Cl)c2c1

Procedure:
From 25.5 g of 6-chloro-2-phenyl-4-quinolinol and 50 ml of phosphorus oxychloride treated according to the procedure of Example 4(b) there was obtained 24.86 g of 4,6-dichloro-2-phenylquinoline, mp 114°-116°.
Reaction SMILES: CS(O[CH2:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[O:19][CH2:20][O:21][C:14]=12)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=O)=O.[I-:22].[Na+]>C(C(C)=O)C>[CH2:20]1[O:19][C:15]2[C:14](=[C:13]([CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][I:22])[CH:18]=[CH:17][CH:16]=2)[O:21]1
Reactant: [I-]
Reactant: CCCCCC(COS(C)(=O)=O)c1cccc2c1OCO2
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCC(CI)c1cccc2c1OCO2
Yield: 86.6 %

Procedure:
Thus obtained 8.76 g (27.9 mmol) of 2-(2, 3-methylenedioxyphenyl)heptyl methanesulfonate was dissolved in 70 ml of methyl ethyl ketone, and the solution was mixed with 6.6 g of sodium iodide. The resultant mixture was refluxed under heating for 10 hours. After cooling, the precipitated salt was filtered off, and the filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel column (eluent; ethyl acetate/hexane=1/20) to give 8.36 g of 2-(2, 3-methylenedioxyphenyl)heptyl iodide as an oil.