Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCC2)cn1
Yield: 81 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using cyclopentylamine (1 M in DMF) instead of methylamine, to the title compound (98 mg, 81%) which was obtained as a white solid. MS: m/e=378.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.[F:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28].C(OCC)(=O)C.O>CN1CCCC1=O.CCCCCC>[F:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: Nc1ccccc1F
Solvent: CCCCCC
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Nc3ccccc3F)ncn2)cc1
Yield: 31 %

Procedure:
N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200 mmol) and 2-fluoroaniline (111 mg, 1.00 mmol) were heated and stirred in 1-methylpyrrolidone (1 ml) at 170° C. for 3 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=3:2), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (26.0 mg, 0.062 mmol, 31%) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1C(C)[CH:10]1[CH3:11].O1C(C=C)C1.C1OC1C1C=CC=CC=1.C(C1OC=CC=1)C.C(C1OC=CC=1)(C)(C)C.CC1OC=CC=1C.O1C2C=CC=CC=2CC1.B(OCC1C=COC=1)(OC)OC.C[Si](C)(C)C1OC=CC=1.C[Si](C)(C)C1C=COC=1.O1C=CN=C1.O1C=NN=C1.ClC(CCl)C1OC1.BrC(CBr)C1OC1>>[CH2:8]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH2:10][O:1]1
Reactant: CC1OC1C
Reactant: C1CCCOCCC1
Agent: BrCC(Br)C1CO1
Agent: C=CC1CO1
Agent: CC(C)(C)c1ccco1
Product: c1ccc2c(c1)CCOC2

Procedure:
oxocane; 2,3-epoxybutane; 1,2-epoxybut-3-ene; styrene oxide; 2-ethylfuran; 2-tert-butylfuran; 2,3-dimethylfuran; 2,3-dihydrobenzofuran; dimethyl 3-furylmethyl borate; 2-trimethylsilylfuran; 3-trimethylsilylfuran; oxazole; 1,3,4-oxadiazole; 3,4-dichloro-1,2-epoxybutane; 3,4-dibromo-1,2-epoxybutane and the like.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[C:24]([C:26]1([CH3:40])[CH2:31][CH2:30][C:29]2[C:32]([CH3:39])=[C:33]([OH:38])[C:34]([CH3:37])=[C:35]([CH3:36])[C:28]=2[O:27]1)#[CH:25].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][C:26]3([CH3:40])[CH2:31][CH2:30][C:29]4[C:32]([CH3:39])=[C:33]([OH:38])[C:34]([CH3:37])=[C:35]([CH3:36])[C:28]=4[O:27]3)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc3c(c1)C(c1ccccc1F)=NCc1nnc(C)n1-3)O2

Procedure:
The title compound was prepared by coupling 6-(2-fluoro-phenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with rac-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol [ref. H. Mayer et al., Helv. Chim. Acta, 67, 650 (1963)]under the conditions described in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The clean fractions containing product were combined and evaporated. The residue was crystallized from ethanol/ethyl acetate to give colorless crystals of rac-2-{[6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]ethynyl}-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with m.p. 265°-267°.
Reaction SMILES: [C:1]([N:8]1[C@H:12]([CH:13]=O)[C@@H:11]([CH3:15])[O:10][C:9]1([CH3:17])[CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CO.CCOC(C)=O>[C:1]([N:8]1[C@H:12]([C:13]#[CH:18])[C@@H:11]([CH3:15])[O:10][C:9]1([CH3:17])[CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C=O
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#C[C@@H]1[C@@H](C)OC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of (4S,5R)-N-Boc-2,2,5-trimethyl-oxazolidine-4-carbaldehyde (1.52 g, 5.43 mmol) (Example 102A above) and dimethyl(1-diazo-2-oxopropyl)phosphonate (1.57 g, 8.15 mmol) in dry MeOH (30 mL) was added K2CO3 at 0° C. The mixture was stirred at 0° C. for 30 min and room temperature for 20 h. After addition of saturated aqueous NH4Cl and EtOAc, the organic layer was separated and aqueous layer was extracted with EtOAc (3×). The ethyl acetate layers were combined and dried with MgSO4. The crude material was purified by flash column chromatography eluting with EtOAc/hexanes (1:6) to give (4R,5R)-N-Boc-2,2,5-Trimethyl-4-ethynyl-oxazolidine. (Yield 0.97 g, 65%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[N-:25]=[N+]=[N-].[Li+].CC(C)=O>C(Cl)(Cl)Cl.O>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH2:25])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Br
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N

Procedure:
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosylamine was prepared as follows. 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl bromide (11.25 g, 30.8 mmol) was reacted with lithium azide (2.25 g, 46 mmol) in refluxing acetone (50 ml) under nitrogen atmosphere for 19 hr. The acetone was then removed under reduced pressure to give a semi-solid residue, which was taken up in a mixture of chloroform and water. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to give the crude azo-saccharide as a brownish residue. This residue was dissolved in ethyl acetate and decolorized with activated carbon. Addition of ether to the ethyl acetate containing the product yielded the sugar azide as a white precipitate. TLC on silica (methanol:chloroform/1:9) showed a single homogenous spot. The resulting azide (4.0 g) was hydrogenated over platinum oxide (0.3 g) at room temperature and atmospheric pressure. After the completion of the reaction, the catalyst was filtered off and the solution was evaporated to dryness to give the aminosaccharide (3.4 g) as a white solid. TLC gave one spot (methanol:chloroform/1:9).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH:6]1[CH2:4][OH:3]
Reactant: CCOC(=O)C1CCc2ccccc2N1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1CCc2ccccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2,3,4-Tetrahydroquinoline-2-carboxylic acid ethyl ester (4.75 g, 25 mmol) in THF (5 ml/mmol) was added dropwise at 0° C. to a suspension of LAH (2 eq.) in THF (50 ml). The reaction mixture was stirred for 1 h at RT and then heated for 4 h under reflux. After addition of saturated aqueous Na2SO4 solution, filtration was carried out and the organic solvent was removed in vacuo. The product was purified by column chromatography (silica gel, ethyl acetate/hexane 3:7).
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C@@H:27]([CH2:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]1=[O:39])[CH2:20]2.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][N:2]1[C:6]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH2:40][C:41]2[CH:42]=[C:43]([F:48])[CH:44]=[C:45]([F:47])[CH:46]=2)[CH2:28][N:29]2[C:30](=[O:39])[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]2=[O:38])[CH2:20]3)=[CH:5][CH:4]=[N:3]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cc(F)cc(F)c1)N1Cc2cc(Br)ccc2C1=O
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cc(F)cc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.557 g, 2.68 mmol), bis(tri-t-butylphosphine)palladium (0.114 g, 0.223 mmol), 2-[(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1, 3(2H)-dione (1.05 g, 2.06 mmol) and N,N-diisopropylethylamine (1.16 mL, 6.69 mmol) in 1,4-dioxane (12 mL, 150 mmol) and water (0.60 mL, 33 mmol) was stirred under microwave at 110° C. for 15 minutes. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with EtOAc/hexane (30-100%) to give 0.72 g (68.4% yield) of the desired product. LCMS found: 513.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH:20]=C)[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[O:30]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:30])[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Reaction time: 0.33 h
Yield: 99 %

Procedure:
The experimental for Intermediate 5 Batch 1 was followed using OsO4 (27 mg, 0.11 mmol), 1-[(4-methylphenyl)sulfonyl]-4-vinyl-1H-indole (0.321 g, 1.08 mmol; Intermediate 4), 2,6-lutidine (0.251 mL, 0.23 mmol), dioxane (12 mL), sodium periodate (0.924 g, 4.32 mmol) and water (4 mL). The mixture was stirred for 20 min. and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered, combined with Intermediate 5 Batch 1, and concentrated to give a total yield of 390 mg, 99% of a black solid. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[CH:19]1[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.O>CCCCCC.C1(C)C=CC=CC=1>[F:28][C:27]([F:29])([F:30])[C:21]1[CH:20]=[CH:19][C:24]([CH:25]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]3=[CH:9][C:8]=2[CH3:18])[OH:26])=[CH:23][CH:22]=1
Reactant: Cc1cc2c(nc1Br)CCCCC2
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc2c(nc1C(O)c1ccc(C(F)(F)F)cc1)CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 ml) in toluene (20 ml) at -20° C., under nitrogen, was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyridine (6.0 g, 0.025 m) in toluen (30 ml). The reaction mixture was kept at -20° C. for 0.25 hours and then blown over into a solution of a,a,a-tri-fluoro-p-tolualdehyde (4.7 g) in toluene (30 ml) at -20° C. The solution was allowed to warm up to room temperature and water added. The organic phase was separated with 2N hydrochloric acid. This was basified with solid potassium carbonate and extracted with chloroform. The combined chloroform extracts were dried (MgSO4) and evaporated. The residue was recrystallised from n-hexane to give the title compound, (5.05 g) m.p. 131°-3° C.
Reaction SMILES: [OH:1]S(O)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>O>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:1])[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCC#Cc1ccccc1Br
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCCC(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into 20 cc of concentrated H2SO4 was dissolved 0.1 g (0.4 mmol) of the product of Example 1 to give a brown solution. The solution was allowed to stand at room temperature for 10 minutes. Thereafter, the solution was cooled to 0° C. in an ice bath and ice was then added to it. The solution was then diluted with water and extracted twice with ethyl acetate. The combined extracts were sequentially washed once each with water and brine and then dried (MgSO4). Removal of the solvent under reduced pressure produced a yellow oil which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41](O)=[O:42])=[CH:33][CH:32]=1>CN(C)C=O>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)O)c1
Reactant: Nc1cccnc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Pyridinamine (0.52 g, 5.47 mmol), EDC (0.84 g, 4.38 mmol), HOBT (0.89 g, 5.83 mmol) and N-ethylmorpholine (0.92 ml, 7.29 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 105; 1 g, 3.65 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 h. The N,N-dimethylformamide was evaporated on a buchi. Saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (100 ml) were added to the residue and the mixture was stirred for 30 min. The organics were separated and washed with water (50 ml), dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a pale yellow solid. No further purification was carried out. 1.23 g.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-(dimethylamino)ethylamine according to general procedure 1 providing the amino compound (456 mg, 74%) as a white solid; Rf=0.43 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=9.6 Hz, 1H), 7.46 (s, 1H), 6.77 (d, J=9.7 Hz, 1H), 3.83 (t, J=5.9 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H), 3.01 (s, 6H); ES-MS: (M+H)=284, 286 m/z.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C>ClCCl>[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:4][CH2:1][CH:2]=[CH2:3])=[CH:10][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: C=CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCNCc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of allylamine (17.8 g; 312 mmol) in 200 ml of dichloromethane was added 4-trifluoromethoxybenzyl bromide (16 g; 62.4 mmol) and DIEA 8.88 g; 68.4 mmol). After stirring at rt overnight the reaction mixture was extracted with one volume of water. The organic phase was dried over sodium sulfate and concentrated to afford N-[4-(trifluoromethoxy)benzyl]prop-2-en-1-amine (14 g; 97% crude yield), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7](=[O:21])[N:6]([CH3:22])[C:5]2([CH2:27][N+:28]([O-])=O)[C:23]([F:26])([F:25])[F:24].CO.O.[Cl-].[NH4+]>C1COCC1.[Fe]>[NH2:28][CH2:27][C:5]1([C:23]([F:25])([F:26])[F:24])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:7](=[O:21])[N:6]1[CH3:22]
Reactant: COc1ccc(CN2C(=O)N(C)C(C[N+](=O)[O-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)N(C)C(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
6-Bromo-1-(4-methoxybenzyl)-3-methyl-4-(nitromethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (217.3 mg, 0.445 mmol) was dissolved in THF (0.9 mL), methanol (0.9 mL) and water (0.5 mL), and iron (497 mg, 8.9 mmol) and ammonium chloride (476 mg, 8.9 mmol) were sequentially added to the reaction solution at room temperature. The reaction solution was stirred at 90° C. for 2.5 hours and then cooled to room temperature and insoluble substances were removed by Celite filtration. After the solvent was evaporated under reduced pressure, to the residue, chloroform and saturated sodium hydrogen carbonate were added, and the mixture was stirred at room temperature. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/4), whereby the objective 4-(aminomethyl)-6-bromo-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (148.3 mg, 72.7%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:5]=[CH:4][C:3]=1[C:25](=[O:27])[CH3:26]>C(O)C.CN(C)C=O.[Pd]>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH:5]=[CH:4][C:3]=1[C:25](=[O:27])[CH3:26]
Reactant: CCCc1c(OCCCOc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCc1c(OCCCOc2ccc(N)cc2)ccc(C(C)=O)c1O
Reaction time: 1.5 h

Procedure:
1-{2-Hydroxy-3-propyl-4-[3-(4-nitrophenoxy)propoxy]phenyl}ethanone (19.6 g) was dissolved in a mixture of ethanol (300 ml) and dimethylformamide (100 ml), to which was added under nitrogen, a slurry of palladium on charcoal catalyst (1.0 g, 5%) in ethanol (50 ml). The suspension was then hydrogenated on a Parr at 60 psi and room temperature for 90 minutes. The suspension was filtered over Celite (registered Trade Mark), washed with ethanol and the filtrate evaporated under reduced pressure to a brown oil, which was triturated with water and filtered to give a brown solid. The solid was recrystallised from ethanol with charcoal to give a white solid, m.p. 75°-77° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][NH:8][C:7]=2[CH:11]=1)#[N:2].[OH-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH2:18][CH2:17][CH2:16][CH2:15][Cl:14])[C:7]=2[CH:11]=1)#[N:2]
Reactant: N#Cc1ccc2nn[nH]c2c1
Reactant: ClCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2nnn(CCCCCl)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
6-cyano-benzotriazole (14.4 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3, and eluted with dichlormethane to produce 17.3 g of 6-cyano-1-(4-chlorobutyl)-1H-benzotriazole, with a yield of 74.0%.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13](F)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CC(C)([O-])C.[Na+].[Cl-].[NH4+]>CN1C(=O)CCC1>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:29][CH:26]3[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCCc1cc(F)c2ncccc2c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: CCCCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1

Procedure:
A solution of 6-butyl-8-fluoroquinoline (for example, as prepared for Intermediate 2) (14.4 g, 70.9 mmol) in NMP (20 ml) was added to a mixture of tert-butyl-4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (21.6 g, 108 mmol) and sodium tert-butoxide (10.4 g, 108 mmol) in NMP (75 ml), and the resulting mixture was stirred at 140° C. for approximately 90 min and then allowed to cool overnight. The reaction mixture was treated with ammonium chloride solution and extracted with EtOAc (×2). The combined organic extracts were washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash chromatography eluting with DCM-EtOAc (1:0 to 1:1) and then twice by Flashmaster chromatography eluting with DCM-EtOAc (1:0 to 3:1) over 40 min to give the title compound (22 g). LCMS RT=3.49 min, ES+ve m/z 385 [M+H]+