Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)[CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[CH:20]=[C:19]2[CH:24]([CH3:26])[CH3:25])=[O:13].[H][H].N#N>C(O)C.[Pd].C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:31][CH2:32]2)[CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[CH:20]=[C:19]2[CH:24]([CH3:26])[CH3:25])=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Reaction time: 0.17 h
Yield: 103.4 %

Procedure:
1,1-Dimethylethyl 4-[7-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1-methyl-3-(1-methylethyl)-1H-indol-5-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate (0.27 g, 0.507 mmol) was dissolved in ethanol (10 mL) and placed in a funnel under a N2 stream for 10 min. Palladium on carbon (0.081 g, 0.076 mmol) was added and the reaction placed alternatingly under N2 and H2 via a 3-way valve. Switched atmosphere to hydrogen (balloon) and stirred at RT overnight. Placed reaction back under N2, diluted with DCM, and added Celite. The mixture was stirred for 5 min, then filtered through analytical grade Celite and washed with 10% MeOH. Solvent was removed in vacuo giving a residue that was dried on hi-vacuum for 1 h to give 1,1-dimethylethyl 4-[7-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1-methyl-3-(1-methylethyl)-1H-indol-5-yl]-1-piperidinecarboxylate (0.28 g, 0.524 mmol, 103% yield). MS (ES) [M+H]+ 535.0.
Reaction SMILES: [C:1](O)(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC.CN(C([O:32]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:58][C:59]#[N:60]>CCOC(C)=O>[OH:23][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:58]=1[C:59]([NH2:60])=[O:32]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC#N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 2-((2-(2-hydroxybenzamido)ethyl)methyl)amino)ethylcarbamate (380 mg, 1.13 mmol) was taken up in 5 mL of a 25% TFA in CH2Cl2 and allowed to stand at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to afford the TFA salt of N-(2-((2-aminoethyl)(methyl)amino)ethyl)-2-hydroxybenzamide. This material was taken up in 10 mL of CH3CN along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 370 mg, 1.13 mmol), HATU (472 mg, 1.24 mmol) and DIEA (0.59 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl25% MeOH) afforded 420 mg of N-(2-((2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)methyl)amino)ethyl)-2-hydroxybenzamide. MS (EI) called for C34H49N3O3: 547.38; found: 548 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:15]=[O:16])=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][CH2:18][O:14][C:11]1[CH:10]=[C:9]([CH:15]=[O:16])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: O=Cc1cc(O)ccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(-c2ccc(Cl)cc2)c(C=O)c1
Temperature: 70 °C

Procedure:
A mixture of EXAMPLE 125A (0.5 g), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.771 g) and cesium carbonate (1.4 g) was suspended in anhydrous N,N-dimethylformamide (5 mL). The reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column purification with 0-5% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:29](=[O:30])[O:28][CH2:27]2.O>CC(N(C)C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([NH:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[C:29](=[O:30])[O:28][CH2:27]3)=[O:13])=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Reactant: Nc1ccc2c(c1)COC2=O
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)Nc1ccc2c(c1)COC2=O
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
1.7 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid is dissolved in 25 ml of dimethyl acetamide and mixed under argon at −8° C. with 0.37 ml of thionyl chloride. After 20 minutes of stirring at −3 to +3° C., 700 mg of 5-aminophthalide is added. It is stirred for 1.5 hours at room temperature, then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na2SO4), and after the solvent is concentrated by evaporation and after chromatography of the crude product on silica gel with hexane/ethyl acetate (80:20), 1.5 g of 5-[4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeroylamino)-phthalide is obtained as a foam.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]2[N:24]([C:25](=[O:35])[C:26]=1[O:27]CC1C=CC=CC=1)[CH2:23][CH2:22][O:21][C:20]2([CH3:37])[CH3:36])=[O:16])=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]2[N:24]([C:25](=[O:35])[C:26]=1[OH:27])[CH2:23][CH2:22][O:21][C:20]2([CH3:37])[CH3:36])=[O:16]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN=[N+]=[N-])c(OCc1ccccc1)c2=O
Agent: [Pd]
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN)c(O)c2=O

Procedure:
The title compound can be prepared by hydrogenolysis (H2, 10% Pd—C) of intermediate 195, (R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide. 1H NMR (400 MHz, MeOD) δ ppm: 7.54 (1H, dd, J=7.0 Hz), 7.25–7.13 (2H, m), 4.62 (2H, m), 4.17 (1H, d, J=15.6 Hz), 4.07 (2H, m), 3.99 (2H, m,), 3.23 (2H, d, J=3.1 Hz), 2.79–2.59 (3H, m), 2.14 (1H, m), 1.66 (6H, s). HRMS calcd for C22H27N5O5F: 460.1996. Found 460.2014.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH2:17]Cl>>[ClH:14].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH2:17][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)=[CH:8][CH:9]=1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Product: Cl
Product: Clc1cccc(Cl)c1COc1ccc(Cc2ncc[nH]2)cc1

Procedure:
This compound is produced according to Example 2 from 4-(1-imidazolylmethyl)-phenol and 2,6-dichlorobenzyl chloride.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[OH-].[Li+].C(OC1C=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20]N=1)C>CC(C)CO>[CH2:22]([O:23][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH:21]([CH3:25])[CH3:20]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CCOc1ccc(C(=O)O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)CO
Product: CC(C)COc1ccc(C(=O)O)cn1
Temperature: 35 °C
Yield: 25 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 25% yield starting from ethyl 6-chloronicotinate and 2-methylpropan-1-ol. The reduction was performed using 3 equiv of lithium hydroxide, the reaction mixture was stirred at 35° C. over night. The product contains 58% of 6-ethoxynicotinic acid; MS (ESI) m/z 194[M−H+].
Reaction SMILES: I[C:2]1[C:3]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][CH:6]=1.I[C:15]([F:20])([F:19])[CH:16]([F:18])[F:17]>[Cu].CN(C=O)C>[F:12][C:7]([F:13])([C:3]1[C:2]([C:15]([F:20])([F:19])[CH:16]([F:18])[F:17])=[CH:6][NH:5][N:4]=1)[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)C(F)(F)I
Reactant: FC(F)(F)C(F)(F)c1n[nH]cc1I
Agent: [Cu]
Solvent: CN(C)C=O
Product: FC(F)C(F)(F)c1c[nH]nc1C(F)(F)C(F)(F)F
Temperature: 122.5 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
4-Iodo-3-pentafluoroethyl-1H-pyrazole (6.24 g), copper powder (3.81 g), Iodo-1,1,2,2-tetrafluoroethane (9.12 g) and DMF (30 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 120-125° C. After cooling to room temperature, the insoluble material was filtered off through Celite and washed with diethyl ether. The filtrate was diluted with water and extracted with diethyl ether. The organic phase was washed with water and dried over sodium sulfate, and concentrated under the reduced pressure. The crude product was distilled under reduced pressure to obtain 3-pentafluoroethyl-4-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole (0.60 g), bp. 125-135° C./20 mbar.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:15]>>[Cl:15][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: OCc1ccc2c(c1)OCCO2
Reactant: O=S(Cl)Cl
Product: ClCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOCl2 (10 mL) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL×3). The combined organic layers were washed with NaHCO3 (sat solution), water and brine, dried over Na2SO4 and concentrated to dryness to obtain 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12 g, 88% over two steps), which was used directly in next step.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.[OH:27][NH2:28].[OH-].[K+]>ClCCl>[OH:27][NH:28][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=3)(=[O:25])=[O:24])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(c1)CC(NS(=O)(=O)c1cccc(Cl)c1)CC2

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with 3-chlorobenzenesulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 381, exp (MH+) 381. 1H NMR (CD3OD, 400 MHz), 7.90 (m, 1H), 7.84 (d, 1H, J=8.0 Hz), 7.66 (d, 1H, J=8.4 Hz), 7.59 (t, 1H, J=8.0 Hz), 7.47 (d, 1H, J=8.0 Hz), 7.36 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 3.55 (m, 1H), 2.95 (m, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C1(S([O-])=O)C=CC=CC=1.C1(C)C=CC=CC=1.[Cl:27]Cl>O>[C:1]1([S:7]([Cl:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(Cl)c1ccccc1
Yield: 133.1 %

Procedure:
A reactor was charged with 29.3 g of sodium benzenesulfinate (0.14 mole) obtained by the fourth step, and the benzenesulfinate was dissolved in 65 mL of water. Then, 105 mL of toluene was charged, and 10.3 g (0.1456 mole, 1.04 times moles) of chlorine was, little by little, blown into the reactor at a temperature of 18 to 20° C. The reaction solution was aged at the same temperature of 18 to 20° C. with stirring, and separated into an organic layer and an aqueous layer. The organic layer was washed with 90 g of a 3% aqueous sodium chloride solution and then concentrated at a reduced pressure and 45° C. or less to obtain 32.9 g of a benzenesulfonyl chloride solution. Gas chromatographic quantitative analysis revealed that the concentration of benzenesulfonyl chloride in the organic layer was 70.7% (weight; 24.21 g, 0.1371 mole), and the yield was 93.9%
Reaction SMILES: Br[C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[N+:8]([O-:10])=[O:9].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[K].CN([CH:26]=[O:27])C>>[CH3:7][C:4]1[C:3]([N+:8]([O-:10])=[O:9])=[C:2]([NH:13][C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:12]([O:27][CH3:26])=[O:11])=[O:21])[S:6][N:5]=1
Reactant: O=C1c2ccccc2C(=O)N1[K]
Reactant: Cc1nsc(Br)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Product: COC(=O)c1ccccc1C(=O)Nc1snc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-3-methyl-4-nitro-isothiazole (200 mg, 0.8967 mmol), (1,3-dioxoisoindolin-2-yl)potassium (174.4 mg, 0.9415 mmol) in dry DMF (2 mL) was stirred at RT overnight. The mixture was quenched by the addition of methanol, stirred at RT for 1 h, then the reaction mixture was concentrated in vacuo. The residue was triturated in a small volume of dry MeOH. The precipitate was collected by filtration and dried in vacuo, yielding methyl 2-((3-methyl-4-nitroisothiazol-5-yl)carbamoyl)benzoate as a pale yellow solid. (165 mg, 57%) MS (ES+) 322.1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([CH:33]=[CH:34][C:35]=1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:12]([OH:32])[CH2:13][N:14]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:15]([CH3:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH2:37]([O:36][C:35]1[CH:34]=[CH:33][C:11]([CH:12]([OH:32])[CH2:13][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]([CH3:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[CH:10][C:9]=1[NH:8][C:1](=[O:3])[CH3:2])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(Cc1ccc(O)cc1)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c(N)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(O)CN(Cc2ccccc2)C(C)Cc2ccc(O)cc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 20 ml. of acetic anhydride there was dissolved 4.0 g. of 3-amino-4-benzyloxy-α-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl] benzyl alcohol [A] prepared above and after heating the mixture to 65°-80° C for one hour and 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of 15 ml. of methanol and 2.0 g. of potassium hydroxide and the solution was stirred for one hour at room temperature. Then, methanol was distilled off under reduced pressure and after water was added to the residue, the residue was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and dried. Thereafter, by distilling off the solvent, 3.8 g. of a crystalline powder of 4-benzyloxy-3-acetylamino-α-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl] benzyl alcohol [A] was obtained. By recrystallizing 2.0 g. of the product thus obtained from 20 ml. of ethanol 1.6 g. of the crystalline pure product was obtained, melting at 141°-143° C.______________________________________Elemental analysis for C32H36N2O4 : C(%) H(%) N(%)______________________________________Calculated: 75.55 6.92 5.34Found: 75.62 7.03 5.21______________________________________
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32](Cl)=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC
Yield: 84 %

Procedure:
21.7 g of 2-(3,4-dimethoxyphenyl)ethylamine are dissolved in 150 cc of anhydrous chloroform and then the solution is added to 15.2 g of anhydrous triethylamine. The solution is cooled at a temperature between 5° and 10° C. and then, under stirring, there is added the 3,4-dimethoxyphenylacetyl chloride prepared in part (a), 26 g, dissolved in 80 cc of anhydrous chloroform. The temperature is allowed to rise to room temperature. It is then warmed under reflux for eight hours. After cooling the mixture, by addition of an additional portion of chloroform, 200 cc, the organic phase is washed with water and then with 5% hydrochloric acid and an additional amount of water, then 5% sodium hydroxide and finally water. The organic phase is dried over anhydrous sodium sulfate and after filtering, the solvent is evaporated under reduced pressure. The solid thus obtained is recrystallized from absolute ethanol. The pure amide, 36 g, is obtained in a yield of 84%, m.p. 128° C. The substance gives a single spot on chromatography using ethanol as eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]4[CH:15]([CH2:16][C:8]=3[N:7]([CH3:17])[C:6]=2[N:18]=1)[CH2:14][CH2:13][CH2:12]4.[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][NH:29][C:28](=[O:32])[CH:27]=2)=[C:22]([F:35])[CH:21]=1>>[ClH:19].[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][N:29]([C:2]3[CH:3]=[CH:4][C:5]4[C:9]5[CH2:10][N:11]6[CH:15]([CH2:16][C:8]=5[N:7]([CH3:17])[C:6]=4[N:18]=3)[CH2:14][CH2:13][CH2:12]6)[C:28](=[O:32])[CH:27]=2)=[C:22]([F:35])[CH:21]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN1CCCC1C2
Product: Cl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5F)cc4=O)nc31)CN1CCCC1C2
Yield: 53.7 %

Procedure:
2-Bromo-11-methyl-5,7,8,9,9a,10-hexahydro-11H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (150 mg, 0.491 mmol) and 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (124 mg, 0.491 mmol) were reacted following the procedure for Example 2 (step b) to provide the title compound (68 mg, 27%) as a yellow solid: mp 210-220° C.; 1H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.84-7.82 (d, J=7.8 Hz, 1H), 7.65-7.62 (t, J=Hz, 1H), 7.56-7.53 (dd, J=9.9, 2.0 Hz, 1H), 7.39-7.37 (m, 2H), 6.17-6.16 (dd, J=7.8, 2.7 Hz, 1H), 6.06 (d, J=2.7 Hz, 1H), 5.20 (s, 2H), 4.82-4.78 (dd, J=14.0, 2.4 Hz, 1H), 4.35-4.30 (m, 1H), 3.91-3.71 (m, 5H), 3.50 (m, 1H), 3.30-3.26 (m, 1H), 3.12-3.06 (m, 1H), 2.47-2.42 (m, 1H), 2.19-2.07 (m, 2H), 1.93-1.86 (m, 1H); ESI MS m/z 479 [M+H]+; HPLC (Method B) 98.1% (AUC), tR=13.9 min.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH2:71]([CH2:73][NH2:74])[OH:72]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:74][CH2:73][CH2:71][OH:72])=[O:19])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:33])[CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NCCO)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure G. To a solution of 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 30 mg, 0.065 mmol) in DMF (3 ml) was added BOP (35 mg, 0.090 mmol) and DIPEA (17 mg, 0.098 mmol), followed by ethanolamine (6 mg, 0.098 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18].C(N(C(C)C)C(C)C)C.[CH3:28][O:29][CH2:30]Cl>COCCOC>[CH3:28][O:29][CH2:30][O:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18]
Reactant: COCCl
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CC(O)C1=O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COCOC1CC(c2ccccc2)([N+](=O)[O-])CN(C)C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 50 mg (0.2 mmol) rac-3-hydroxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one and 52 ul (0.3 mmol) N-ethyl diisopropylamine in 1,2-dimethoxyethane were added 23 ul (0.3 mmol) chloromethyl methyl ether at room temperature. After 1 hour, the solution was heated in a 60° C. oil bath for 20 hours. The mixture was cooled to room temperature. 52 ul (0.3 mmol) N-ethyl diisopropylamine and 23 ul (0.3 mmol) chloromethyl methyl ether were added. The mixture was heated in a 60° C. oil bath for 4 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed once with water. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 30 mg (51%) of the title compound as a yellow oil. MS (m/e): 295.2 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:6]=[CH:7][C:8]1=[N:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]1=2.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30]O.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:6]=[CH:7][C:8]1=[N:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13]2[CH:18]=[C:17]([O:19][CH2:30][C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)[CH:16]=[CH:15][C:14]1=2
Reactant: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccc(O)cc21
Reactant: OCc1cccs1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccc(OCc3cccs3)cc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 6.8 %

Procedure:
To a stirred solution of 50 mg (0.14 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-8-ol (prepared as described in Example 157) in 5 ml of dry tetrahydrofuran was added 0.014 ml (0.14 mmol) of thiophene-2-methanol and 0.053 ml (0.21 mmol) of tributylphosphine. The solution was cooled, under an atmosphere of nitrogen, to 0° C. and 37 mg (0.21 mmol) of 1,1′-azobis(N,N-dimethylformamide) was added. The mixture was allowed to warm up to room temperature and then stirred for 16 hours. A further 0.053 ml (0.21 mmol) of tributylphosphine and 37 mg (0.21 mmol) of 1,1′-azobis(N,N-dimethylformamide) were added and the mixture stirred for a further 4 hours. The mixture was filtered and the filtrate evaporated and then chromatographed on silica gel using dichloromethane/methanol (98:2) for the elution. There was obtained 4.2 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-8-(2-thenyloxy)-1H-1,4-benzodiazepine as an orange gum MS: m/e 442.8 [M+H]+.