Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:3]1=2.[ClH:41]>CO.CCOCC>[ClH:41].[ClH:41].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][NH:31][CH2:32][CH2:33][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 38 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (73 mg, 0.13 mmol) was dissolved in MeOH (0.5 mL) and 2 N HCl in Et2O (3 mL) was added. The reaction was allowed to proceed for 3 h. The mixture was concentrated and purified by preparative HPLC. Conversion to the HCl salt (2 N HCl/Et2O) provided the title compound (26 mg, 38%) as a yellow solid: mp 311-315° C.; 1H NMR (500 MHz, CD3OD) δ 7.77 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.2 Hz, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.50 (s, 1H), 7.09 (dd, J=8.3, 1.8 Hz, 1H), 6.38 (dd, J=7.6, 2.7 Hz, 1H), 6.17 (d, J=2.7 Hz, 1H), 5.33 (s, 2H), 4.51 (s, 2H), 3.77 (s, 3H), 3.71 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.1 Hz, 2H); ESI MS m/z 454 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.2 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][O:22][CH:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:36][CH:37]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCOC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCOC2CCNCC2)cc1
Reaction time: 0.5 h
Yield: 180.4 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-[2-[1-(tert-butoxycarbonyl)piperidin-4-yloxy]ethoxycarbonyl]-1,2-benzenediamine (180 mg, 0.362 mmol) in methylene chloride (2 mL) was treated with trifluoroacetic acid (0.30 mL). After 0.5 h, the mixture was concentrated in vacuo. The residue was treated with 1 N aqueous sodium hydroxide followed by ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was taken up in methanol and treated with hydrochloric acid (gas, 1-2 eq) and concentrated in vacuo yielding the hydrochloride salt of the title compound (270 mg).
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.C(N)C.C(N(CC)CC)C.C1COCC1>C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH3:4])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Agent: CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)OCc1ccc(OC(C)=O)c(OC)c1
Yield: 70.4 %

Procedure:
A solution of VII (207 mg, 0.606 mmol), ethylamine (2M in THF, 31.5 mg, H2NEt, 350 μL of solution, 1.16×0.606 mmol H2NEt) and triethylamine (122 mg, 169 μL, 2×0.606 mmol) anhydrous THF (3 mL, 5 mL/mmol of 6) was stirred for one hour. The reaction mixture was diluted with CH2Cl2 and extracted with 1N HCl and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel using CH2Cl2/ethyl acetate (94:6, v/v) to give 114.1 mg (70%) of 18 as an oil: Rf=0.37 (CH2Cl2/EtOAc, 96:4, v/v); 1HNMR (CDCl3) δ 6.98 (d, 3J=8 Hz, 1H), 6.95 (bs, 1H), 6.92 (bd, 3J=8 Hz, 1H), 5.04 (bs, 2H), 4.68 (bs, 1H), 3.82 (s, 3H), 3.22 (m, 2H) and 1.13 (t, 3J=7.25 Hz, 3H). Exact mass (ESI) calculated for C13H18NO5 [M+H]=268.1179. found 268.1189.
Reaction SMILES: BrC1C=C(C=O)C=NC=1.Cl.N12CCC(CC1)C(=O)C2.[OH-].[K+].[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]2[C:35](=[O:36])[CH:34]3[CH2:37][CH2:38][N:31]2[CH2:32][CH2:33]3)[CH:26]=[N:27][CH:28]=1.[BH4-].[Na+]>>[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]2[CH:35]([OH:36])[CH:34]3[CH2:37][CH2:38][N:31]2[CH2:32][CH2:33]3)[CH:26]=[N:27][CH:28]=1
Reactant: O=C1C(=Cc2cncc(Br)c2)N2CCC1CC2
Agent: Cl
Agent: O=C1CN2CCC1CC2
Agent: O=Cc1cncc(Br)c1
Product: OC1C(=Cc2cncc(Br)c2)N2CCC1CC2

Procedure:
The manner in which 2-((4-, 5-, and 6-substituted-3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes can be synthesized can vary. For example, 5-bromopyridine-3-carboxaldehyde and 3-quinuclidinone hydrochloride (commercially available from Aldrich) can be reacted together in the presence of methanolic potassium hydroxide as described in Neilsen and Houlihan, Org. React. 16: 1 (1968). The aldol condensation product, 2-((5-bromo-3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one, can then be treated with sodium borohydride to yield the alcohol, 2-((5-bromo-3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol, as a crystalline solid. This intermediate is reacted with neat thionyl chloride at room temperature to give 3-chloro-2-((5-bromo-3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a pure crystalline solid. Reductive removal of the chlorine can be accomplished using lithium trimethoxyaluminum hydride and copper iodide as described by Masamune et al., J. Am. Chem. Soc. 95: 6452 (1973) to give the desired product, 2-((5-bromo-3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octane, as a crystalline solid. This methylene intermediate can then be converted to the desired product, 2-((5-bromo-3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane, by hydrogenation in the presence of palladium catalyst. The isomeric compounds, 2-((4-bromo-3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane and 2-((6-bromo-3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane can be prepared in a similar manner by replacing 5-bromopyridine-3-carboxaldehyde with 4-bromopyridine-3-carboxaldehyde or 6-bromopyridine-3-carboxaldehyde, respectively, in the synthetic approach given above.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][NH:8][C:7](=[O:17])[CH:6]=1)=O.B.[OH-].[Na+]>O1CCCC1>[CH3:18][N:2]([CH2:3][C:5]1[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:9][NH:8][C:7](=[O:17])[CH:6]=1)[CH3:1]
Reactant: CN(C)C(=O)c1cc(=O)[nH]nc1-c1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)Cc1cc(=O)[nH]nc1-c1ccccc1

Procedure:
2,3-Dihydro-3-oxo-6-phenyl-5-pyridazinecarboxylic acid is treated with ethyl chloroformate, triethylamine, and dimethylamine according to the procedure of Example 3 to give N,N-dimethyl-2,3-dihydro-3-oxo-6-phenyl-5-pyridazinecarboxamide. A solution of this amide (12.5 g) in 400 ml of tetrahydrofuran is treated with 100 ml of 1 M borane in tetrahydrofuran and the resulting mixture is heated under reflux for 4 hours, then cooled and treated with 5% sodium hydroxide (100 ml) and heated under reflux for 1 hour. The tetrahydrofuran is removed on the rotary evaporator and the pH of the residual liquid is adjusted with acetic acid followed by ammonium hydroxide to 10. The product is extracted into dichloromethane and the dichloromethane is filtered and concentrated on the rotary evaporator. The residue is chromatographed on silica gel with 2% methanol and chloroform to give 5-(dimethylaminomethyl)-6-phenyl-3(2H)-pyridazinone.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=O>>[S:9]1[C:8]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([F:19])=[C:11]([Br:10])[CH:12]=2)=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: c1ccc2sccc2c1
Product: Fc1ccc(Cc2cc3ccccc3s2)cc1Br

Procedure:
Thianaphthene and 3-bromo-4-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]=[CH:9][CH2:8]2)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(O)=[O:20].[OH-].[Na+]>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]1[O:20][CH:9]1[CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)CC=CC2
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)CC1OC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
A solution of 15.12 g of 1,4-dihydro-6-naphthol acetate in 160 ml of dichloromethane is cooled to 0° C. while 10.5 g of m-chlorobenzoic acid is added over 10 minutes. The mixture is stirred overnight at room temperature and then poured into a slurry of 100 g of ice and 50 ml of 10% aqueous sodium hydroxide. The layers are separated, the aqueous layer re-extracted with dichloromethane (two 100 ml portions), and the combined extracts are washed with water, dried, and evaporated in vacuo to give 16 g of the title compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.CCN(CC)CC.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:10]=1
Reactant: COc1ccccc1-c1cc(N)ncn1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(NC(=O)Cc2ccccc2)ncn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (0.15 g, 0.74 mmol) in THF (10 ml) was added NEt3 (0.210 ml, 1.49 mmol) under an atmosphere of nitrogen at ice bath temperature, followed by phenyl acetyl chloride (XLVI) (0.819 mmol) at the same temperature. The reaction mixture was stirred for 1 hour at 0° C. and then brought to room temperature and stirred for another hour. Usual work up as described above followed by column chromatographic purification over silica gel (30% ethyl acetate/hexane) yielded N-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-2-phenyl-acetamide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1.[CH2:12]([O:19][C:20]([O:22]N1C(=O)CCC1=O)=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:19][C:20](=[O:22])[N:2]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[CH3:1])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNC[C@H]1CC[C@H](CO)CC1
Solvent: CO
Product: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.1 g (13.35 mmol) trans-(4-methylaminomethyl-cyclohexyl)-methanol (example 1.1) were dissolved in 20 ml methanol. 3.32 g (13.35 mmol) N-(benzyloxycarbonyloxy)-succinimide were added and the solution was stirred at room temperature for 2 hours, then for 1 hour at 50° C. Afterwards, the solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was washed with water (2 times), then with brine and finally dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel with a 4:1 v/v mixture of dichloromethane and diethyl ether as the eluent. 1.67 g (42.9%) trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid benzyl ester were obtained as colorless oil, M: 289 (M).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[CH2:26]Cl.[K+].[Br-]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[CH2:26][N:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cc(Cl)cc(Cl)c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 3,5-dichlorobenzyl chloride, in 89% overall yield. A sample was crystallized from CH2Cl2 /hexane/ether to afford a white solid, mp 104°-106° C.; IR (KBr) 3525, 1680, 1570, 1505, 1398, 1063, 760 cm-1 ; 1H NMR (CDCl3) δ1.92 (brs, 1H), 2.17-2.37 (m, 2H), 3.93 (t, J=5.7 Hz, 2H), 4.87 (q, J=5.4 Hz, 1H), 5.13 (ABq, JAB =16.3 Hz, 2H), 6.78 (d, J=7.3 Hz, 1H), 6.93-7.05 (m, 2H), 7.12 (br d, J=1.7 Hz, 2H), 7.26-7.28 (m, 2H); Anal. Calc'd for C17H15Cl2NO3 : C, 57.97; H, 4.29; N, 3.98. Found: C, 57.96; H, 4.17; N, 3.87.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:3][NH:4][C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[N:7][N:6]=1.N.[CH3:32][C:33]([CH3:35])=O>CO>[NH2:1][C@@H:2]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)[CH2:3][NH:4][C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[C:13]3=[C:33]([CH3:35])[CH3:32])=[N:7][N:6]=1
Reactant: CC(C)=O
Reactant: N[C@H](CNc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)cc1
Agent: N
Solvent: CO
Product: CC(C)=C1C(=O)Nc2ccc(-c3nnc(NC[C@@H](N)Cc4ccc(C(F)(F)F)cc4)s3)cc21
Reaction time: 1 h

Procedure:
Example 2 (5-(5-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-1,3,4-thiadiazol-2-yl)indolin-2-one) (40 mg, 46 μmol) was dissolved in 1 mL of anhydrous acetone. To the resulting solution was added 2.0 mL of 2.0M ammonia in MeOH. The resulting mixture was stirred for one hour. After removing the solvent, the title compound was obtained as a white solid (20 mg, 48%). LCMS (API-ES) m/z (%): 474.1 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.45 (s, 3H) 2.59 (s, 3H) 3.06-3.18 (m, 2H) 3.54-3.65 (m, 1H) 3.66-3.76 (m, 1H) 3.86-3.96 (m, 1H) 6.94 (d, J=8.22 Hz, 1H) 7.49-7.57 (m, 3H) 7.62-7.70 (m, 2H) 8.00 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C@H:7]([O:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH3:8])[O:4][N:3]=1.CC(C)=O.[NH4+].[Cl-]>O.CCOC(C)=O.[Cl-].[Ti+3].[Cl-].[Cl-]>[CH3:1][C:2]1[CH:6]=[C:5]([C@H:7]([O:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH3:8])[O:4][N:3]=1
Reactant: Cc1cc([C@@H](C)Oc2ncccc2[N+](=O)[O-])on1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc([C@@H](C)Oc2ncccc2N)on1
Temperature: 5 °C

Procedure:
A mixture of 0.5 g (2.09 mmol) 3-methyl-5-[(1R)-1-[(3-nitro-2-pyridyl)oxy]ethyl]isoxazole and acetone are cooled to 5° C. and 87 ml (17.4 mmol) of titanium(III)chloride 20% in water and 24 ml (96 mmol) of a 4M solution of NH4Cl in water are added. The mixture is warmed to RT and stirred over night diluted with EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried and evaporated. The residue is purified by FC (DCM/MeOH 95:5).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)=[O:5])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1N
Yield: 47.9 %

Procedure:
The solution of N-(ethoxycarbonyl)-2-nitroaniline (2.0 g, 9.5 mmol) in absolute ethanol (25 mL) was hydrogenated at atmospheric pressure in the presence of 10% palladium hydroxide/carbon catalyst (200 mg). The catalyst was filtered off using a celite pad and the filtrate was evaporated. The residue was crystallized from isopropyl ether to give 2-[(ethoxycarbonyl)amino]aniline as a colorless solid (820 mg, 64.6% ).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])([O-:3])=[O:2].CI.[C:15](=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Br:11])[C:5]=1[O:12][CH3:15])([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Agent: [K+]
Solvent: CI
Product: COc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Yield: 96.5 %

Procedure:
2-Nitro-4-chloro-6-bromoanisole was prepared by the same procedure as described for Step 2 of Preparation 2a using 2-nitro-4-chloro-6-bromophenol (16 g), methyl iodide (10.8 g), and potassium carbonate (26.3 g). Workup gave crude 2-nitro-4-chloro-6-bromoanisole (16.3 g, 96%) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ7.80 (d, J=2.5 Hz, 1 H), 7.77 (d, J=2.5 Hz, 1H), 4.01 (s, 3H). 13C NMR (75 MHz, CDCl3) δ149.7, 137.2 (2C), 130.0, 124.4, 120.5, 62.8.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]2[NH:38]N>>[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]2[N:38]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: Cc1cc(NN)c2cc(F)ccc2n1
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c2cc(F)ccc2n1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (6-fluoro-2-methyl-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=482.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4].[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(Oc3ccc(F)cc3)cccc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2c(Oc3ccc(F)cc3)cccc2c1O
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A mixture of 8-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (1.21 g, 3.87 mmol), N-bromosuccinimide (723 mg, 4.06 mmol) and benzoyl peroxide (47 mg, 0.19 mmol) in carbon tetrachloride (20 mL) was refluxed for 4 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, and was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexane to give the title compound as a pale yellow solid (843 mg): MS: (+) m/z 392.00, 393.93 (M+1, 79Br/81Br).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:18]=[CH:17][CH:16]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:21]([C:22]#[N:23])([CH3:25])[CH3:24])[N:20]=2)[CH:7]=1
Reactant: CC(C)(C#N)c1cccc(N)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C#N)n1
Temperature: 130 °C

Procedure:
A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (1.4 g, 6.33 mmol) and 2-(6-aminopyridin-2-yl)-2-methylpropanenitrile (2.04 g, 12.7 mmol) was dissolved in acetonitrile (3.00 mL) and heated to 130° C. for 18 h. The mixture was cooled, concentrated, the residue was adsorbed on silica gel and purified by flash chromatography (silica gel 45 μM, 160 g, Thomson) eluting with 0 to 20% acetone in dichloromethane over 20 min, impure desired product was isolated, all fractions containing desired product were concentrated and the residue dissolved in a dichloromethane and evaporated to a small volume where a solid precipitated, filtered and dried and corresponded to the desired ethyl 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (792 mg, 36.2% yield). 1H NMR (CHLOROFORM-d) δ: 10.86 (s, 1H), 9.27 (s, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 4.58 (q, J=7.2 Hz, 2H), 1.81 (s, 6H), 1.52 (t, J=7.2 Hz, 3H); LC-MS 346.1 [M+H]+.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>>[CH3:13][C:12]1[C:7]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:33])([F:34])[F:23])=[CH:31][CH:30]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(OC(F)(F)F)cc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [4-(trifluoromethoxy)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (s, 3H), 2.34 (s, 3H), 4.70 (d, J=3.6 Hz, 2H), 5.92 (bs, 1H), 6.44 (bs, 1H), 7.01-7.21 (m, 3H), 7.16 (bs, 1H), 7.44-7.61 (m, 3H), 8.58 (bs, 1H); MS (ESI) m/z 390.7 (M+1)+.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][C:12]1[CH:25]=[CH:24][C:15]2[N:16]3[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:17]3[S:18][C:14]=2[CH:13]=1>C1COCC1>[CH3:11][C:12]1[CH:25]=[CH:24][C:15]2[N:16]3[C:21]([CH:22]([CH2:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[OH:23])=[CH:20][N:19]=[C:17]3[S:18][C:14]=2[CH:13]=1
Reactant: Cc1ccc2c(c1)sc1ncc(C=O)n12
Reactant: BrCCc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)sc1ncc(C(O)CCc3ccccc3)n12

Procedure:
Magnesium (0.29 g, 12 g atom) in THF (60 mL) was treated with (2-bromoethyl)-benzene (1.64 mL) and reacted for 18 hours. The suspension was treated with solid 7-Methyl-imidazo [2,1-b]benzothiazole-3-carboxaldehyde (Formula K-3) (0.65 g) and reacted for 2 hours. The reaction mixture was decanted into cold 5% ammonium chloride solution and precipitated 7-Methyl-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol (Formula K-4) (0.96 g) was filtered. An aliquot was crystallized from methylene chloride/ethanol solution to yield pure 7-Methyl-α-(2-phenylethyl) imidazo[2,1-b]benzothiazole-3-methanol (Formula K-4), m.p. 209-210°.