Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[CH:17]1([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[CH:17]1([CH2:22][CH2:23][C:24]([NH:16][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: ClCCl
Product: O=C(CCC1CCCC1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 63.8 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.13 g, 0.60 mmol), 3-cyclopentylpropionyl chloride (0.10 g, 0.63 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (15 mL) provided 3-cyclopentyl-N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)propanamide (0.13 g). MS (ESI) m/z 340 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[CH:7]=1.N12CCCN=C1CCCCC2>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:16])([F:15])[F:17])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C[C@@]1(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 65 °C
Yield: 95.9 %

Procedure:
A solution of N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (4 g, 789 mg, 1.718 mmol) in anhydrous MeOH (20 mL) was treated with 1,8-diazabicyclo-[5.4.0]undec-7-ene (Aldrich; 311 μL, 2.063 mmol) and heated to 65° C. for 16 h. The reaction mixture was concentrated and extracted into EtOAc from saturated aqueous NH4Cl. The organic extract was dried over MgSO4, concentrated, and purified by flash chromatography on silica gel (Gradient: 0%→50% EtOAc/hexane) to give (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (585 mg, 1.647 mmol) as a white foam. MS m/z=355 M+. Calculated for C12H11BrF4N2O: 355.1
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH3:15])=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17].[C:20](=[O:22])=[O:21].Cl>CCCCCC.CCOCC>[CH2:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([C:20]([OH:22])=[O:21])=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)[CH3:15]
Reactant: CCSc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCSc1ccc(C(=O)O)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of n-butyllithium in hexane (2.5M, 115 ml) was added dropwise with cooling to a stirred solution of 2-bromo-5-(ethylsulphenyl)benzotrifluoride (80.0 g) in anhydrous ether whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1.5 hours and poured onto solid carbon dioxide pellets. The mixture was stirred for 20 minutes then treated with hydrochloric acid (2M). The layers were separated and the organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness. The residue was triturated with cyclohexane and filtered to give 4-(ethylsulphenyl)-2-trifluoromethylbenzoic acid as an off-white solid, m.p. 133.5° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:18])(=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>O>[CH2:13]([N:12]([CH2:15][CH3:16])[S:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[C:6]([OH:8])=[O:7])(=[O:18])=[O:17])[CH3:14]
Reactant: CCN(CC)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Product: CCN(CC)S(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1
Temperature: 80 °C

Procedure:
29 Grams of 4-chloro-3-diethylsulfamoyl-benzoic acid were heated with 30 g of N-methylpiperazine for 4 hours at 140° C. Subsequently the reaction solution, which had cooled down to 80° C., was introduced into 0.4 l of water, and the solution was neutralized with 5N HCl. As soon as the precipitate, which was amorphous at first, became crystallized, it was suction-filtered and recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=[C:11]([CH:13]=O)[N:12]=1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=[C:11]([CH2:13][NH:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:12]=1
Reactant: O=Cc1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: NC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(-n2cc(CNC3CCCCC3)nc2-c2ccccc2Cl)cc1
Temperature: 4 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxaldehyde (62 mg, 0.20 mmol) in methanol (7 mL) was added cyclohexylamine (58 μL, 0.5 mmol). The mixture was stirred overnight, and cooled to 4° C. NaBH4 (40 mg, 1.1 mmol) was added. The mixture was stirred at rt for 1 h, and concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC (50% EtOAc in hexane) to give N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]methyl}-N-cyclohexylamine (65 mg, 81% yield): LC-MS m/z (400.7 MH+), retention time 2.32 min (method 1).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[N:14]=[C:15]([C:19](Cl)(Cl)Cl)[NH:16][C:17]=1[Cl:18].C(N(CC)CC)C>O1CCOCC1>[Cl:12][C:13]1[N:14]=[C:15]([C:19]2[O:11][C:8]([O:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9][N:10]=2)[NH:16][C:17]=1[Cl:18]
Reactant: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Reactant: NNC(=O)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1nc(-c2nnc(Oc3ccccc3)o2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
16.7 g (0.11 mol) of carbazic acid phenyl ester were added in portions, at room temperature, to a solution of 25.4 g (0.1 mol) of 4,5-dichloro-2-trichloromethyl-imidazole in 200 ml of dioxane. After the slightly exothermic reaction had subsided, the mixture was gradually warmed to the boil and boiled for a further 2 hours under reflux. It was then cooled to room temperature and 20.2 g (0.2 mol) of triethylamine were added dropwise. The mixture was stirred for a further 2 hours at 50° C., the insoluble constituents were filtered off and the filtrate was evaporated in vacuo. The residue was treated with water and the product was filtered off, washed with water and dried. 21.5 g (72.5% of theory) of 2-(4,5-dichloro-imidazol-2-yl)-5-phenoxy-1,3,4-oxadiazole were obtained. Melting point: 109° C. (from toluene).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:44][CH:45]1[CH2:50][CH2:49][O:48][C:46]1=[O:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:44][CH:45]3[CH2:50][CH2:49][O:48][C:46]3=[O:47])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Reactant: NC1CCOC1=O
Agent: Br
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)NC3CCOC3=O)cc2)cc1

Procedure:
The product from Example 234B and alpha-amino-gamma-butyrolactone hydrobromide were processed as described in Example 251A to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ8.94 (s, 1 H), 8.33 (d, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.53 (dd, 1 H), 4.34 (t, 1 H), 4.20 (m, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (t, 2 H), 3.44 (m, 1 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.16 (m, 3 H), 1.55-1.78 (m, 4 H); MS (ESI+) m/z 672 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=C(OC)C=CC=1C[N:21]1[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][C@@H:23]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)(=[O:33])=[O:32])[C:22]1=[O:41]>ClCCl>[F:29][C:25]1([F:28])[CH2:26][CH2:27][NH:21][C:22](=[O:41])[C@H:23]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)(=[O:32])=[O:33])[CH2:24]1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)c3ccc(Cl)cn3)C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cn1

Procedure:
A mixture containing trifluoroacetic acid/trifluoromethanesulfonic acid (5:2 v/v, 2.44 ml) was added to 5-chloro-pyridine-2-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-amide (0.37 g, 0.76 mmol) in dichloromethane (20 ml). After 2 h the reaction mixture was concentrated under reduced pressure and the residue taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified over silica gel (heptane-ethylacetate, 1:1-0:1); white solid 0.22 g (84%); MS: m/e=340.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C-]#N.[K+].[OH2:13]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)C(O)c1ccc(Cl)cc1

Procedure:
42.2 g of 4-chlorobenzaldehyde and 5 g of KCN were heated under reflux in 300 ml of a 1:1 mixture of ethanol and water for 6 hours. After cooling, the ethanol was stripped off, the residue was cooled in an ice bath and the supernatant aqueous phase was decanted off. The product was recrystallized from ethanol/petroleum ether and dried. 22 g of the compound Z1 mentioned in the title were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[C:21]([O:28][CH3:29])[CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:34]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:39]=1>>[CH2:34]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:30]=[CH:31][CH:32]=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH:14]=2)=[CH:20][C:21]=1[O:28][CH3:29])[CH3:39]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1cc(NC(=O)c2cccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)ccc1C(=O)O
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)cc1OC

Procedure:
4-[3-(3,5-Dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid, MS (ISP): m/e=493.2 (M−H), was prepared in analogy to example 17, steps A to D. Step C was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,5-dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.P(Cl)(Cl)([Cl:17])=O.Cl.OP(O)(O)=O>C(#N)C>[Cl:17][C:3]1[N:4]=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccccc2)n[nH]c1=O
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)nnc1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
6.0 g (32 mmol) of 14 was placed in a 250 nit single neck round bottom flask and 30 ml acetonitrile was added to create a pale yellow slurry. 6.0 ml (64 mmol, 2 equiv) of phosphorus oxychloride was added and the reaction mixture was heated at reflux for 2.5 h. After the reaction was completed, the Mixture was cooled to ambient temperature and placed in an ice water bath. Ice water (150 mL) was slowly poured into the reaction mixture with stirring to decompose the phosphorus oxychloride into HCl and H3PO4. The solid was then collected by filtration and washed with Milli-Q water (3×50 mL). The solid was suspended in 100 mL of water and 1N NaOH was added until the aqueous suspension was at pH=8. The mixture was stirred for 5 minutes to remove all trace starting material contaminants. The solid was filtered and washed with Milli-Q water (3×100 mL). The product was dried over a medium frit sintered glass funnel in vacuo to provide 15 as a light pink powder in 96% yield. 1H NMR (DMSO-d6): δ 829 (s, 1H), 8.10 (at, 2H), 7.53 (m, 3H), 2.41 (s, 3H), HPLC (tr/purity): 2888.98 min, >94%. ESI m/z (MeOH) 205.49 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Li+].[Li+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(O)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
To a solution of 2,5-dihydroxybenzaldehyde (10.41 g, 75.4 mmol) in 100 mL of DMF was added lithium carbonate (16.71 g, 226 mmol), followed by benzyl bromide (13.5 mL, 113 mmol). The solution was warmed to 60° C. and stirred for 30 hours. The reaction was poured into EtOAc and washed with water, saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown oil which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(C(C)C)C(C)C)C.N1(C(N2C=CN=C2)=O)C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]2[C@@H:39]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)[N:38]([C@H:47]([CH2:53][CH3:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:37](=[O:55])[C@@H:36]([CH2:56][C:57](O)=[O:58])[CH2:35]2)[CH:31]=[CH:32][CH:33]=1.[NH4+].[Cl-]>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:30]([C@H:34]2[CH2:35][C@H:36]([CH2:56][C:57]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:58])[C:37](=[O:55])[N:38]([C@@H:47]([CH2:53][CH3:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[C@@H:39]2[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)[C@@H](CC)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)NS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methanesulfonamide (0.02 g, 0.2 mmol), N-ethyl-N-isopropylpropan-2-amine (0.05 ml, 0.3 mmol), di(1H-imidazol-1-yl)methanone (0.04 g, 0.2 mmol) and 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3, 0.030 g, 0.06 mmol) were combined in 2 mL of THF. After being stirred at 25° C. for 12 h, sat. NH4Cl solution was added and the reaction mixture was extracted with EtOAc. The combined organic layers were successively washed with sat. aq. NaHCO3 solution and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase HPLC (10 to 90% AcCN/H2O with 0.1% TFA in 45 min) to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1.C[O-:18].[Na+]>CO>[OH:18][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2c(cc1Cl)-c1ccccc1CO2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2c(cc1O)-c1ccccc1CO2

Procedure:
Add 23.1 gm of 2-chloro-4,6-dihydro-3H[2]benzopyrano[3,4-b]pyridin-3-one to 300 ml of methanol containing 30 gm of sodium methoxide. Heat the system in a steel bomb at about 200° C. for 12 hours. Stop the reaction and remove the solvent by stripping. Treat the residue with water and then isolate the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:24]([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[CH3:25]>>[CH2:24]([N:26]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][C:22]=4[F:23])[N:19]=[CH:18][CH:17]=[CH:16]5)[OH:12])=[CH:9][N:10]=3)[N:7]=2)[CH:28]=[N:27]1)[CH3:25]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Product: CCn1cc(-c2ccc3ncc(C(O)c4cc5cccnc5cc4F)n3n2)cn1

Procedure:
The title compound was prepared in analogy to Example 9 using (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol (Stage 174.3) instead of (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-imidazo[1,2-a]pyridin-6-yl-methanol (Stage 9.1) and 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (tR 3.38 min (conditions 3), MH+=389.2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)CC)C.Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:34][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20]
Reactant: CCCCCCCCN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), octylamine (0.460 g, 3.56 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (50 ml), and the mixture was extracted with ethyl acetate (50 ml×3 portions). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from ether to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-octyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.410 g, 30.2% yield).
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[C:28]([CH:31]=1)[C:29]#[N:30]>CS(C)=O.ClCCl>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[O:15])=[CH:12][CH:13]=2)=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(Nc3ccc(Br)cc3C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.8 %

Procedure:
KOtBu (2.81 g, 25.08 mmol) was dissolved in 20 ml DMSO in a round bottom flask. (4-aminophenyl)(4-methylpiperazin-1-yl)methanone (5.0 g, 22.80 mmol) in 30 ml DMSO was added and the resulting mixture was stirred for 15 minutes at r.t. The mixture was cooled in an iced bath for 5 minutes. 5-bromo-2-fluorobenzonitrile (4.6 g, 23.00 mmol) in 20 ml DMSO was added. The ice bath was removed and the mixture stirred for 5 hours while warming to room temperature. Additional KOtBu (2 g, 17.82 mmol) was added and the mixture stirred at room temperature overnight. The mixture was diluted with dichloromethane, extracted twice with water, once with brine, then dried over MgSO4, filtered and concentrated. 8.8 g crude brown oil were isolated. The crude product was recrystallized from dichloromethane+ethyl acetate+hexanes. 5.012 g pale yellow crystals were collected by filtration. The mother liquor was concentrated and purified by chromatography on silica, using a gradient from 100% Solvent A to 50% Solvent A+50% Solvent B. Solvent A: 99% dichloromethane+1% Triethylamine, Solvent B: 99% Ethylacetate+1% Triethylamine. Evaporation of product containing fractions gave additional 1.8 g product of ˜70% purity. MS (ESI) m/z 399/401(M+H). 1H NMR (CDCl3) δ ppm 7.63 (s, 1H), 7.48 (d, 1H, J=9.2), 7.42 (d, 2H, J=7.9), 7.18-7.14 (m, 3H), 6.41 (s, 1H), 3.80-3.40 (bm, 4H), 2.42 (bs, 4H), 2.32 (s, 3H).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Br)[CH:20]=[CH2:21]>>[CH2:21]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: C=CCn1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-Allylbenzimidazo[2,1-b]quinazolin- 12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and allyl bromide.
Reaction SMILES: CS[C:3]1[NH:8][C:7]2[CH:9]=[CH:10][N:11]=[CH:12][C:6]=2[S:5](=[O:14])(=[O:13])[N:4]=1.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:21][C:3]2[NH:8][C:7]3[CH:9]=[CH:10][N:11]=[CH:12][C:6]=3[S:5](=[O:14])(=[O:13])[N:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Reactant: NC1CCCCC1
Product: O=S1(=O)N=C(NC2CCCCC2)Nc2ccncc21

Procedure:
A solution of 0.7 g of 3-methylthio-4H- pyrido[4,3-e][1,2,4]thiadiazine 1,1-dioxide in 7 cm3 of cyclohexylamine is heated at reflux for 4 hours. The reaction mixture is concentrated under partial vacuum and the residue is taken up in 10 cm3 of water and is slightly basified by addition of 10% sodium hydroxide solution. The aqueous phase is stirred with 25 cm3 of diethyl ether in order to extract a possible excess of cyclohexylamine. After separation by settling, the aqueous solution is adjusted to a pH of 7 and the white precipitate is collected on a filter and washed with water. It is recrystallized from hot water.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([O-])=O>CCOC(C)=O.O=[Pt]=O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:16]=[CH:15][CH:14]=2)[CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Oc2cccnc2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1cccc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 3-(3-nitrophenoxy)pyridine (4.43 g, 20.5 mmol) in EtOAc (50 mL) was added PtO2 (0.4 g) and the mixture was stirred at RT overnight under H2 (1 atm). The mixture was filtered through Celite®, the Celite® washed with EtOAc (2×20 mL) and the combined filtrates concentrated to yield (3.77 g, 99% yield) pure 3-(pyridin-3-yloxy)benzenamine as a syrup. 1H NMR (400 MHz, DMSO-d6): δ 8.34-8.32 (m, 2H), 7.40-7.39 (m, 2H), 7.02 (t, J=8.0 Hz, 1H), 6.37-6.35 (m, 1H), 6.02-6.14 (m, 2H), 5.28 (brs, 2H); MS (ESI) m/z: 187.0 (M+H+).