Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[OH-].[Na+].[NH2:7][C:8]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:12][CH3:13])=[O:11].[Br:19]Br>O>[NH2:7][C:8]1[C:17]([CH3:18])=[CH:16][C:15]([Br:19])=[CH:14][C:9]=1[C:10]([NH:12][CH3:13])=[O:11]
Reactant: BrBr
Reactant: CNC(=O)c1cccc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Br)cc(C)c1N
Temperature: 55 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A 1000-mL flask equipped with a mechanical stirrer, thermocouple, condenser and Teflon® fluoropolymer tubing ( 1/16″ (0.16) cm I.D.×⅛″ (0.32 cm) O.D.) (positioned such that the end of the tubing was submerged below the surface of the reaction mixture) was charged with acetic acid (226 mL). A solution of aqueous sodium hydroxide (50%, 25 g) in water (85 g) was added over 15 minutes, and then 2-amino-N,3-dimethylbenzamide (50 g, 0.305 mol) (see PCT Patent Publication WO 2006/062978 for a method of preparation) was added and the mixture was heated at 55° C. A two-necked 200-mL flask fitted on one neck with a Teflon® tubing dip tube was charged with liquid bromine (50.1 g), and the other neck was connected to the Teflon® tubing on the 1000-mL flask. Nitrogen gas was then flowed through the dip tube below the surface of the liquid bromine at a rate of about 0.012 m3 (0.4 cu ft) per h for 2.5 h, during which time all of the bromine evaporated and the bromine vapor entrained in the nitrogen gas flowed out of the two-necked 200-mL flask and entered the reaction mixture through the Teflon® tubing. The reaction temperature was held at about 55° C. during the bromine vapor addition and for 30 minutes thereafter, and then cooled to 45° C. and stirred overnight. A solution of aqueous sodium hydroxide (50%, 52 g) in water (88 mL) was added to the reaction mixture at a rate of 0.8 mL/minute. After about 10% of the total volume of the sodium hydroxide solution had been added, the addition was stopped and the reaction mixture was stirred for 1 h at 45° C. After 1 h the remaining sodium hydroxide solution was added at a rate of 0.8 mL/minute. After the addition was complete, the reaction was stirred for 30 minutes at 45° C., and then cooled to 10° C. and stirred for 1 h. The mixture was filtered and the solid collected was washed with methanol (130 mL) and water (260 mL), and then dried to a constant weight in a vacuum-oven at 45° C. to give the title compound as a solid (67 g, 99.4 area % purity by HPLC, 89.7% yield) melting at 133-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1cc(Br)ccc1N1CCCCC1

Procedure:
5-Bromo-2-fluorobenzonitrile and piperidine were heated at 80° C. in DMSO in the presence of cesium carbonate to obtain 5-bromo-2-piperidin-1-ylbenzonitrile. F: 265.
Reaction SMILES: [I-].[K+].[CH3:3][N:4]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:5]1[N:10]=[C:9]([N:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][N:6]=1.Cl[CH2:21][CH2:22][CH2:23][CH:24]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:24]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:23][CH2:22][CH2:21][N:17]2[CH2:18][CH2:19][CH:14]([N:4]([CH3:3])[C:5]3[N:10]=[C:9]([N:11]([CH3:12])[CH3:13])[CH:8]=[CH:7][N:6]=3)[CH2:15][CH2:16]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: CN(C)c1ccnc(N(C)C2CCNCC2)n1
Agent: [I-]
Agent: [K+]
Product: CN(C)c1ccnc(N(C)C2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)n1

Procedure:
Using the same procedure as describe in example B.1 and adding a small amount of potassium iodide to the reaction mixture, intermediate 2 was reacted with 1,1′-(4-chlorobutylidene)bis[4-fluorobenzene] to form N2-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-N2,N4,N4-trimethyl-2,4-pyrimidinediamine (comp. 44, mp. 106.3° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:21](OC)([CH3:23])[CH3:22].CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH3:22][C:21]1([CH3:23])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][O:14]1
Reactant: COC(C)(C)OC
Reactant: COC(=O)[C@@H](CO)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: COC(=O)[C@H]1COC(C)(C)N1C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of methyl N-[(benzyloxy)carbonyl]-D-serinate (1013 mg) and 2,2-dimethoxypropane (4166 mg) in acetone (20 mL) was added pyridin-1-ium 4-methylbenzenesulfonate (201 mg) at room temperature, and the reaction mixture was stirred at 60° C. overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (860 mg).
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:1]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][N:3]2[CH3:8])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1CCCCC1=N
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)Nc1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to the free base in benzene in the usual manner. After drying over K2CO3 and filtering, a benzene solution of 0.05 mole of p-chlorophenylisocyanate is added dropwise with stirring. After addition is complete, further stirring is continued for about 6 hours at room temperature. The benzene is evaporated in vacuo and the solid residue is recrystallized from methanol to give the product, 1-(4-chlorophenyl)-3-(1-methyl-2-piperidylidene)urea.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH3:21])[CH:17]=3)[CH:12]=[C:11]([N:22]3[CH2:25][CH2:24][CH2:23]3)[N:10]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:21][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[CH:12]=[C:11]([N:22]3[CH2:23][CH2:24][CH2:25]3)[N:10]=[C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[C:29]4[CH:30]=[CH:31][C:26]([CH3:35])=[CH:27][CH:28]=4)=[CH:3][CH:4]=3)[N:14]=2)[NH:20][N:19]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(N)cc3)n2)[nH]n1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccc(Sc3nc(Nc4cc(C)n[nH]4)cc(N4CCC4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
2-(4-Aminophenylthio)-6-(azetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine (200 mg, 0.57 mmol) was taken up in pyridine (2 mL) and p-toluoyl chloride (0.187 mL, 1.42 mmol) was added dropwise at room temperature. After 15 minutes the reaction mixture was concentrated in vacuo and the residue taken up in methanol (3 mL). Sodium methoxide (25% w/w solution in MeOH, 1 mL) was added and the resulting cloudy solution stirred at room temperature for 15 minutes. The reaction mixture was purified directly by chromatography (silica, 5-100% EtOAc-petrol gradient elution) to give the title compound (91 mg, 34%) as a white solid. 1H NMR: (400 MHz, DMSO) 1.99 (3H, brs), 2.33 (2H, qn), 2.40 (3H, s), 3.88 (4H, t), 5.38 (1H, brs), 5.59 (1H, vbrs), 7.36 (2H, d), 7.53 (2H, d), 7.87 (2H, d), 7.91 (2H, d), 9.20 (1H, brs), 10.36 (1H, s), 11.66 (1H, brs); MS (ES+) 472.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:36])[CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.O.NN>C(O)C>[NH2:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:37])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)[CH3:22])=[O:36]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Yield: 99.3 %

Procedure:
A mixture of 8-[2,6-dichloro-3-[N-(phthalimido-acetyl)-N-methylamino]benzyloxy)-2-methylquinoline (3.98 g), hydrazine monohydrate (0.72 ml) and ethanol (40 ml) was heated under reflux for 1 hour. The precipitate was removed by vacuum filtration and the filtrate was evaporated in vacuo. The residue was dissolved with dichloromethane and the precipitate was removed by vacuum filtration. The filtrate was evaporated in vacuo to give 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy)-2-methylquinoline (2.99 g) as a yellow amorphous powder.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:10]1[CH:2]=[CH:3][CH:4]=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1c(F)cccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 13, substituting 6-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid. 1H NMR (400 MHz, CD3OD): 7.96 (s, 2H), 7.87-7.82 (m, 1H), 7.70 (td, J=8.1, 5.1 Hz, 1H), 7.59 (ddd, J=9.7, 8.4, 1.4 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[S:24][C:23](=[O:25])[NH:22][C:8]=2[N:9]=[C:10]([S:12]([CH2:15][C:16]2C=C[CH:19]=[CH:18][CH:17]=2)(=O)=O)[N:11]=1)[CH3:4].C(S)C1[O:31]C=CC=1>>[O:31]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:15][S:12][C:10]1[N:11]=[C:6]([NH:5][C@H:3]([CH3:4])[CH2:2][OH:1])[C:7]2[S:24][C:23](=[O:25])[NH:22][C:8]=2[N:9]=1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2ccccc2)nc2[nH]c(=O)sc12
Reactant: SCc1ccco1
Product: C[C@H](CO)Nc1nc(SCc2ccco2)nc2[nH]c(=O)sc12

Procedure:
The titled compound was prepared from the product of example 24 step (a), using the method of example 23, step (b) using furfuryl mercaptan
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[Br:24]Br.O>C(Cl)(Cl)Cl>[Br:24][CH:11]1[C:10](=[O:14])[C:9]2[CH:15]=[C:16]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[O:13][CH2:12]1
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)CO2
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
In 300 ml of chloroform was dissolved 33.3 g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. To this solution being maintained at 25°-30° C. was dropwise added 16.3 g of bromine in 30 minutes. After the completion of the dropwise addition, the mixture was stirred for 30 minutes at 25°-30° C. 100 ml of water was added thereto. The organic layer was separated, washed with a 5% aqueous sodium thiosulfate solution, water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 40.1 g (yield: 97.3%) of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[CH3:18])[CH:7]=1.[CH:21](O)([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:1][C:2]1[C:3](=[O:20])[N:4]([CH:21]([CH3:23])[CH3:22])[C:5](=[O:19])[N:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[CH3:18])[CH:7]=1
Reactant: Cc1ccc(C(F)(F)F)cc1-n1cc(I)c(=O)[nH]c1=O
Reactant: CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)F)cc1-n1cc(I)c(=O)n(C(C)C)c1=O
Temperature: 25 °C

Procedure:
To a solution of 5-iodo-1-(2-methyl-5-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 118) (645 mg) in THF (20 ml) were added isopropyl alcohol (0.25 ml), triphenylphosphine (855 mg), diethyl azodicarboxylate (2.2 M toluene solution, 1.48 ml), and the resulting mixture was stirred at room temperature for twenty-five minutes. The reaction solutions were concentrated under reduced pressure and the residue was then purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-iodo-3-isopropyl-1-(2-methyl-5-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (548 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5]CC)=O.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O1CCOCC1>[OH:1][CH2:2][C:3]([N:12]1[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]1)=[O:5]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CO
Solvent: C1COCCO1
Product: CN1CCN(C(=O)CO)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-1-(4-methyl piperazin-1-yl)ethanone was prepared according to the following procedure: Ethyl 2-hydroxyacetate (6.85 g, 65.8 mmol, 1.0 eq) and 1-methylpiperazine (5.26 g, 52.6 mmol, 0.8 eq) were dissolved in 1,4-dioxane (10 mL) in a sealed tube and the mixture was stirred at 120° C. overnight. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2% MeOH-DCM) to afford the product 2-hydroxy-1-(4-methyl piperazin-1-yl)ethanone.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH2:27][C:26]([F:30])([F:29])[F:25])=[O:24])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 98 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (115 mg, 98%) which was obtained as a white solid. MS: m/e=393.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[N:19]([CH3:20])[N:18]=[N:17][N:16]=2)(=[O:9])=[O:8])=[N:5][N:4]=[N:3]1.[OH:21]O.O>C(O)=O>[CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([C:15]2[N:19]([CH3:20])[N:18]=[N:17][N:16]=2)=[O:21])(=[O:8])=[O:9])=[N:5][N:4]=[N:3]1
Reactant: OO
Reactant: Cn1nnnc1SCCCCS(=O)(=O)c1nnnn1C
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1S(=O)CCCCS(=O)(=O)c1nnnn1C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)thiobutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (1 g) is dissolved in formic acid (10 ml), and thereto is added with stirring 30% hydrogen peroxide (0.4 g) at room temperature, and the mixture is stirred for 3 hours. Water is added to the mixture and the precipitated crystals are collected by filtration and recrystallized from ethanol-chloroform to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)sulfinylbutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (0.4 g) as colorless scales, m.p. 147°-149° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([N+:25]([O-])=O)=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[O:6])[CH2:3][CH2:2]1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:13]=2)=[CH:16][CH:17]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1)NC1CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)NC3CC3)c2)c2ccccc12

Procedure:
A solution of 1-cyclopropyl-3-(4-((4-nitronaphthalen-1-yl)oxy)pyridin-2-yl)urea (118 mg, 0.324 mmol) in a mixture of MeOH (20 mL) and AcOH (0.5 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 70 mm, 10% Pt—C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo and the residue was partitioned between DCM (20 mL) and saturated aq. NaHCO3 (10 mL). The organic phase was separated and was washed with brine (10 mL), and then dried and evaporated in vacuo to afford the title compound, Intermediate D3, as a brown solid (90 mg, 83%); Rt 1.52 min (Method 2); m/z 335 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[N:30]1([CH2:35][CH2:36]O)[CH:34]=[CH:33][N:32]=[CH:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:36][CH2:35][N:30]5[CH:34]=[CH:33][N:32]=[CH:31]5)[C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OCCn1ccnc1
Product: O=C1SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCn1ccnc1

Procedure:
5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-(2-imidazol-1-ylethyl)thiazolidine-2,4-dione was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and 2-imidazol-1-ylethanol following General Procedure J.
Reaction SMILES: C(OC([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)(OCC)C)C.[Li]CCCC.[Br:19][C:20]1[CH:33]=[C:32]2[C:23]([O:24][C:25]3[C:26]([F:37])=[CH:27][C:28]([O:35][CH3:36])=[CH:29][C:30]=3[C:31]2=[O:34])=[CH:22][CH:21]=1>C(OCC)C>[Br:19][C:20]1[CH:33]=[C:32]2[C:23]([O:24][C:25]3[C:26]([F:37])=[CH:27][C:28]([O:35][CH3:36])=[CH:29][C:30]=3[C:31]2([C:10]2[NH:9][CH:13]=[CH:12][N:11]=2)[OH:34])=[CH:22][CH:21]=1
Reactant: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Reactant: CCOC(C)(OCC)n1ccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(F)c2c(c1)C(O)(c1ncc[nH]1)c1cc(Br)ccc1O2
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
1-(1,1-Diethoxyethyl)-1H-imidazole (7 g, 38.0 mmol) was dissolved in diethyl ether (100 ml) and cooled to −40° C. and n-BuLi (1.6M in hexane) (23.75 ml, 38.0 mmol) was added. The solution was stirred for 10 minutes and 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (Example 5, 6.14 g, 19.00 mmol) was added in one portion. The solution was stirred one hour at −40° C., then allowed to warm to RT for 15 minutes. The solution was quenched with 2 N HCl until at pH 1, stirred for 15 minutes, then made basic with concentrated sodium carbonate and stirred for 15 minutes. The product was collected by filtration. The filtrate was also extracted with EtOAc, the extracts were concentrated and combined with the material collected by filtration. The product was loaded onto silica and purified via silica gel column chromatography (RediSep 80 g column) using 10-50% 90/10/1 (DCM/MeOH/ammonia) in DCM to afford 7-bromo-4-fluoro-9-(1H-imidazol-2-yl)-2-methoxy-9H-xanthen-9-ol (3.4 g, 8.69 mmol) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:16][CH2:15]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][CH2:15]2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](OCCCCO)CC1)S(=O)(=O)c1ccc(Cl)cc1
Product: CN(C[C@H]1CC[C@H](OCCCCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-4-chloro-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-benzenesulfonamide was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-(4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-cyclohexyloxy)-butyl ester as colorless solid, MS: 468 (MH+, 1Cl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:14]1[S:22][C:21]2[C:16](=[N:17][CH:18]=[CH:19][C:20]=2[NH:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH3:33])=[CH:27]3)[CH:15]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[S:22][C:21]4[C:16](=[N:17][CH:18]=[CH:19][C:20]=4[NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][C:28]([CH3:33])=[CH:27]5)[CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc6c(c5)OCO6)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 1,3-benzodioxole-5-boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.00 (d, 1H), 7.38 (s, 1H), 7.26 (m, 2H), 7.13 (m, 2H), 6.93 (d, 1H), 6.77 (d, 1H), 6.52 (d, 1H), 6.08 (s, 1h), 5.92 (s, 2H), 2.39 (s, 3H); RP18-HPLC RT: 6.09 minutes; API MS: 400 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[C:19]([F:20])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:21])[CH:12]=2)[CH:5]=[N:6][C:7]=1Cl.[H-].[Na+].[CH:24]([OH:27])([CH3:26])[CH3:25].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[C:19]([F:20])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:21])[CH:12]=2)[CH:5]=[N:6][C:7]=1[O:27][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)O
Reactant: O=C(O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(COc2cc(F)c(C(=O)O)cc2F)cc1Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a solution of 4-((5,6-dichloropyridin-3-yl)methoxy)-2,5-difluorobenzoic acid (Preparation 14, 210 mg, 0.67 mmol) in THF (5 mL) was added an oil dispersion of NaH (60%, 157 mg, 3.93 mmol) followed by iso-propanol (5 mL) and the reaction mixture was warmed to 80° C. and stirred for 18 hours under a nitrogen atmosphere. Aqueous hydrogen chloride solution (1 M, 20 mL) was added and the mixture extracted with EtOAc (3×30 mL). The combined organics were dried over magnesium sulfate and the solvent was removed in vacuo. The resulting crude was purified by reverse phase chromatography eluting with H2O/MeCN/HCOOH (95/5/0.1 to 5/95/0.1, Biotage™ 40 g C18-silica gel) to yield the title compound (105 mg, 46%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[N:23]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[N:23]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCCn1nnc2cc(C3=NNC(=O)CC3)ccc21
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNCCn2nnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.