Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].C(N(CC)CC)C>C1COCC1>[C:6]([O:10][C:1](=[O:4])[CH:2]=[CH2:3])(=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)Cl
Reactant: C=CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC(=O)C=C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Acrylic anhydride was synthesized in 70-80% yield as in the following example. Acryloyl chloride (2.7 g, 30 mmol) was added dropwise over 5 min to an ice-cooled solution of acrylic acid (2.0 g, 30 mmol) and triethylamine (2.8 g, 30 mmol) in THF (50 mL), and the solution was stirred at room temperature for 16 h. The NH4+Cl− precipitate was collected in a fritted glass filter, and the solvent was then removed from the filtrate by rotary evaporation. The residue was dissolved in CH2Cl2 (25 mL), washed twice with dilute aq. NaHCO3 (50 mL each) and once with satd. NaCl aq. soln. (50 mL), and dried over anhy. Na2SO4. After filtration and removing the solvent by rotary evaporation, 2.8 g (80%) of acrylic anhydride was obtained as a light yellow liquid. It was used without further purification. 1H NMR (CDCl3, 77.23 ppm): 6.04 (m, ═CH trans to CO2), 6.14 (m, ═CH gem to CO2), 6.50 (d, ═CH cis to CO2). 13C NMR (CDCl3/DMSO-d6): 127.4 (═CH), 134.7 (′CH2), 161.2 (C═O).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=[C:9]([CH3:23])[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])=[O:4].[CH2:30](O)[C:31]#[C:32][CH3:33]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=[C:9]([CH3:23])[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:30][C:31]#[C:32][CH3:33])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[CH3:12])=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)cc(C)c1N(C)S(=O)(=O)c1ccc(O)cc1
Reactant: CC#CCO
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(C)cc(-c3ccccc3)cc2C(=O)OC)cc1
Yield: 88.9 %

Procedure:
According to the procedure of Example 5 242 mg (0.58 mmol) of the product of Example 42 and 0.049 ml (0.65 mmol) of 2-butyn-1-ol provides 0.239 g (98%) of 4-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-5-methyl-biphenyl-3-carboxylic acid methyl ester. Electrospray Mass Spec: 464.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1.[CH3:18][NH2:19]>O>[CH3:18][NH:19][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1
Reactant: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Reactant: CN
Solvent: O
Product: CNc1cc(Oc2ccc3[nH]ccc3c2)ncn1

Procedure:
Dissolved in 6 ml methylamin solution (2 M in THF), 245 mg (1.0 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-indole (WO 03/099771; Stage 163.1) are stirred for 24 h at rt and 8.5 h at 50° C. The concentrated reaction mixture is dissolved in water and EtOAC, the aqueous layer separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc/hexane 1:1→3:1) gives the title compound: MS: [M+1]+=241; TLC(EtOAc): Rf=0.15.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=1)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: Cc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 3.88 g, 96.98 mmol) was added portionwise to a stirring solution of ethyl 5-bromo-1H-indole-2-Carboxylate (20.0 g, 74.6 mmol) in DMF (140 mL) at 0° C. under a nitrogen atmosphere over a period of 10 min. The mixture was then warmed to room temperature. After the reaction mixture was stirred at room temperature for one hour, 4-methylbenzyl bromide (14.2 g, 74.6 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous ammonium chloride and diluted with water. The aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate. This mixture was concentrated to give a semi-solid contained 0.8 mole equivalent DMF. Mass spectrum (ESI, [M+H]+) m/z 372. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, 1H, J=7.94 Hz), 7.55 (d, 1H, J=9.01 Hz), 7.40 (dd, 1H, J=8.85 and 1.98 Hz), 7.32 (s, 1H), 7.04 (d, 2H, J=7.96 Hz), 6.90 (d, 2H, J=7.94 Hz), 5.79 (s, 2H), 4.28 (q, 2H), 2.20 (s, 3H), and 1.28 ppm (t, 3H).
Reaction SMILES: O1CCOCC1.[ClH:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1.C1(C)C=CC=CC=1>O1CCOCC1.C(O)(=O)C>[ClH:7].[NH:24]1[CH2:25][CH2:26][CH:21]([CH2:20][NH:19][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[CH:10]3)=[O:18])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc3[nH]ncc3c2)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C(NCC1CCNCC1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A 4N-hydrogen chloride-1,4-dioxane solution (0.200 mg, 0.800 mmol) was added to a solution of tert-butyl 4-{[(1H-indazol-5-ylcarbonyl)amino]methyl}piperidine-1-carboxylate (36.0 mg, 0.100 mmol) in a mixture of 1,4-dioxane (0.4 ml) and acetic acid (0.7 ml) at room temperature, and the resulting mixture was stirred for 3 hours while being maintained at room temperature. Toluene was added to the reaction solution and the resulting mixture was stirred while being maintained at room temperature. Then, the resulting slurry was collected by filtration and dried under reduced pressure, and the resulting crude product residue was stirred in methanol (3.0 ml) for 1 hour with heating under reflux while maintaining the temperature. The resulting mixture was concentrated to dryness to obtain N-(piperidin-4-ylmethyl)-1H-indazole-5-carboxamide hydrochloride (29.8 mg, 100%).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH:2]12.C(=O)([O-])[O-:12].[Na+].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O.S(=O)(=O)(O)O>[OH:1][C@@H:3]1[CH2:4][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:6][C@H:2]1[OH:12]
Reactant: COC(=O)C1CC2OC2C1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1C[C@@H](O)[C@H](O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,2-Epoxy-4-methoxycarbonylcyclopentane (37.7 g) was dissolved in a mixed solvent of tetrahydrofuran (500 ml) and water (500 ml), and sulfuric acid (13.3 ml) was added dropwise under ice cooling to stir the mixture at room temperature for 4 hours. Sodium carbonate and sodium hydrogencarbonate were added to the reaction mixture to make the mixture neutral or weakly alkaline, and the solvent was distilled off under reduced pressure. The residue was extracted with dichloromethane and ethyl acetate, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (35.5 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[C:11]([CH:29]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:3]=1[C:4](OC(C)(C)C)=[O:5].COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[C:41]([O:40][C:38](=[O:39])[NH:37][CH:29]([C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:14]=[C:2]([NH2:1])[C:3]=1[CH:4]=[O:5])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc(N)c1C(=O)OC(C)(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc(N)c1C=O
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-6-[2-(benzyloxy)phenyl]-4-{1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}nicotinate (0.100 g, 0.198 mmol) in THF (1.50 mL) was added dropwise Vitride® (0.500 mL), and the stirring was continued for 2 hrs. The mixture was quenched at 0° C. with saturated aqueous NH4Cl solution, and extracted with ethyl acetate. The separated organic phase was washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 1:1) to give tert-butyl-1-{2-amino-6-[2-(benzyloxy)phenyl]-3-formyl-4-pyridinyl}-2-phenylethylcarbamate as a colorless oil (0.044 g, yield; 51%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([N+:16]([O-:18])=[O:17])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][O:3]1.[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH3:1][C:2]1([CH3:19])[O:3][CH2:4][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:12][CH:11]=2)([N+:16]([O-:18])=[O:17])[CH2:6][O:7]1
Reactant: CC1(C)OCC(CCc2ccccc2)([N+](=O)[O-])CO1
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)c1ccc(CCC2([N+](=O)[O-])COC(C)(C)OC2)cc1

Procedure:
The title compound was prepared from 2-dimethyl-5-nitro-5-phenethyl-1,3-dioxane (20) and octanoyl chloride, according to example 2, affording compound (21) with 68% yield, which was used at the next step without additional purification.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:47]1[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48]1>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([O:27][CH2:52][C:49]1[CH:50]=[CH:51][O:47][CH:48]=1)[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: OCc1ccoc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCc3ccoc3)cccc2[nH]1
Reaction time: 2 h

Procedure:
DEAD (2.1 ml, 13.65 mmol) is slowly added to a solution of 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 g, 9.75 mmol), triphenylphosphine (3.58 g, 13.65 mmol) and furan-3-yl-methanol (1.18 ml, 12.26 mmol) in 10 ml of THF, so that the temperature always remained below 30° C. Stirring is continued for 2 hours and the solvent is then evaporated. The crude residue is triturated with ether and the white precipitate is filtered off. It contained mainly product. The mother liquor is purified by chromatography (cyclohexane:EtOAc/95:5) and combined with the first precipitate. Yield: 3 g (>100%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH2:20](Br)[CH:21]=[CH2:22]>>[CH2:22]([N:7]1[C:6](=[O:8])[C:5]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=[C:2]1[NH2:1])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)c(=O)[nH]1
Product: C=CCn1c(N)nc(-c2ccco2)c(-c2ccncc2)c1=O

Procedure:
The title compound was synthesized in a manner similar to that described for Example 3 from 2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone and allyl bromide.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([NH2:24])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)(C)C.C(OCC)C>[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([NH:24][C:5]2[C:6]3[N:7]([N:8]=[CH:9][N:10]=3)[C:2]([Br:1])=[CH:3][N:4]=2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: Brc1ncc(Br)n2ncnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CCOCC
Product: Brc1cnc(NC2CCN(Cc3ccccc3)C2)c2ncnn12
Temperature: 85 °C

Procedure:
5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.1 g, 0.36 mmol), (R)-1-Benzyl-pyrrolidin-3-ylamine (0.07 g, 0.396 mmol, 1.10 equiv.) and DiPEA (0.15 mL, 0.72 mmol, 2.00 equiv.) are mixed in isopropanol (5 mL) under nitrogen. The reaction is heated to 85° C. until completion of the reaction (typically 5 h). The mixture is then allowed to cool down to room temperature and diluted with diethyl ether, causing the precipitation of the title compound as a solid that is used without further treatment.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:34]1([NH:40][CH2:41][CH2:42][S:43]([F:46])(=[O:45])=[O:44])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:22])[N:40]([CH2:41][CH2:42][S:43]([F:46])(=[O:45])=[O:44])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: O=S(=O)(F)CCNc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCS(=O)(=O)F)c2ccccc2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.9 ml) and DMF (0.025 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.610 g) in anhydrous dichloromethane (50 ml). The reaction was stirred at room temperature for 1 h then 2-phenylamino-ethanesulfonyl fluoride(0.257 g), DMAP (0.018 g) and DIPEA (0.261 ml) were added. The reaction mixture was stirred at room temperature for 20 h and partitioned between ethyl acetate and 1M aqueous hydrochloric acid. The aqueous layer was removed and the organic phase washed with saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with using ethyl acetate:petroleum ether (3:1 v/v) to give the title compound as a white foam (0.40 g).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][S:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([N:23]=O)=[C:18]([NH2:25])[N:17]=1.[O:26]1CC[CH2:28][CH2:27]1>CN(C)C=O>[NH2:25][C:18]1[C:19]2[N:23]=[CH:28][C:27](=[O:26])[NH:22][C:20]=2[N:21]=[C:16]([S:15][CH2:14][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=2[F:6])[N:17]=1
Reactant: C1CCOC1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Temperature: 25 °C

Procedure:
To a solution of triethyl phosphonoacetate (15.0 g) in tetrahydrofuran (60 ml) cooled in an ice bath was added butyllithium (2.5M in hexanes, 25.6 ml) at a rate such that the internal temperature was maintained below 30° C. To this mixture was then added a solution of the product of Example 2 step (b) (10.0 g) in N,N-dimethylformamide (60 ml). The reaction mixture was heated at reflux for 1 hour, then cooled to room temperature and quenched with acetic acid (6 ml). The solid thus precipitated was isolated by filtration, washed with water, ethanol and diethyl ether, and dried over P2O5 at 50° C. to give the sub-titled product as a pale green solid (9.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)(Cl)=O.[BH4-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:20][CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:23]=3)[CH:10]2[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(O)cc1)N(CCc1cccc(OCc2ccccc2)c1)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Oc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-2-(4-hydroxyphenyl)-N-{2-[3-(phenylmethoxy)phenyl]ethyl}acetamide (7.6 g, 0.015 mol) in acetonitrile (30 ml) was added phosphorus oxychloride (4.19 ml, 0.045 mol). The reaction was allowed to reflux at 80° C. for 6 hours. Solvent was removed and the reaction was placed on ice. To the flask was added ice and water. The reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated, and then dissolved in methanol. To the flask was added small aliquots of sodium borohydride (1.02 g, 0.027 mol). The reaction was allowed to stir overnight. The solvent was removed and the reaction was diluted with dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with additional dichloromethane. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (0.5 g, 6.8% yield): ES-MS (m/z) 490 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1COCC1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>C(O)C>[C:19]([NH:23][CH2:13][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)C(CNC(C)(C)C)c1ccc(Cl)cc1
Reaction time: 20 h
Yield: 422.2 %

Procedure:
A solution of methyl 2-(4-chlorophenyl)acrylate (2.00 g, 10.2 mmol) in 1:1 THF:ethanol (20 mL) was treated with tert-butyl amine (389 uL, 2.23 mmol) at 60° C. The reaction stirred for 20 hours to completion, and the solvent/excess amine were removed in vacuo. The residue was purified by chromatography on silica gel (eluted with 1:1 hexanes:ethyl acetate) to afford the pure methyl 3-(tert-butylamino)-2-(4-chlorophenyl)propanoate (2.54 g, 93%) as a colorless oil. LCMS (APCI+) m/z 270.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[N:6]([CH:14]([CH3:16])[CH3:15])[C:5]2=[O:17].[H-].[Na+].[Br:20][C:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[N:23]([C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[N:22]=1.C(Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:26]([C:24]1[N:23]([C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=3)[N:22]=[C:21]([Br:20])[CH:25]=1)=[O:27])[C:7](=[O:13])[N:6]([CH:14]([CH3:15])[CH3:16])[C:5]2=[O:17]
Reactant: Cc1cc(Br)cc2c(=O)n(C(C)C)c(=O)[nH]c12
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)cc2c(=O)n(C(C)C)c(=O)n(C(=O)c3cc(Br)nn3-c3ncccc3Cl)c12
Temperature: 25 °C

Procedure:
To a solution of the quinazolinedione of Step G (245 mg, 0.825 mmol) in dimethylformamide (5 mL) was added sodium hydride (60% oil dispersion, 36 mg, 0.90 mmol) and the reaction was allowed to stir at room temperature. In a separate reaction flask containing a solution of the pyrazole acid of Step D (500 mg, 1.65 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.17 mL, 1.95 mmol) and one drop of DMF. This mixture was stirred for 2 hours, then concentrated and placed under vacuum. The acid chloride was divided into two equal portions. One of these portions was taken up in 5 mL of DMF and added to the quinazolinedione/NaH reaction mixture and the resulting mixture was stirred at room temperature for 3 hours. The reaction was partitioned between ethyl acetate and water, washed twice with water, then with brine and dried over sodium sulfate. The crude product was purified by chromatography on silica gel with 99:1 chloroform/acetone as eluent to afford the title compound, a compound of the present invention.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:15]([CH2:41][CH2:42][CH3:43])[N:16]2[C:21]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)=[N:17]2)=[O:12])[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:15]([CH2:41][CH2:42][CH3:43])[N:16]2[C:21]=1[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:19][C:18]([N:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1)=[N:17]2)=[O:12])[CH3:9]
Reactant: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCNCC3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of 2-(4-t-butoxycarbonyl-piperazin-1-yl)-4-phenyl-7-propyl-pyrrolo[1,2-b]pyridazine-5,6-dicarboxylic acid diethyl ester (101) (105 mg, 0.186 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 1 h at ambient temperature and concentrated. Purification by flash chromatography (silica gel, 10% methanol/CHCl3) provided the title compound. 1H NMR (DMSO-d6) δ 1.05-1.11 (m, 6H), 1.39 (t, 3H, J=7.2 Hz), 3.34 (t, 2H, J=7.4 Hz), 3.40-3.42 (m, 4H), 3.72 (q, 2H, J=7.0 Hz), 3.92-3.95 (m, 4H), 4.35 (q, 2H, J=7.1 Hz), 6.99 (s, 1H), 7.57-7.67 (m, 5H), 8.94 (brs, 2H). Mass Spectrum (ES+) m/e=465.1 (M+1-114 (CF3CO2H)).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7](NCN=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:31][OH:32]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:32][CH3:31])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=NCNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reactant: CO
Solvent: CCN(CC)CC
Product: COC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1

Procedure:
A mixture of 3.3g (0.01M) of 7-chloro-3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one, 5 ml of triethylamine and 50 ml. of methanol was heated to reflux for 2 hrs. The solvents were evaporated under reduced pressure and the residue was crystallized from ether/hexane to yield the above named product, m.p. 136°-138°.