Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H]([C@H](OC(=O)C1C=CC=CC=1)C(O)=O)C(O)=O)(=O)C1C=CC=CC=1.[NH2:27][C@@:28]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[CH2:32][O:31][C@H:30]([C:33]([F:36])([F:35])[F:34])[C@H:29]1[CH2:37][OH:38].CCOC(C)=O.[OH-].[Na+].[C:54]([N:62]=[C:63]=[S:64])(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(Cl)Cl>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C@@:28]1([NH:27][C:63]([NH:62][C:54](=[O:61])[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[S:64])[C@H:29]([CH2:37][OH:38])[C@@H:30]([C:33]([F:36])([F:34])[F:35])[O:31][CH2:32]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO
Agent: O=C(O[C@H](C(=O)O)[C@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Temperature: -3 °C
Reaction time: 0.08 h
Yield: 106.1 %

Procedure:
To chiral salt ((2S,3R,4S)-4-Amino-4-(2-fluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (2S,3S)-2,3-bis(benzoyloxy)succinate (0.361 kg, 0.556 mol) was added EtOAc (1.08 L) and the suspension was cooled to −3° C. 1.0 N aq. NaOH (1.30 L) was added over 20 mins while maintaining T <5° C. After 5 mins, benzoyl isothiocyanate (80.0 mL, 594 mmol) was added over 8 mins while maintaining T <5° C. After 1 h, EtOAc (722 mL) was charged. The aq. layer was removed, and the organics were washed with sat. aq. NaHCO3 (361 mL) and sat. aq. NaCl (361 mL). The organics were filtered over celite (90 g) and rinsed with EtOAc (360 mL). The organics were concentrated under vacuum to afford a residue which was re-dissolved into CH2Cl2 (1.1 L) and concentrated to afford the title compound as yellow foam (261 g, 99% yield accounting for residual solvents) which was used in the following step. 1H NMR (500 MHz, DMSO) δ ppm 12.04 (s, 2H), 11.20 (s, 2H), 7.95 (d, J=7.4 Hz, 2H), 7.69-7.60 (m, 1H), 7.56-7.42 (m, 2H), 7.37-7.28 (m, 1H), 7.24-7.12 (m, 2H). 5.59 (t, J=4.5 Hz, 1H), 5.03 (d, J=9.7 Hz, 1H), 4.92 (d, J=9.7 Hz, 1H), 4.75-4.63 (m, 1H), 3.92-3.74 (m, 2H), 2.77-2.66 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 179.98, 167.85, 159.75 (d, JCF=245.0 Hz), 133.44, 132.58, 129.88, 129.81, 129.04, 128.85, 126.31 (d, JCF=9.8 Hz), 124.36, 116.83 (d, JCF=23.4 Hz), 76.11 (q, JCF=31.0 Hz). 74.37 (d, JCF=6.1 Hz), 68.77 (d, JCF=3.4 Hz), 57.03, 52.23.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.O.Cl.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH2:28].C(=O)([O-])[O-].[Ca+2]>C(O)(C)C>[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]=12
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Reactant: COc1ccccc1OCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 43.2 g 4-(oxirane-2-ylmethoxy)-9H-carbazole (II), 80.0 g of 2-(2-methoxyphenoxy)ethylamine hydrogenchloride monohydrate (IV) and 52.4 g of anhydrous calcium carbonate in 330 ml isopropanol is, with intensive stirring, heated at 80° C. for 4 hours. When the epoxide has reacted, the mixed salts are filtered off from the reaction mixture and isopropanol is distilled off from the filtrate. The obtained honey-like concentrate is dissolved, when hot, in 210 ml of ethylacetate, the solution is cooled to the temperature of 40° C., inoculated and stirred at the temperature of 40° C. for 30 minutes. After the crystal precipitates, the mixture is cooled to 0° C., and is kept like that with stirring for a minimum of four hours. After filtration and washing with cooled ethylacetate, 65 to 70 g of wet crude Carvedilol is obtained (HPLC contents>98 area %, HPLC contents of the bis-derivative 1.2-1.5 area %).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([O:11][C:22](=[O:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1c(O)ccc([N+](=O)[O-])c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1c(OC(C)=O)ccc([N+](=O)[O-])c1C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 3-methyl-4-nitro-2-(2-propenyl)-phenol (5.19 g, 26.9 mmol) in dichloromethane (200 ml) at 0° was added triethylamine (5.43 g, 53.8 mmol) and acetic anhydride (3.29 g, 32.3 mmol). After 30 min, the reaction mixture was evaporated to a residue which was purified by chromatography (silica, 2% to 10% ethyl acetate in hexane) to give an orange oil (4.80 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1.N([O-])=O.[Na+].[I-:24].[K+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([I:24])[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1
Reactant: [I-]
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])ccc1Cl
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Product: Cc1nc(N)nc(N)c1-c1cc(I)ccc1Cl

Procedure:
This compound was prepared in a similar manner to the compound of Example 54 by reaction of the diazonium salt with potassium iodide, mp. 232°-234° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[Cl:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]([C:22](Cl)=[O:23])[CH:17]=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[Cl:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]([C:22]([N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][C:2]([F:11])([F:12])[F:1])=[O:23])[CH:17]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: FC(F)(F)CNc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N(CC(F)(F)F)c1ccccc1
Reaction time: 2 h

Procedure:
200 mg (1.14 mmol) N-(2,2,2-trifluoroethyl)aniline and 1.14 mL (1.14 mmol) of a 1M sodium hydroxide solution were added dropwise to 212 mg (1.2 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane while cooling with a bath of ice and ethanol. The mixture was first stirred for 2 h with cooling and then stirred for 1 h at RT. 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for 10 min. The organic phase was separated off, washed with water and 1M hydrochloric acid, dried on sodium sulphate, filtered and concentrated by rotary evaporation i.vac.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:8][O:9][CH2:10]CO.[C-]#N.[K+].COC1C=CC(O)=CC=1.C(OC)(=O)C(C)=C.CO>>[C:1]([O:6][CH2:7][CH2:8][O:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: COCCO
Agent: COc1ccc(O)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: C=C(C)C(=O)OCCOC
Temperature: 75 °C
Reaction time: 4 h

Procedure:
400 g of methyl methacrylate (4 mole), 152 g of ethylene glycol monomethyl ether (2 mole), 2.75 g of KCN (0.5%) and 0.14 g of hydroquinone monomethyl ether (250 ppm) are added to a 1 liter round-bottomed flask. The batch is heated to about 75° C. and the methyl methacrylate/methanol-azeotrope is distilled-off by way of a 1 m vigreux column at 65° C. temperature at the head of the column. After 4 hours, the trans-esterification is completed. After cooling of the flask, the sump is filtered to remove the potassium cyanide, and the filter residue is washed with a little methyl methacrylate. The filtrate is concentrated at 40° C. under a water jet vacuum. A residue of ethylene glycol monomethylether methacrylate of 260 g = 90% results.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14](=[N:20][OH:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Br:33])[C:31]=1[OH:32])[C:26](O)=O>N1C=CC=CC=1>[Br:22][C:23]1[CH:24]=[C:25]([C:26]2[O:21][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=2)[CH:29]=[C:30]([Br:33])[C:31]=1[OH:32]
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)c1cc(Br)c(O)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(-c2cc(Br)c(O)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.32 g, 10 mmol) was added in one portion to a stirred solution of ethyl 2-amino-2-(hydroxyimino)acetate (1.32 g, 10 mmol) plus 3,5-dibromo-4-hydroxybenzoic acid (2.95 g, 10 mmol) in pyridine (20 mL), the resulting solution was stirred at room temperature for 2 h and then at 90° C. for 5 h. After standing at room temperature overnight the pyridine was evaporated in vacuo and the residue was purified by flash chromatography (silica gel, 10% ethyl acetate/dichloromethane) to give the title compound (0.48 g, 12%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 1.48 (3 H, t), 4.47 (2 H, d), 8.13 (2 H, s), 11.54 (1 H, s, br).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:15]([OH:18])[CH2:16]Cl)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.ClCCl>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:15]1[O:18][CH2:16]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
A solution of potassium hydroxide (6.52 g. 0.1–16 mol, 1.2 equiv.) in 970 mL of absolute ethanol was treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32.3 g, 0.097 mol). This solution was stirred at room temperature for 15 minutes and then concentrated in vacuo to give a white solid. The solid was dissovled in dichloromethane and washed with water, dried over anhyd MgSO4, filetered and concentrated in vacuo to give a white solid. The solid was crystallized from hexanes and ethyl acetate to give 22.3 g, 77% of 3(S)-[N-(benzyloxycarbonyl)amino]-1,2(S)-epoxy-4-phenylbutane, mp 102–103° C., FAB MS: MH+=298.
Reaction SMILES: C(O[C:4]1[CH:5]=C(C=[CH:10][C:11]=1C)C=O)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18].BrCCCC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])[CH2:4][CH2:11][CH3:10]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCBr
Product: CCCCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate D10, vide infra) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with 4-bromo-butane in DMF using K2CO3 as base. MS (ISP): 209.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].[Br:22]C1N=C(N)C=CC=1.C(N=C=O)C>>[Br:22][C:9]1[N:8]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1cccc(Br)n1
Agent: CCN=C=O
Product: CCNC(=O)Nc1cccc(Br)n1

Procedure:
The title compound was synthesized by a method analogous to Intermediate 1 synthesis starting with 6-bromopyridin-2-amine and ethyl isocyanate. The crude residue was purified by flash chromatography (EtOAc/hexanes as eluent). MS (ESP): 245 (M+H+) for C8H10BrN3O; NMR: 1.08 (t, 3H), 3.16 (m, 2H), 7.26 (d, 1H), 7.64 (s, 1H), 7.75 (s, 1H), 8.08 (d, 1H), 9.29 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].[CH3:22][N:23]([CH3:28])[CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:22][N:23]([CH3:28])[CH2:24][C:25]([O:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21])=[O:26]
Reactant: CN(C)CC(=O)O
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CN(C)CC(=O)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a suitable reaction vessel containing 5 ml of pyridine, there is added one g (0.0035 mols) of 3-hydroxymethyl-diphenylhydantoin, 0.36 g (0.0035 mols) of N,N-dimethylglycine and 0.79 g (0.0035 mols) of dicyclohexylcarbodiimide (DCCI). The reaction mixture is stirred at room temperature for a period of approximately 24 hours, after which the final product, mp 128°-130°, yield 0.86 g (66.7%) is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[F:13])[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[I-:14].[Na+].O>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[F:13])[CH2:8][I:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CBr)ccc1F
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(CI)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of 3-tert-butyl-4-fluorobenzyl bromide (1.49 g, 6.08 mmol) in acetone (50 ml), sodium iodide (9.1 g, 60.8 mmol) was added, followed by stirring at room temperature overnight. The reaction mixture was mixed with water and extracted with n-hexane. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane) to give the titled compound (1.18 g, 66%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]2[N:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20](=[O:22])[NH:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[N:5]1([CH2:4][CH2:3][CH2:2][N:26]2[CH2:25][CH2:24][CH:23]([N:19]3[C:18]4[CH:29]=[CH:30][C:15]([Cl:14])=[CH:16][C:17]=4[NH:21][C:20]3=[O:22])[CH2:28][CH2:27]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: ClCCCn1cnc2ccccc21
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCn2cnc3ccccc32)CC1
Yield: 14 %

Procedure:
A mixture of 9 parts of 1-(3-chloropropyl)-1H-benzimidazole, 10 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 7.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2.9 parts (14%) of 1-{1-[3-(1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 224° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.C(O)CCC>CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reactant: Fc1ccc(F)c([C@H]2CCCN2)c1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: O=[N+]([O-])c1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 140 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A suspension of 6-chloro-3-nitroimidazo[1,2-b]pyridazine (1.0 g, 5.0 mmol) and (R)-2-(2,5-difluorophenyl)pyrrolidine (Prepared as described in Preparation A; 1.9 g, 11 mmol) in n-butanol (4.6 mL, 50 mmol) was sealed in a pressure reaction tube and stirred in a 140° C. oil bath overnight. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (250 mL), then washed with water (2×150 mL) and brine (150 mL), filtered through a Biotage Phase Separator filter paper and concentrated. The crude material was purified by silica gel chromatography, eluting with 2:1 EtOAc/hexanes to yield the product as a foamy yellow powder (1.3 g, 75% yield).
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:18][CH2:17][C:13]2([CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[C:27]2=[O:35])=[CH:22][CH:21]=1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]2([CH2:16][N:15]([C:32](=[O:33])[CH2:31][N:28]3[CH2:29][CH2:30][C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)[C:27]3=[O:35])[CH2:14]2)[CH2:17][CH2:18]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2CCC3(CC2)CNC3)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccccc3)CC2)C1
Reaction time: 8 h

Procedure:
7-Benzyl-2,7-diazaspiro[3.5]nonane dihydrochloride from Example 7F (0.237 g, 0.749 mmol), the product from Example 14D (0.248 g, 0.749 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.199 ml, 1.123 mmol) and N-methylmorpholine (0.247 ml, 2.247 mmol) were stirred together in dichloromethane (2 mL). After stirring overnight, the reaction mixture was diluted with dichloromethane (20 mL) and washed with 1 N HCl (10 mL), brine (10 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv 40 gm silica gel column and the product was eluted with a gradient of 0.4% methanol/dichloromethane containing 0.2 N NH3 to 6% methanol/dichloromethane containing 0.2 N NH3 to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.15 (m, 9H), 6.99 (t, J=8.2, 4H), 3.97 (s, 2H), 3.72 (d, J=20.0, 4H), 3.53 (t, J=6.5, 2H), 3.46 (s, 2H), 2.75 (t, J=6.4, 2H), 2.32 (s, 4H), 1.73 (s, 4H); MS (ESI+) m/z 530.2 (M+H)+.
Reaction SMILES: [Li].C[Si]([NH-])(C)C.Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:34][CH:35]=2)=[CH:27][CH:26]=1>C1COCC1.CN(C=O)C>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:34]([CH2:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])[CH:35]=2)=[CH:29][CH:30]=1
Reactant: O=C(CBr)N1CCN(c2ccccn2)CC1
Reactant: COc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Agent: C[Si](C)(C)[NH-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(CC(=O)N3CCN(c4ccccn4)CC3)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
250 μl 1 mol/L lithium his (trimethylsilyl) amide solution in THF was added to 29 mg 2-bromo-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone in 1 mL DMF. The mixture was stirred 10 min at RT and 28 mg 4-(4-methoxy-phenyl)-2-phenyl-1H-imidazole was added. The reaction was stirred 2 h at 60° C. The mixture was purified by HPLC to give 30 mg desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)C.Br[CH2:18][CH2:19][CH2:20][OH:21].[OH-].[Na+]>O>[OH:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCOc1ccc(-c2ccccc2)cc1
Yield: 42.6 %

Procedure:
Into a 200 ml flask, 7.82 g (41.1 mmol) of 4-hydroxybiphenyl, 83 ml of ethanol, 6 g (43.2 mmol) of 3-bromo-1-propanol and a NaOH aqueous solution (1.73 g (43.2 mmol) of NaOH/6 ml of water) were sequentially added, and the mixture was heated and refluxed for 6.5 hours. To the reaction solution, 50 ml of water was added, whereupon precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 4.0 g (yield: 43%) of 4-(3-hydroxypropoxy)biphenyl (1) as a colorless powder.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][CH2:28][CH3:29].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN1CCCC1=O>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1ccccc1
Yield: 39.5 %

Procedure:
Under a nitrogen atmosphere triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (50 mL). Benzoyl chloride (972 mg, 5.55 mmol) was added dropwise. When analysis by HPLC indicated that the reaction was complete, the reaction solution was poured into distilled water (500 mL). The pH was adjusted to 10 using solid potassium carbonate. A solid was isolated by filtration, rinsed with water and then dried in a vacuum oven. This material was stirred with chloroform (500 mL) and then filtered. The filtrate was loaded onto a silica gel column. The column was eluted with 1-5% methanol in chloroform. The purified material was dried in a vacuum oven to provide 800 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as a solid, m.p. 189.4-190.0° C. Analysis: Calculated for C24H27N5O. 0.82H2O: % C, 69.25; % H, 6.93; % N, 16.82; Found: % C, 69.50; % H, 7.15; % N, 17.02.
Reaction SMILES: N1CCCCC1.FC(F)OC1C=C(C=CC=1OC(F)F)C=O.C(CC(N[C:30]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=O)(O)=O>C1(C)C=CC=CC=1>[Br:39][C:36]1[CH:37]=[CH:38][CH:30]=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33]
Reactant: O=C(O)CC(=O)Nc1ccc(Br)cc1C(=O)O
Agent: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C(O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 107.1 %

Procedure:
Piperidine (100 μL, 1.01 mmol) was added to a suspension of 3,4-bis(difluoromethoxy)benzaldehyde (240 mg, 1.01 mmol) and 2-[(carboxyacetyl)amino]-5-bromobenzoic acid (277 mg, 0.92 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5 mL) and water (2 mL) and the solution was acidified with 50% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water and filtered to afford (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-bromobenzoic acid (198 mg, 45%) as a colourless crystalline solid; mp 223-226° C.; δH (400 MHz, DMSO-d6) 6.96 (d, J=15.6 Hz, 1H, CH═CHCO), 7.26 (t, J=73 Hz, 1H, OCHF2), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.38 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.68 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.78 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.80 (dd, J3,4=9.2, J4,6=2.8 Hz, 1H, H4), 8.08 (d, J4,6=2.8 Hz, 1H, H6), 8.55 (d, J3,4=9.2 Hz, 1H, H3), 11.28 (s, 1H, NH); δC (100 MHz, DMSO-d6) 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 116.5, 119.3, 120.1, 120.8, 122.6, 123.5, 126.7, 132.7, 133.2, 136.4, 139.7, 139.8, 141.9, 142.8, 163.6, 168.0; HRMS (ESL) calculated for C18H12BrF4NO5 [M-H ]− 475.9751, found 475.9752; νmax 1102, 1152, 1509, 1595, 1673, 1694, 3128 cm−1.