Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)=[O:4].Cl[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.C(OCC)C>[F:19][C:16]([F:17])([F:18])[C:11]1[C:12]([C:14]#[N:15])=[CH:13][C:7]2[N:6]=[C:5]([C:3]3([C:2]([F:20])([F:1])[F:21])[O:25][CH2:24][CH2:23][O:4]3)[NH:9][C:8]=2[CH:10]=1
Reactant: N#Cc1cc2nc(C(=O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cc2nc(C3(C(F)(F)F)OCCO3)[nH]c2cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile (0.50 g; 1.5 mmol), was dissolved in DMF (4 mL), then treated with 2-chloroethanol (0.35 mL; 5.2 mmol) and potassium carbonate (0.73 g; 5.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate (40 mL) and diethyl ether (40 mL), washed with water (50 mL) and brine (3×30 mL), then dried over Na2SO4. The reaction mixture was filtered, concentrated to yield a light brown solid, which was purified by column chromatography (SiO2; 100% ethyl acetate) to yield the title compound as a light yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[CH:28]=3)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:37][CH3:38])[CH:12]=1.ClC1C(C2C3C(=CC=CC=3)N(C)C=2)=NC(NC2C=C([N+]([O-])=O)C(F)=CC=2OC)=NC=1.CCN(C(C)C)C(C)C>FC(F)(F)CO.CO>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[C:13]([O:37][CH3:38])[CH:12]=2)[CH2:6]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CN(C)C1CNC1
Agent: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 89 %

Procedure:
N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 79 mg, 0.46 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129 (which may be prepared by the method described for Intermediate 87), 150 mg, 0.38 mmol) and DIPEA (0.264 mL, 1.53 mmol) in 2,2,2-trifluoroethanol (3 mL). The mixture was heated at 140° C. in a microwave for 1 h. The mixture was then purified directly by ion exchange chromatography, using an SCX column (50 g) and eluting with 1:1 7M methanolic ammonia in CH2Cl2. Concentration of appropriate fractions in vacuo gave a brick red solid. This solid was suspended in CH3OH and the solid was collected by filtration, washed with CH3OH (10 mL) and dried in vacuo to give the title compound (160 mg, 89%) as a red solid; m/z: ES+ MH+ 474.61.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=S)[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1.Cl.CN(C[C:24]([NH:26][NH2:27])=O)C.[CH2:28]([N:30]([CH2:33]C)[CH2:31]C)C>CN(C)C=O>[CH3:28][N:30]([CH2:33][C:15]1[CH:16]=[CH:17][C:10]2[N:9]3[CH:24]=[N:26][N:27]=[C:8]3[C:7]3[CH2:6][CH2:5][CH:4]=[C:3]4[CH:2]=[CH:1][N:12]([C:13]=34)[C:11]=2[CH:14]=1)[CH3:31]
Reactant: CN(C)CC(=O)NN
Reactant: CCN(CC)CC
Reactant: S=C1Nc2ccccc2N2CCc3cccc1c32
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc2c(c1)-n1ccc3c1=C(CCC=3)c1nncn1-2
Yield: 47.2 %

Procedure:
1,2-Dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin6-thione (4 g) was added to a solution of dimethylaminoacetic hydrazide hydrochloride (2 g) and triethylamine (2.4 ml) in dimethylformamide (25 ml). The mixture was refluxed overnight, cooled, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (2.5% methano/dichloromethane). The appropriate fractions were triturated with dry ether to yield 2.4 g (47.2%) of product, mp 164°-165° C.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: C1=COCCC1
Reactant: OCCCCCCCCO
Product: OCCCCCCCCC1CCCCO1

Procedure:
1,8-Octanediol is treated with one equivalent of dihydropyrane in the presence of acid to give the 8-(tetrahydropyran-2-yl)octanol. 8-(Tetrahydropyran-2-yl)octanol, N-hydroxyphthalimide and triphenylphosphine in DMF are treated at 0° C. with diisopropylazodicarboxylate utilizing Mitsunobu reaction conditions to give O-[8-(tetrahydropyran-2-yl)octanol)phthalimide. Acid treatment of O-[8-(tetrahydropyran-2-yl)octanol]phthalimide will yield O-(octanol)phthalimide which in turn when treated with phosphorous tribromide and pyridine utilizing the reaction conditions of Hall, et al., Synthetic Procedures in Nucleic Acid Chemistry, Zorbach and Tipson, Editors, Volume 1, John Wiley & Sons, 1968 will yield O-(8-bromooctanol)phthalimide.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:73])[C@@H:15]([NH:16][C:17](=[O:72])/[C:18](/[C:47]3[N:48]=[C:49]([NH:52]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:50][CH:51]=3)=[N:19]\[O:20][CH2:21][C:22]3[N:23]=[C:24]([NH:27]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:25][CH:26]=3)[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:74][O:75][C:76](=[O:78])[CH3:77])=[O:7])(C)(C)C.[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82].[NH2:52][C:49]1[S:50][CH:51]=[C:47](/[C:18](=[N:19]/[O:20][CH2:21][C:22]2[N:23]=[C:24]([NH2:27])[S:25][CH:26]=2)/[C:17]([NH:16][C@@H:15]2[C:14](=[O:73])[N:13]3[C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH2:74][O:75][C:76](=[O:78])[CH3:77])[CH2:10][S:11][C@H:12]23)=[O:72])[N:48]=1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)/C(=N\OCc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCc3csc(N)n3)c3csc(N)n3)[C@H]2SC1

Procedure:
2.3 g of the (6R,7R)-7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-tritylaminothiazol-4-yl)methoxyimino]acetamido]-3-(acetoxymethyl)-ceph-3-em-4-carboxylic acid t-butyl ester was suspended in 2.1 ml of anisole, 21 ml of trifluoroacetic acid was added with ice cooling, and reacted at the same temperature for about 3 hours. After the completion of the reaction, the reaction mixture was poured into 200 ml of isopropyl ether with ice cooling, and the supernatant was removed. The residue was washed thoroughly with isopropyl ether, and the precipitates were filtered off to obtain 1.4 g of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-aminothiazol-4-yl)methoxyimino]acetamido]-3-(acetoxymethyl)-ceph-3-em-4-carboxylic acid trifluoroacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:19])[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Br)ccc1C(O)CCC(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(Br)ccc1C(Cl)CCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutan-1-ol (545 g) in toluene (5.4 L) was added thionyl chloride (393 g) at room temperature. The reaction mixture was stirred at 50° C. overnight and concentrated under reduced pressure to give the title compound. This reaction was performed for 3 batches, and the obtained compounds were used in step D without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][NH2:22].[OH2:23]>N1C=CC=CC=1.C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:22][CH2:21][CH2:20][N:19]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:18][CH2:17][CH2:16][N:15]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14][CH2:13][NH:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:8])=[O:23])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O
Reactant: NCCNCCCNCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCN(CCCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a stirred solution of p-toluenesulfonyl chloride (262 g, 1.37 mole) in anhydrous pyridine (600 ml) at 5° C. was added a solution of 1,4,8,11-tetraazaundecane (49.1 g, 0.306 mole) in anhydrous pyridine (200 ml) under a dry argon atmosphere, maintaining the temperature <20° C. The addition required 1 h. The mixture was stirred overnight at room temperature. H2O (1.5 l) was slowly added to the cooled (ice bath) mixture. The resulting oil was dissolved in CH2Cl2, separated from the aqueous layer. The CH2Cl2 layer was washed with 5% HCl and H2O and dried (MgSO4). The solvent was removed in vacuo to give an oil which solidified on standing. The resulting solid was ground to a powder and dried in vacuo to give 186 g (78% yield) of the crude product: 1H NMR (CDCl3) δ 1.98 (quint, J=7.3 Hz, 2H), 2.40 (s, 6H), 2.42 (s, 6H), 3.11 (t, J=7.3 Hz, 4H), 3.17 (s, 8H), 5.76 (t, J=6.0 Hz, 2H), 7.29 (m, 8H), 7.64 (d, J=8.3 Hz, 4H), 7.75 (d, J=8.3 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[C:12]4[CH:15]=[CH:16][C:17]([N:19]5[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]5)=[CH:18][C:11]=4[NH:10][C:9](=[O:32])[C:8]=3[C:7]([C:33]3[CH:38]=[CH:37][C:36]([O:39]C)=[CH:35][CH:34]=3)=[N:6][C:5]=2[NH:4][N:3]=1.B(Br)(Br)[Br:42].CO>ClC(Cl)C>[BrH:42].[NH2:1][C:2]1[C:14]2[C:13]3[C:12]4[CH:15]=[CH:16][C:17]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)=[CH:18][C:11]=4[NH:10][C:9](=[O:32])[C:8]=3[C:7]([C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[N:6][C:5]=2[NH:4][N:3]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(-c2nc3[nH]nc(N)c3c3c2c(=O)[nH]c2cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Solvent: CC(Cl)Cl
Solvent: CO
Product: Br
Product: Nc1n[nH]c2nc(-c3ccc(O)cc3)c3c(=O)[nH]c4cc(N5CCNCC5)ccc4c3c12
Temperature: 40 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A solution of 350 mg (0.64 mmol) of tert-butyl 4-(1-amino-5-(4-methoxyphenyl)-6-oxo-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-9-yl)piperazine-1-carboxylate is dissolved in 15 ml of anhydrous dichloroethane. The reaction medium is cooled to −78° C. before the slow addition of 0.30 ml (3.23 mmol) of boron tribromide. The reaction medium is carried at reflux for 4 hours. Methanol (roughly 10 ml) is added at 0° C. and then the reaction medium is stirred at 40° C. for 1 hour. The solid formed is filtered under heat and then rinsed with diethyl ether. Recrystallization of the solid in isopropanol yields 0.26 g (80%) of 1-amino-5-(4-hydroxyphenyl)-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one hydrobromide in the form of a light orange solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@@:7]12[CH2:13][CH:12]([CH3:14])[CH:11]1[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:8]2)=[O:6].Cl>O1CCCC1.CO>[CH2:18]([O:17][C:15]([N:9]1[CH2:10][CH:11]2[C@@:7]([C:5]([OH:6])=[O:4])([CH2:13][CH:12]2[CH3:14])[CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@]12CC(C)C1CN(C(=O)OCc1ccccc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1C[C@@]2(C(=O)O)CN(C(=O)OCc3ccccc3)CC12
Reaction time: 0.5 h

Procedure:
A 1N sodium hydroxide solution (21 ml) was added dropwise to a mixed solution of (S)-6-methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylic acid 3-benzyl ester 1-methyl ester (3.2 g, 10.4 mmol) in tetrahydrofuran (60 ml) and methanol (20 ml) under ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was neutralized with 1N hydrochloric acid, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure to give 3.0 g (quantitative) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]3[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=3[N:3]=2)=[C:28]([CH3:33])[CH:27]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Cc1cc(Br)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2ccc(Br)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 2.00 g, 5.39 mmol), 4-bromo-2-methylaniline (3.01 g, 16.2 mmol), p-toluenesulfonic acid monohydrate (1.10 g, 5.78 mmol) and xylene (15 mL) was stirred at 150° C. for 20 hr. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated, in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-15% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (2.11 g, 4.05 mmol, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.[O:17]1CCC[CH2:18]1.C(Cl)(Cl)=O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:18]2=[O:17])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(NNc1ccc(F)cc1)c1cccs1
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1oc(-c2cccs2)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
N′-(4-fluorophenyl)thiophene-2-carbohydrazide (575 mg, 2.43 mmol) was dissolved in dichloromethane (14 mL) and tetrahydrofuran (10 mL) in a glass flask. The flask was cooled in ice. Phosgene (20% in toluene, 3.42 mL, 6.49 mmol, 2.67 eq.) was added, and the solution was stirred overnight under a nitrogen atmosphere, allowing it to warm to room temperature. Ethyl acetate (40 mL) was added, and the solution was then washed with water (2×25 mL) and brine (25 mL). The solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.59 grams of crude product as a light brown solid. Purification using ISCO flash chromatography (silica, gradient heptanes/ethyl acetate) gave 3-(4-fluorophenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazol-2(3H)-one (210 mg, 0.800 mmol, yield 33.0%) as an off-white solid with an HPLC purity of 99.7%. LC-MS [M+H] 263.02 (C12H7FN2O2S+H, expected 263.02). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: ClC(F)(F)C([I:5])F.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].Cl[C:16]([F:22])(Cl)[C:17]([F:20])([F:19])[Cl:18]>>[I:5][CH:9]([CH2:10][CH:16]([F:22])[C:17]([F:20])([F:19])[Cl:18])[C:8]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: FC(I)C(F)(F)Cl
Reactant: FC(F)(Cl)C(F)(Cl)Cl
Reactant: C=CC(=O)OCC
Product: CCOC(=O)C(I)CC(F)C(F)(F)Cl
Reaction time: 25 h

Procedure:
In a transparent quartz tube having an inner volume of 300 ml, 48 g (0.20 mol) of 1-chloro-2-iodo-1,1,2-trifluoroethane and 26 g (0.24 mol) of ethyl acrylate were placed in conjunction with 100 ml of 1,1,2-trichlorotrifluoroethane and were exposed to an ulraviolet ray issuing from a spiral light source for 25 hours. After this irradiation, the solvent trichlorotrifluoroethane was expelled from the resultant mixture by distillation under normal pressure and, subsequently, the unaltered reactants were recovered by distillation under a slightly lowered pressure. By subjecting the remaining reaction mixture to vacuum distillation, there was obtained 9.5 g (0.028 mol) of ethyl 2-iodo-4,5,5-trifluoro-5-chloropentanoate of b.p. 79° to 82° C./3 mm, nD20 1.4610, d420 1.728 and νC=0 1732 cm-1. This adduct was a mixture of two diastereomers (42:58). This reaction by-produced ethyl 4,5,5-trifluoro-5-chloro-2-pentanoate due to removal of hydrogen iodide from the adduct and ethyl 4,5,5-trifluoro-5-chloropentanoate due to substitution of iodine with hydrogen, etc. in small amounts.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[S:19])=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:6][C:5]([N:9]2[C:17](=[O:18])[N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[S:19])=[C:4]([F:20])[CH:3]=1
Reactant: Clc1ncccn1
Reactant: O=c1n(-c2cc(O)c(Cl)cc2F)c(=S)n2n1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1n(-c2cc(Oc3ncccn3)c(Cl)cc2F)c(=S)n2n1CCCC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
2-(4-Chloro-2-fluoro-5-hydroxyphenyl)hexahydro-3-thioxo-1H-[1,2,4]triazolo-[1,2-a]pyridazin-1-one (0.5 g) was mixed with 2-chloropyrimidine (1 equiv) and potassium carbonate (2 equiv) in dimethylsulfoxide (20 ml) and the resulting mixture stirred at 100° C. for 1.5 hour and at room temperature overnight. The mixture was processed and the residue column chromatographed (silica gel, methylene chloride:ethyl acetate, 3:1). to give the product (0.34 g, 55%). 1H NMR (CDCl3, TMS): 1.92(4H, m), 3.69(2H, m), 3.99(2H, m), 7.05(1H, m), 7.37(1H, d, J=6.5 Hz), 7.39(1H, d, J=9.0 Hz), 8.53(2H, d, J=4.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)=[CH:8]2)=[CH:4][CH:3]=1.C([Sn](=O)CCCC)CCC.[N:35]([Si](C)(C)C)=[N+:36]=[N-:37]>C1(C)C=CC=CC=1>[N:22]1[NH:35][N:36]=[N:37][C:21]=1[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[CH:11][C:12](=[O:13])[N:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:8]=2)=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=c1ccc(-c2ccc(Cc3nn[nH]n3)cc2)cn1Cc1ccc(Cl)cc1
Yield: 37.5 %

Procedure:
According to Scheme 15 Method D: 2-(4-(1-(4-Chlorobenzyl)-1,6-dihydro-6-oxopyridin-3-yl)phenyl)acetonitrile (1 eq, 0.24 mmol, 0.08 g) was heated at 110° C. under nitrogen overnight with dibutyltin oxide (0.22 eq, 0.05 mmol, 0.01 g) and azidotrimethylsilane (6.0 eq, 1.43 mmol, 0.19 mL) in toluene (4 mL). The suspension was filtered and the filtrate concentrated under vacuo. The crude product was purified by chromatography on silica gel using MeOH/AcOEt 20/80 as eluent and recrystallised in diisopropyl ether to afford the title compound as a white solid (0.09 mmol, 35 mg, 39%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[OH:14])[CH:9]=O.[C:19]1([C:25](=O)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH2:34][C:35]([NH2:37])=[O:36].Cl>C(O)C>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:37][C:35](=[O:36])[NH:34]2)[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[OH:14]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CN(C)CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CN(C)CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 24.3 %

Procedure:
To a solution of 3-(2-(dimethylamino)ethoxy)-4-hydroxy-5-nitrobenzaldehyde (Intermediate 89) (100 mg, 0.39 mmol), 1,2-diphenyl-ethanone (77 mg, 0.39 mmol) and urea (70 mg, 1.2 mmol) in ethanol (3 mL) was added conc. HCl (0.2 mL); the resulting mixture was refluxed overnight. The mixture was concentrated and purified by prep-HPLC (0.1% TFA as additive) to give Compound 170 (45 mg, yield 22%) as yellow solid. 1H NMR (MeOD 400 MHz) δ 7.81 (d, J=2.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.38-7.25 (m, 5H), 7.16-7.04 (m, 3H), 6.98-6.88 (m, 2H), 5.47 (s, 1H), 4.46-4.35 (m, 2H), 3.71-3.62 (m, 2H), 3.08 (s, 6H). MS (ESI): m/z 475.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=[CH:26][C:27]2=3)=[O:11])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: CC(C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a mixture of 2-[4-chloro-3-(trifluoromethyl)phenyl]propanoic acid (47 mg, 0.184 mmol) and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (40 mg, 0.184 mmol) in DMF (1 mL) was added Hunig's base (59 mg, 0.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (77 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, and then was partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine and dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (24 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.48-7.42 (m, 4H), 7.16-7.11 (m, 2H), 4.11 (m, 1H), 3.76 (m, 1H), 3.52 (m, 1H), 2.77 (m, 2H), 1.96 (m, 1H), 1.80 (m, 1H), 1.55 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C22H18ClF4N3O [M+H]+ 452.1, found 452.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[NH:9][CH2:10][CH2:11][OH:12].Cl.[CH:14](O)=O>>[Br:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][OH:12])[CH:14]=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)c1NCCO
Reactant: O=CO
Agent: Cl
Product: OCCn1cnc2cccc(Br)c21

Procedure:
2-[(2-Amino-6-bromophenyl)amino]ethanol (0.14 g, 0.54 mmol) was dissolved in formic acid (3 mL) and irradiated in microwave oven at 135° C. for 2 h. The mixture was cooled and treated with 37% hydrochloric acid (1 mL) at 50° C. for 0.5 h. The volatiles were removed under reduced pressure. The residue was partitioned between ethyl acetate and to saturated aqueous sodium bicarbonate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated to yield 2-(7-bromo-1H-benzimidazol-1-yl)ethanol, 0.14 g (90%). MS (ESI) m/z: 241.09 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.76 (q, J=5.5 Hz, 2H) 4.55 (t, J=5.4 Hz, 2H) 4.97 (t, J=5.4 Hz, 1H) 7.12 (m, 1H) 7.43 (m, 1H) 7.66 (dd, J=8.0, 1.0 Hz, 1H) 8.19 (s, 1H).