Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/[N:21](C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[F:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:33]([C:29]5[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=5)[N:21]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Reactant: NNc1cccc(F)c1
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=413.2 (M+H)+
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][S:5]1(=[O:14])=[O:13])([CH3:3])[CH3:2].[Cl:15][CH2:16][CH2:17][C@@H:18]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([Cl:27])[CH:21]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:15][CH2:16][CH2:17][C@@H:18]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([CH:1]([CH3:3])[CH3:2])[S:5]1(=[O:13])=[O:14])[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([Cl:27])[CH:21]=1
Reactant: CC(C)N1c2ccccc2NS1(=O)=O
Reactant: O[C@@H](CCCl)c1cc(F)cc(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1c2ccccc2N([C@H](CCCl)c2cc(F)cc(Cl)c2)S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To mixture of 1-isopropyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1.28 g, 6.00 mmol), (1S)-3-chloro-1-(3-chloro-5-fluorophenyl)propan-1-ol (1.34 g, 6.00 mmol) and triphenylphosphine (1.73 g, 6.60 mmol, 1.1 equiv.) in tetrahydrofuran (20 mL) under nitrogen was added slowly diisopropyl azodicarboxylate (1.28 mL, 6.60 mmol, 1.1 equiv.) via a syringe at 0° C. The resulting solution was stirred at room temperature overnight. Solvent was removed under reduced pressure and the viscous brown liquid residue was purified using Isco CombiFlash Companion column chromatography (silica gel, 0-15% ethyl acetate/hexane) to give 2.06 g (82%) of 1-[(1R)-3-chloro-1-(3-chloro-5-fluorophenyl)propyl]-3-isopropyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.[OH:24]O.[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([NH2:23])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Temperature: 40 °C

Procedure:
A mixture of 4-(3-aminophenyl)-8-(trifluoromethyl)quinoline-3-carbonitrile (0.30 g, 0.96 mmol), 30% hydrogen peroxide (5 mL), NaOH (0.5 g, 12 mmol) and ethanol (15 mL) was heated to ˜40° C. for 3 hours. The pH of the solution was adjusted to ˜6 by diluted HCl. The reaction mixture was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded onto silica gel and chromatographed with hexanes:ethyl acetate (50% to 100%) to afford 0.13 g of the title compound as an off-white solid. MS (ESI) m/z 332;
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:39][CH2:40][CH2:41][CH2:42][S:43][C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:13]=1[OH:14])[C:8]([NH:39][CH2:40][CH2:41][CH2:42][S:43][C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1)=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)NCCCSc2ccncc2)cc(C(C)(C)C)c1O
Yield: 27.3 %

Procedure:
To a solution of 1.49 g (5.94 mmol) of 3,5-di-t-butyl-4-hydroxybenzoic acid and 889 mg (7.73 mmol) of N-hydroxysuccinimide in 60 ml of methylene chloride was added 1.38 g (7.13 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. Further 1.00 g (5.94 mmol) of 4-(3-aminopropylthio)pyridine was added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was washed with water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 650 mg of the desired compound (27.3%, colorless powder) mp: 203.0°-204.0° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.CCN(CC)CC.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=[C:38]([CH3:46])[CH:37]=1>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:27]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=[C:38]([CH3:46])[CH:37]=2)=[O:33])=[CH:8][CH:7]=1
Reactant: Cc1cc(N)c2ccccc2n1
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c2ccccc2n1
Temperature: 42.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (18, 0.612 g, 2.0 mmol) in dry CHCl3 (35 mL) containing Et3N (0.4 mL) was added dropwise a solution of triphosgene (231 mg, 0.8 mmol.) in an ice bath with vigorous stirring for 30 min. The reaction mixture was evaporated and the residue diluted with THF (20 mL), filtered through a pad of Celite, washed with THF (5 mL). The filtrate and washings were combined and then added dropwise into a solution of commercially available 4-amino-2-methylquinoline (0.177 g, 2.0 mmol) in dry DMF (15 mL) containing Et3N (0.5 mL) at 0° C. After being stirred at room temperature for 3 h, the reaction mixture was heated at 40-45° C. for 16 h and then evaporated in vacuo to dryness. The residue was dissolved in a mixture of CHCl3/MeOH, mixed silica gel (10 g) and then evaporated in vacuo to dryness. The residue was put on the top of a silica gel column (2×30 cm) and chromatographed using CHCl3/MeOH (100:2 v/v) as eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness and the residue was recrystallized from acetone to give 1-{4-[bis(2-chloroethyl)amino]phenyl}-3-(2-methylquinolin-4-yl)urea (BO-1038); 187 mg (40.1%); mp 128-129° C.; 1H NMR (CHCl3-d6) δ 2.63 (3H, s, Me), 3.57 (4H, t, J=6.6 Hz, 2×CH2), 3.66 (4H t, J=6.6 Hz, 2×CH2), 6.56 (2H, d, J=7.9 Hz, 2×ArH), 7.12-7.14 (1H, m, ArH), 7.21 (2H, d, J=8.8 Hz, 2×ArH), 7.26 (1H, s, ArH), 7.44-7.56 (2H, m, 2×ArH), 7.92 (2H, d, J=8.5 Hz, 2×ArH), 8.14 (1H, s, ArH), 8.40 (1H, brs, exchangeable, NH). Anal. Calcd. for (C21H22Cl2N4O: C, 57.94; H, 5.56; N, 12.87. Found: C, 58.27; H, 5.56; N, 12.6.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:4].O.C(=O)(O)[O-].[Na+].[C:19](Cl)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([NH:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH3:4])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(C)CN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)CNC(C)=O)cc1
Yield: 99.8 %

Procedure:
A mixture of 19.8 g of 1-amino-2-(4-methoxyphenyl)propane, 200 ml of ethyl acetate, 200 ml of water and 84 g of sodium bicarbonate is cooled at 5° to 10° C. under stirring, and 18.8 g of acetyl chloride in 100 ml of ethyl acetate are added dropwise thereto at the same temperature. After the reaction, the ethyl acetate layer is separated therefrom, washed, dried and then condensed to dryness under reduced pressure. 24.8 g of 1-acetylamino-2-(4-methoxyphenyl)propane are obtained as oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=[O:2].[Mn]([O-])(=O)(=O)=[O:13].[K+]>O.CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)([OH:13])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-formylphenylboronic acid (3.35 g, 22.34 mmol) (Lancaster) in a 1:1 mixture of distilled water-acetone (64 mL) was slowly treated with potassium permanganate (6.00 g, 37.98 mmol) in small portions. The dark reaction mixture was stirred at room temperature for 1 h and then filtered through a pad of Celite®. The pad of Celite® was washed with 200 mL of distilled water then washed with 200 mL of acetone. The filtrate was concentrated in vacuo to a volume of approximately 200 mL. The resulting aqueous filtrate was treated with concentrated hydrochloric acid until pH=1 and then cooled using an ice/water bath. The desired product precipitated upon cooling. The solid was filtered and washed well with cold distilled water to provide 3-carboxyphenylboronic acid as a cream-colored solid which was used without further purification. (Yield 1.95 g, 53%; mp 232-234° C.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]([CH3:18])([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1.[CH2:1]([O:8][C:9]([NH:10][C:11]([CH3:12])([CH3:18])[CH2:13][CH2:14][N+:15]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:16])[CH3:17])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Product: CCCCCCOCC[N+](C)(C)CCC(C)(C)NC(=O)OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of benzyl(4-(dimethylamino)-2-methylbutan-2-yl)carbamate (0.72 g, 2.7 mmol) and 2-(hexyloxy)ethyl 4-methylbenzenesulfonate (1.8 g, 6.0 mmol) was stirred overnight at 75° C. The crude reaction mixture was purified by reverse phase HPLC eluting from a C18 column with a gradient of 5 to 95% CH3CN in water (with 0.01% acetic acid) to give 0.96 g of white solid (64% yield). 1H NMR (400 MHz, D2O) δ 0.75-78 (m, 3H), 1.18 (s, 6H), 1.44-1.27 (m, 2H), 2.06 (br m, 2H), 2.29 (s, 3H), 3.03 (s, 6H), 3.17-3.21 (m, 2H), 3.30 (br m, 2H), 3.36-3.39 (t, J=6.5 Hz, 2H), 3.67 (br s, 2H), 4.97 (br s, 2H), 7.26-7.28 (d, J=8.1 Hz, 2H), 7.30-7.37 (m, 5H), 7.58-7.60 (d, J=8.1 Hz, 2H). LRMS (ESI/APCI) m/z 393 [M]+.
Reaction SMILES: C[O:2][C:3]1[C:10](OC)=C[CH:8]=[CH:7][C:4]=1[C:5]#N.C[Mg]Br.C[C:17](O)=[O:18].C[CH2:21][O:22][CH2:23][CH3:24]>>[CH3:10][C:3]([C:4]1[CH:7]=[CH:8][CH:24]=[C:23]([O:22][CH3:21])[C:5]=1[O:18][CH3:17])=[O:2]
Reactant: COc1cccc(C#N)c1OC
Reactant: CCOCC
Reactant: CC(=O)O
Agent: C[Mg]Br
Product: COc1cccc(C(C)=O)c1OC
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a stirred solution of 2,3-dimethoxybenzonitrile (25)(5.0 g, 30 mmol) in Et2O (12.5 mL) under N2 atmosphere was added methylmagnesium bromide (37% in Et2O) (12.5 mL, 37 mmol). The mixture was stirred for 16 h, and then 50% AcOH (20 mL) was added. After it was stirred for 30 min, the solution was poured into crushed ice, extracted with CH2Cl2, washed with 10% Na2CO3 and then with water, dried over MgSO4 and concentrated. The crude was purified by column chromatography (SiO2, n-hexane: EtOAc=4:1) to give 26. Liquid; yield: 92.5%; 1H-NMR (CDCl3, 200 MHz): δ 2.56 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 6.99-7.02 (m, 2H), 7.13-7.18 (m, 1H); 13C-NMR (CDCl3, 50 MHz): δ 31.18, 55.98, 61.29, 115.83, 120.80, 123.94, 133.62, 148.63, 153.04, 200.26; Anal. calcd for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.60; H, 6.73.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([O:19][CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([O:19][CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cnc(OC)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(OC)cc3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
To a solution of ethyl 4-{4-chloro-7-(1-ethylpropyl)-2-[(6-methoxy-4-methylpyridin-3-yl)amino]-1H-benzimidazol-1-yl}butanoate (170 mg, 0.359 mmol) in tetrahydrofuran (3 mL) was added lithium borohydride (24 mg, 1.08 mmol) portionwise at 0° C. The mixture was warmed, to room temperature and stirred for 12 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (109 mg, 0.252 mmol, 70%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([N:16]=[C:17]=[O:18])[C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].O1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(Br)(Br)(Br)[Br:25]>>[Br:25][CH2:20][CH2:21][CH2:22][CH2:23][O:12][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:7]=[C:8]([N:16]=[C:17]=[O:18])[C:9]=1[OH:15]
Reactant: CC(C)(C)Oc1cc(N=C=O)c(O)c(C(=O)O)c1
Reactant: C1CCOC1
Reactant: BrC(Br)(Br)Br
Product: CC(C)(C)Oc1cc(N=C=O)c(O)c(C(=O)OCCCCBr)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-tertbutyloxy-carbonylamino-2-hydroxy-benzoic acid (20 g, 85.7 mmoles) in tetrahydrofuran (200 ml) triphenylphosphine (44.9 g, 171 mmoles) and lastly carbon tetrabromide (56.7 g, 171 mmoles) are added. The reaction mixture is left under stirring at room temperature for 24 hours and then evaporated under vacuum. The obtained residue is purified by silica gel column chromatography (eluent: n.-hexane/ethyl acetate 8/2 vol./vol.), monitoring the content of the collected fractions by chromatography on thin layer. The product is obtained by collecting the head fractions, after elution from the column of the CBr4 reactive used in the synthesis. The fractions are collected and dried. A white solid (21.16 mg) having m.p. 108°-111° C. is recovered.
Reaction SMILES: [NH3:1].[ClH:2].[F:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](=[NH:10])O)=[CH:6][CH:5]=1>C(O)C>[ClH:2].[F:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:1])=[NH:10])=[CH:6][CH:5]=1
Reactant: N
Reactant: N=C(O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: N=C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
310 cm3 of ethanol saturated with ammonia was added to 83 g (0.41 mol) of 4-fluorobenzimidate hydrogen chloride and stirred at room temperature for one day and night. Approximately half of the ethanol was distilled off and the residue was recrystallized to yield 70 g (0.40 mol) of 4-fluorobenzamidine hydrogen chloride.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH3:14]I.Cl>CN(C)C=O>[CH3:14][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: CI
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
A dimethylformamide (hereinafter referred to as DMF) (500 ml) solution of isatin (14.70 g, 100 mmol, purity 98%; manufactured by SIGMA-ALDRICH) was cooled to 0° C. in an ice bath, and sodium hydride (4.73 g, 118 mmol, 60% in oil; manufactured by Tokyo Chemical Industry Co., Ltd.) was added by portions with a spatula over a period of 10 min. After stirring for 15 min, methyl iodide (7.5 mL, 120 mmol) was added by portions with a Komagome pipette over a period of 10 min. The mixture was stirred at 0° C. for 1 hr and was then poured into 1 L of an aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate, and an ethyl acetate phase was washed twice with water. The ethyl acetate phase was concentrated to obtain 13.6 g of a crude product of N-methylisatin (HPLC assay: 79 area %). The HPLC assay was carried out in the same manner as described above.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][N+:23]([O-])=O)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(C)cc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(C)cc1)OCC

Procedure:
A solution of 6.5 g of ethyl 2-(4-methylphenyl)-3-nitropropyl-(diethoxymethyl)phosphinate in 60 ml of ethanol is added to 52 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-methylphenyl)propyl-(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.6 ppm (CDCl3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8]1([C:17]([O:19]C)=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(Cl)Cl.Cl>CCO.C1COCC1>[C:1]([O:5][C:6](=[O:21])[CH2:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CC(=O)OC(C)(C)C)Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a solution of methyl 2-(2-tert-butoxy-2-oxoethyl)-2,3-dihydro-1H-indene-2-carboxylate (4.5 g, 15.50 mmol) in EtOH/THF (70 mL, 1:1) at room temperature was added 1 M sodium hydroxide (35 ml, 35.0 mmol), and the mixture was stirred at room temperature for 1.5 hour. To the reaction mixture was added DCM and acidified by 1 M HCl to pH=7. The mixture was extracted with DCM, and the combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 10 to 30% EtOAc/HEP) and gave the title compound: 1.4 g (yield: 15%). LCMS (condition B): 275.2 (M−1); retention time=1.17 min.
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[NH2:3].N1C=CC=CC=1.C(#N)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([NH:3][N:2]([CH3:1])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])=[O:27]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N(C)NC(=O)c2c(F)cccc2Cl)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
Into a 100 mL three necked round bottom flask equipped with a magnetic stirrer, thermometer, and condenser, under an atmosphere of nitrogen, was added 2-methyl-2-[(4-methylphenyl)sulfonyl] hydrazine (9.5 g, 47.4 mmol), pyridine (3.75 g, 3.83 mL, 47.4 mmol), 4-dimethylaminopyridine (0.30 g, 2.4 mmol) and acetonitrile (50 mL). The resulting mixture was cooled to 10° C. and 2-fluoro-6-chlorobenzoyl chloride (8.99 g, 45.2 mmol) dropwise at a rate such that the temperature did not rise above 10° C. The cooling bath was removed and the mixture was allowed to stir at RT overnight. The solvent was removed from the reaction mixture in vacuo to give an off white solid and the solid was diluted with methylene chloride and extracted with 1N HCl (20 mL), saturated sodium chloride solution (20 mL), dried (Na2SO4), and the solvent removed in vacuo to give an off-white solid. This material was recrystallized from ethyl acetate to give 5.6 g (34.7% yield) of 1-(2-fluoro-6-chlorobenzoyl)-2-methyl-2-[(4-methylphenyl)sulfonyl] hydrazine as a crystalline solid: mp 135-136° C.; 1H NMR (CDCl3) δ 7.6-7.8 (m, 3H), 7.0-7.4 (m, 5H), 3.4 and 3.0 (singlets combined for 3H), 2.4 and 2.45 (singlets combined for 3H); 13C (CDCl3) 160.2, 144.7, 133.6, 132.7, 132.6, 132.1, 131.9, 130.2, 129.6, 129.0, 128.7, 125.7, 114.6, 114.3, 37.7, 21.7. Anal. Calcd. For C15H14ClFN2O3S: C, 50.49; H, 3.95; N, 7.85. Found: C, 50.55; H, 3.89: N. 7.81.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([CH:8]([C:19](=O)[CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)=[CH:4][CH:3]=1.[NH2:24][N:25]1[C:29]([CH2:30][CH3:31])=[CH:28][CH:27]=[C:26]1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C(O)C.O>[CH2:30]([C:29]1[N:25]2[N:24]=[C:6]([C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:26]2=[CH:27][CH:28]=1)[CH3:31].[CH2:32]([C:26]1[N:25]2[N:24]=[C:19]([CH3:20])[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]([C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)[C:29]2=[CH:28][CH:27]=1)[CH3:34]
Reactant: CCc1ccc(C(=O)c2ccc(F)cc2)n1N
Reactant: CCOC(=O)CCCCCC(C(C)=O)C(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCc1c(-c2ccc(F)cc2)nn2c(CC)ccc2c1-c1ccc(F)cc1
Product: CCOC(=O)CCCCCc1c(C)nn2c(CC)ccc2c1-c1ccc(F)cc1

Procedure:
A mixture of ethyl 7-(4-fluorobenzoyl)-8-oxononanoate (300 mg), (1-amino-5-ethyl-1H-pyrrol-2-yl)(4-fluorophenyl)methanone (216 mg), and p-toluenesulfonic acid monohydrate (35.4 mg) in ethanol (6 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 6-[7-ethyl-2,4-bis(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-3-yl]hexanoate (83 mg) and ethyl 6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate (40 mg) as an oil.