Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N>CCCCCC.ClCCl>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([NH2:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Agent: N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: NC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reaction time: 1 h

Procedure:
[2-(1-cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (100 mg) and triethylamine (53 mg) were added to dichloromethane (2ml). After addition of diphenylphosphoryl azide (145 mg) with stirring under ice cooling, the mixture was stirred at room temperature for 1 hour. Conc. aqueous ammonia (5 ml) was added to the reaction mixture and stirring was further continued for 1 hour. Hexane (5 ml) was added and crystals deposited were filtered off. The crystals were recrystallized from dichloromethane and methanol to obtain the title compound as needles, m.p. 244°-245° C., yield 64 mg (64.6%).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:46]([CH3:48])[CH3:47]>CN(C)C=O.O>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:46]([CH3:48])[CH3:47])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 2-iodopropane (226 μl, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (287 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](I)[CH:3]=1.[C:12]1([Mg]Cl)[CH:17]=CC=C[CH:13]=1.C([Cu])#N.C(Br)C=C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:17][CH:12]=[CH2:13])[CH:3]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1I
Agent: N#C[Cu]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To 4-fluoro-2-iodo-1-nitrobenzene (40.0 g, 150 mmol) in THF (200 mL) at −40° C. was added phenylmagnesium chloride (80.0 mL, 2M in THF, 161 mmol) dropwise. The reaction was stirred for 30 min followed by dropwise addition of CuCN.2LiCl (26.0 g, 150 mmol) in THF. The mixture was stirred an additional 30 min at which time allyl bromide (20.0 g, 161 mmol) was added. The reaction was stirred at −40° C. for 2 h followed by rt overnight. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step B (11.0 g, 60.7 mmol, 42%). 1H NMR (400 MHz, CDCl3) δ ppm 3.70 (d, J=6.4 Hz, 2H), 5.08-5.71 (m, 2H), 6.87-6.02 (m, 1H), 7.01-7.11 (m, 2H), 7.95-8.05 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[N:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:27][CH:28]=[C:29]([CH:31]=O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:31][C:29]3[N:30]=[C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[S:27][CH:28]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[N:14]=[CH:13][N:12]=1
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)ncnc1OC
Product: COc1ncnc(OC)c1C1CCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(4,6-dimethoxypyrimidin-5-yl)pentanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 410.79 g/mol.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22](O)[CH2:21][CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([O:1][C:2]1[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=1)[CH2:21][CH2:20][CH2:19]2
Reactant: OC1CCCc2cc(F)ccc21
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OC2CCCc3cc(F)ccc32)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.82-1.88 (1H, m), 1.99-2.10 (2H, m), 2.28-2.34 (1H, m), 2.74-2.94 (2H, m), 5.35 (1H, t, J=4.0 Hz), 5.85 (1H, d, J=1.6 Hz), 6.84-6.89 (2H, m), 7.29 (1H, dd, J=5.6 Hz, 8.4 Hz), 7.36 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.63 (1H, d, J=2.0 Hz), 7.86 (1H, s), 8.65 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H15FN4O, 335. Found, 335.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:18][C:19]4[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=4[C:21]([O:23]C)=[O:22])=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].Cl.O>CO>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:18][C:19]4[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=4[C:21]([OH:23])=[O:22])=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccccc1C(=O)O)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 60 °C
Yield: 92.7 %

Procedure:
A suspension of methyl 2-{[(1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-8-yl)carbonyl]amino}benzoate (503 mg, 1.3 mmol) in methanol (7 mL) and 2M NaOH solution (2.0 mL, 4.0 mmol) is heated at 60° C. for 3 h. 1M HCl solution (10 mL) and water (80 mL) are added. The resulting solid is collected by filtration and dried to afford the title compound (438 mg, 90%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C[C:11]#[N:12].NC.[OH-].[Na+]>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:12][CH3:11])[N:7]=1
Reactant: CC#N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of cyanuric chloride (300 mg, 1.63 mmol, 1.00 equiv) in 1:1 CH3CN:H2O (2.7 mL) at 0° C. was added NH2Me (2.0 M solution in THF, 0.81 mL, 1.6 mmol). The solution was treated with 1 N NaOH to maintain a pH of 9-10 and stirred for 5 min at 0° C. The resulting suspension was used in the next step without workup or purification. MS (ES+): m/e 178.9 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:42]2[CH:50]=[C:49]3[C:45]([C:46](C4C=CC=CC=4)=C(Br)C3=O)=[CH:44][CH:43]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:32])[C:2]=1[C:42]1[CH:50]=[CH:49][C:45]([CH3:46])=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Yield: 73 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and p-tolylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (73%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: CCOC(=O)c1ccc(Cl)c(O)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(Cl)c2)c1
Yield: 53 %

Procedure:
Following the method of Example 3, Step A, ethyl 4-chloro-3-hydroxybenzoate (5.75 g, 28.7 mmol), sodium hydride (0.724 g, 28.7 mmol), DM (30 mL), and 2-chloro-4-nitropyridine (4.54 g, 28.7 mmol) were combined to give the desired product (4.75 g, 47.8% yield) as a yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.CC[N:36]([CH:40]([CH3:42])C)[CH:37]([CH3:39])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:36]6[CH2:37][CH2:39][CH2:42][CH2:40]6)=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)=[O:33])[CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
To a solution of acid 225 (70 mg, 0.151 mmol), DIPEA (0.105 mL, 0.603 mmol) and pyrrolidine (0.025 mL, 0.301 mmol) in DMF (4 mL) was added HATU reagent (143 mg, 0.377 mmol). The mixture was stirred for 16 h at RT then partitioned between ethyl acetate and water. The organic phase was collected, washed with water, 1M NaOH, and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10 g cartridge), then using chromatotron (eluent MeOH/DCM, 5-10%) followed by trituration with a mixture Et2O/MeOH/Acetone to give title compound 226 (15 mg, 0.029 mmol, 19% yield) 1H NMR (400 MHz, DMSO-d6) δ (ppm): OH from carboxylic acid is missing, 9.66 (bs, 1H), 8.98 (dd, J=1.9, 0.9 Hz, 114), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.22 (dd, J=8.1, 1.9 Hz, 1H), 8.17 (dd, J=8.1, 0.9 Hz, 1H), 7.77 (dd, J=13.7, 2.5 Hz, 1H), 7.45 (bs, 1H), 7.37 (t, J=9.1 Hz, 1H), 7.26 (dd, J=8.9, 1.5 Hz, 1H), 6.62 (d, J=5.3, 0.8 Hz, 1H), 2.60-2.52 (m, 1H), 0.69-0.56 (m, 2H), 0.50-0.37 (m, 2H). MS (m/z): 465.3 (M+H)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:31][CH3:32])[CH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:22]>C(O)CC>[CH2:31]([N:23]([CH2:21][CH3:22])[CH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:25]1)[CH3:32]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)C1CCCCNC1
Solvent: CCCO
Product: CCN(CC)C1CCCCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-(diethylamino)-hexahydro-1H-azepine to give colorless crystals, mp. 222°-224° C. (n-propanol).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=1)[C:6]([OH:8])=[O:7]
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1ccc(C(=O)O)cc1F
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-3-fluorobenzoic acid (110 mg, 0.5 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (207 mg, 1.5 mmol), tetrakistriphenylphosphine Pd(0) (29 mg, 0.025 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (107 mg, 0.55 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (98 mg, 89%): LC-MS (ES) m/z=221 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]CC)=[O:25])=[C:12]2[O:29][CH2:30][CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[O:29][CH2:30][CH2:31][CH2:32][C:33]([F:34])([F:35])[F:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(C(=O)O)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 78.8 %

Procedure:
To a solution of ethyl 6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylate (6.57 g, 13 mmol) in ethanol (50 mL) was added an aqueous solution (20 mL) of sodium hydroxide (2.08 g, 52 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium, sulfate and concentrated under reduced pressure. The obtained, crystals were recrystallized from ethyl acetate-n-hexane to give 6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylic acid (4.89 g, 78.7%) as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[NH:19][CH:20]=[CH:21][N:22]=3)=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[OH:25]O.[OH-].[Na+].O>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[NH:19][CH:20]=[CH:21][N:22]=3)=[CH:9]2)=[CH:23][CH:24]=1)(=[O:25])[NH2:2]
Reactant: OO
Reactant: N#Cc1ccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-(4-Cyanobenzyl)-3-(1-imidazolylmethyl)indole (1.0 g) was dissolved in ethanol (10 ml) and 30% hydrogen peroxide (5 ml) and 6 N sodium hydroxide (5 ml) were added. The resulting mixture was stirred for 2 hours at 50° C. and then poured into water. The solid product was filtered off, washed with water and crystallised from ethanol to give 1-(4-carbamoylbenzyl)-3-(1-imidazolylmethyl)indole (0.65 g), m.p. 173°-175° C. Found: C, 72.63; H, 5.54; N, 16.29. C20H18N4O4 requires: C, 72.71; H, 5.49; N, 16.96.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([CH2:7]P(=O)(OC)OC)[CH2:4][O:3]1.[N:14]1([CH2:19][CH2:20][O:21][CH:22]2[CH2:34][CH2:33][C:25]3([CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]3)[CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.[H-].[Na+]>[N:14]1([CH2:19][CH2:20][O:21][CH:22]2[CH2:34][CH2:33][C:25]3([CH2:30][CH2:29][CH:28]([CH:31]=[CH:7][C:5]4[CH2:4][O:3][C:2](=[O:1])[CH:6]=4)[CH2:27][CH2:26]3)[CH2:24][CH2:23]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COP(=O)(CC1=CC(=O)OC1)OC
Reactant: O=CC1CCC2(CC1)CCC(OCCN1CCCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(C=CC2CCC3(CC2)CCC(OCCN2CCCC2)CC3)CO1
Yield: 108 %

Procedure:
Sodium hydride (0.045 mg, 60% dispersion in mineral oil) was added under nitrogen atmosphere and at room temperature, to a mixture of 0.740 g of dimethyl (2-oxo-[5H]-4-furyl)methylphosphonate and 0.080 g of 9-(2-(N-pyrrolidinyl)ethoxy)-3-formyl-spiro[5.5]-undecane (I-af, Ex. 30) in 5 ml of anhydrous tetrahydrofuran. After 2 hrs the reaction was quenched with sodium dihydrogenophosphate (5% water solution) and diluted with ethyl acetate; the organic layer was separated, dried over sodium sulfate and evaporated to dryness under reduced pressure The residue was purified by flash chromatography (SiO2 ; chloroform/methanol 80/20) to give 0.110 g of (EZ)-9-(2-(N-pyrrolidinyl)ethoxy)-3-(2-(2-oxo-[5H]-4-furyl)vinyl)-spiro[5.5]-undecane (I-b) as amorphous solid. TLC: Rf=0.32 (SiO2 plates, chloroform/methanol 80/20). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 6.50-5.70 (2H, m); 6.30 (1H, bs); 4.81 (2H, bs); 3.68 (2H, t), 3.45(1H, m), 2.75 (2H, t), 2.70-2.00 (5H, m); 1.97-0.99 (22H, m).
Reaction SMILES: [CH:1]([P:3](=[O:8])([O-:7])[O:4][CH2:5][CH3:6])=[CH2:2].C(OCC)(OCC)O[CH2:11][CH3:12].C(OCC)(=O)C>C(O)C>[CH:1]([P:3](=[O:7])([O:8][CH2:11][CH3:12])[O:4][CH2:5][CH3:6])=[CH2:2]
Reactant: CCOC(OCC)OCC
Reactant: C=CP(=O)([O-])OCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=CP(=O)(OCC)OCC
Temperature: 150 °C
Yield: 83.6 %

Procedure:
25 g of vinylphosphonic acid and 70 g of diethyl 2-acetoxyethanephosphonate were heated with stirring to 180° C. 252 g of diethyl 2-acetoxyethanephosphonate were then slowly added dropwise over 14 hours while the temperature gradually increased to 200° C. and ethyl acetate distilled off. The mixture was then stirred for 9 hours at 190° C. 190 g of crude monoethyl vinylphosphonate were obtained. Distillation produced 128 g of ethyl acetate and additionally 8 g of light ends which were trapped in a cold trap downstream from the apparatus. 95 g of the crude monoethyl vinylphosphonate and 124 g of triethyl orthoformate were refluxed for 8 hours at about 75° C. The temperature was then gradually increased in the course of 5.5 hours to 150° C. while ethyl acetate and ethanol distilled off. A further 100 g of triethyl orthoformate were then added at room temperature and the mixture was gradually heated again to 150° C. while light ends distilled off. A cold trap downstream from the apparatus collected less that 1 g. The mixture was then distilled and 96.5 g of diethyl vinylphosphonate were obtained. This corresponded to a yield of about 70%, relative to the amount of vinylphosphonic acid and diethyl 2-acetoxyethanephosphonate started with. During the reaction with the orthoester, about 160 g distilled off which contained 28 percent of ethanol and about 10 percent of diethyl ether in addition to about 60 percent of ethyl formate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: COc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1C
Reaction time: 27 h
Yield: 76.4 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.36 g, 6.15 mmol) and triethylamine (170 ml, 1.23 mmol) in THF (30 ml) was added 2-methoxyphenyl isocyanate (820 ml, 6.15 mmol), and the resulting mixture was stirred for 27 h. The mixture was concentrated to a small volume in vacuo, and hexane was added to the residue to give precipitate, which was collected by filtration to give tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methylphenylacetate (1.74 g, 76%) as a white crystalline material. mp 157–158° C.; 1H-NMR (CDCl3) δ 1.46 (s, 9 H), 2.30 (s, 3 H), 3.50 (s, 2 H), 3.76 (s, 3 H), 6.43 (s, 1 H), 6.83 (br d, J=8.4 Hz, 1 H), 6.95 (br d, J=8.0 Hz, 1 H), 6.98–6.99 (m, 2 H), 7.13 (br s, 1 H), 7.23 (br s, 1 H), 7.48 (d, J=8.8 Hz, 1 H), 8.14 (d, J=8.4 Hz, 1 H); MS (ESI) m/z 371 (M++H).
Reaction SMILES: C(OCC1C=C(C2N=C3CCCN3C=2C2C=CN=CC=2)SC=1)(=O)C.[SH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH2:45][CH2:44][CH2:43][N:35]3[C:36]=2[C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:28][CH:27]=1.C(N(CC)CC)C.[CH:53]1[CH:58]=[CH:57][C:56]([O:59][C:60](Cl)=[S:61])=[CH:55][CH:54]=1>COCCOCCOC>[O:59]([C:60]([S:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[C:34]3[CH2:45][CH2:44][CH2:43][N:35]3[C:36]=2[C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:30][CH:31]=1)=[S:61])[C:56]1[CH:57]=[CH:58][CH:53]=[CH:54][CH:55]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Agent: CC(=O)OCc1csc(-c2nc3n(c2-c2ccncc2)CCC3)c1
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: S=C(Oc1ccccc1)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice-bath cooled solution containing 1.0 q (3.4mmole) of 2 (4-mercaptophenyl) 3 (4-pyridyl) 6,7dihydro[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of diglyme is added 0.48 ml (3.5mmole) of phenyl chlorothionoformate. The reaction is allowed to warm to room temperature and heated at 40° to 120° C. for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.