Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=2)[CH:12]=[N:13][CH:14]=1)(C)(C)C.[ClH:26]>CCOC(C)=O>[ClH:26].[ClH:26].[NH2:7][CH2:8][CH2:9][C:10]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=2)[CH:12]=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCc1cncn1Cc1ccc(C#N)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CCN)cc1F
Reaction time: 2 h

Procedure:
A solution of {2-[3-(4-cyano-3-fluoro-benzyl)-3H-imidazol-4-yl]-ethyl}-carbamic acid tert-butyl ester (1.0 g, 0.0029 mol) in EtOAc (30 mL) was cooled to −20° C. and saturated with HCl gas. The cooling bath was removed and the reaction was stirred for 2 h. The solvent was removed in vacuo to obtain the title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH:12]=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].P(Br)(Br)[Br:17]>CCO>[Br:17][CH2:12][C:9]1[O:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=1
Reactant: COc1cccc2cc(C=O)oc12
Reactant: BrP(Br)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2cc(CBr)oc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Compound 29 (450 mg, 2.56 mmol) was dissolved in EtOH (10 mL). NaBH4 (104 mg, 2.81 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvent was evaporated off in-vacuo. The resulting crude alcohol residue was dissolved in toluene (5 mL) and the solution was cooled to 0° C. PBr3 (240 μL, 2.56 mmol) was added dropwise over 10 min.
Reaction SMILES: [OH:1][C@H](CCCCC)CC(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=O.[OH:59][C@H:60]([CH2:112][CH2:113][C:114]1[CH:119]=[CH:118][CH:117]=[CH:116][CH:115]=1)[CH2:61][C:62](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=[O:63]>>[OH:59][CH:60]([CH2:112][CH2:113][C:114]1[CH:119]=[CH:118][CH:117]=[CH:116][CH:115]=1)[CH2:61][C:62]([OH:63])=[O:1]
Reactant: CCCCC[C@@H](O)CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCc1ccccc1
Product: O=C(O)CC(O)CCc1ccccc1

Procedure:
The example 21 was reproduced except that (R)-3-hydroxyoctanoyl CoA was replaced by (R)-3-hydroxy-5-phenylvaleryl CoA (prepared by hydrolyzing 3-hydroxy-5-phenylvaleric acid ester obtained by a Reformatsky reaction to obtain 3-hydroxy-5-phenylvaleric acid and then by the method described in Eur. J. Biochem., 250, 432–439(1997)) to obtain colorant 10.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH2:34][NH:33][CH2:32][CH2:31][C:22]=1[NH:23]2.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C1COCC1>[C:35]([N:33]1[CH2:32][CH2:31][C:22]2[NH:23][C:24]3[C:20]([C:21]=2[CH2:34]1)=[C:19]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N:8]2[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9]2)[C:2]=1[CH3:1])[CH:27]=[CH:26][C:25]=3[C:28]([NH2:30])=[O:29])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Solvent: C1CCOC1
Product: CC(=O)N1CCc2[nH]c3c(C(N)=O)ccc(-c4cccc(-n5cnc6ccccc6c5=O)c4C)c3c2C1
Yield: 39 %

Procedure:
A cloudy solution of 9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (20 mg, 0.044 mmol) in THF (0.5 mL) was treated with TEA (0.019 mL, 0.133 mmol) and stirred on an ice-water bath. The mixture was treated with acetic anhydride (nominally 8.40 μl, 0.089 mmol, probably more was added) and the resulting clear solution was stirred at room temperature for 1.5 h. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC. Effluent fractions containing the desired product were treated with NaHCO3 (aq) and concentrated under vacuum. The resulting aqueous suspension was filtered and the precipitate was washed with water and dried under vacuum to provide the desired product as a white solid (7.0 mg). The filter and aqueous phase were extracted three times with EtOAc, and the organic extracts were dried and concentrated to provide additional desired product as a white solid (1.5 mg) for a total of 8.5 mg (39% yield). LCMS (M+H)+ m/z 492.2, (M+Na)+514.2. 1H NMR (400 MHz, methanol-d4) δ 8.30-8.55 (2 H, m), 7.87-7.97 (1 H, m), 7.83 (1 H, t, J=7.9 Hz), 7.70 (1 H, dd, J=7.7, 1.3 Hz), 7.61-7.68 (1 H, m), 7.44-7.59 (3 H, m), 6.90-7.05 (1 H, m), 3.58-4.61 (4 H, m), 2.86-3.08 (2 H, m), 1.80-2.21 (6 H, multiple singlets).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[C:4]([NH2:18])[CH:3]=1
Reactant: CC(C)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CC(C)c1ccc(Oc2ccc(Cl)cc2N)cc1
Yield: 84.1 %

Procedure:
The product from Example 179a (13.7 g, 46.8 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (10.3 g, 84.4%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[N:28]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ncccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: Cc1ncccc1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Yield: 18 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2-methyl-pyridin-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 50) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methyl-pyridin-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid (0.26 g, 18%); ES+-HRMS m/e calcd for C25H32N6O4 [M+H+] 481.2558 found 481.2556. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.27-1.74 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 2.38 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.4, J=10.8 Hz, 1H), 5.74 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.39 (dd, Jo=8.1 Hz, Jo=4.7 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 7.73 (dd, Jo=8.1 Hz, Jm=1.3 Hz, 1H), 8.18 (d, J=2.9 Hz, 1H), 8.45 (dd, Jo=4.7 Hz, Jm=1.3 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.O.[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2]>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][CH:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5][N:4]3[C:10]2=[N:11][C:2]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)=[CH:3]3)[CH2:14][CH2:15]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cn3c(n2)C(OC2CCN(C)CC2)c2ccccc2CC3)cc1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2) (50 mg, 0.12 mmole) in 1,4-dioxane (0.5 mL) are added water (0.1 mL), 4-methylbenzeneboronic acid (25 mg, 0.18 mmole), Pd(OAc)2 (1.4 mg, 6 μmmole), 1,1-bis(diphenylphosphino)ferrocene (3.3 mg, 6 μmmole) and K2CO3 (50 mg, 0.36 mmole). The vial is evacuated and filled with argon. The reaction mixture is stirred at 100° C. for 3.5 hours. Water is added to the reaction mixture, and the pH is adjusted to 9-10 by adding saturated Na2CO3 solution. The aqueous phase is extracted three times with AcOEt. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (99:5:0.1) to (95:5:0.5). The residue is purified by preparative TLC eluting with (CH2Cl2:MeOH:NH4OH) (9:9:0.1) to give 4-(1-methylpiperidin-4-yloxy)-2-p-tolyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=2[O:10][CH3:11])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(F)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-fluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].C(OC([N:21]1[C:30]2[C:25](=[CH:26][C:27](Br)=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:32])=O)(C)(C)C.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:21][C:22](=[O:32])[CH2:23][CH2:24]3)[C:9]1=[O:13]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCc2cc(Br)ccc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)CCC(=O)N3)C1=O
Yield: 31.5 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 6-bromo-2-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (276 mg, 0.8474 mmol), 1,4-dioxane (5 mL), copper iodide (16.14 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.1 mg, 0.2542 mmol) and potassium carbonate (234.3 mg, 1.6948 mmol) to afford the crude product. Purification by preparative HPLC afforded 86 mg of the product (31.5% yield).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([NH:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3F)ccc2O1
Agent: Cl
Product: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NNC(=O)OCC)cc3F)ccc2O1

Procedure:
The title carbamate was prepared as described in Example 88 from 436 mg (1.0 mmol) of the amidine from Example 69 and 119 mg (1.1 mmol) ethyl chloroformate. It was recrystallized from dichloromethane/hexane. Yield: 0.35 g (74%) of a white powder, m.p. 168-169° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[CH:43][C:42]=1[OH:56].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:56][C:42]1[CH:43]=[CH:44][C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)=[CH:46][C:41]=1[O:40][CH3:39]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)ccc1O
Yield: 76 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (101 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol) using 1,2-dimethoxyethane (0.96 ml) and water (0.24 ml) as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 63 mg (68% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C([Li])CCC.CN(C)[CH:32]=[O:33].Cl>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:3]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)cc2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3C=O)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 46 mmol of 3,4,5-trifluoro-4′-(4-propylcyclohexyl)biphenyl in 100 ml of dry tetrahydrofuran is cooled to −75° C., and 50 mmol of n-butyllithium (1.6 M solution in n-hexane) are added dropwise under a protective-gas atmosphere at such a rate that the internal temperature does not exceed −75° C. The mixture is subsequently stirred at this temperature for a further 2 hours. 60 mmol of N,N-dimethylformamide are then likewise added dropwise at such a rate that the internal temperature always remains below −75° C. When the addition is complete, the reaction solution is allowed to thaw slowly and is hydrolysed at −10° C. by transfer of the reaction solution into ice-water. The mixture is acidified using hydrochloric acid (pH=3) and extracted with tert-butyl methyl ether. The combined organic extracts are washed with water and saturated sodium chloride solution and dried using sodium sulfate. After the solvent has been removed under reduced pressure, the crude product is chromatographed on silica gel with dichloromethane/n-heptane 1:1 as eluent, giving 3,4,5-trifluoro-4′-(4-propylcyclohexyl)biphenyl-2-carbaldehyde in the form of slightly yellowish crystals; m.p. 62° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
4-Trifluoromethoxy aniline (3.4 g, 19.21 mmol)was dissolved in THF (25 ml) before pyridine (4.44 ml, 54.88 mmol) was added. 4-Acetyl-benzenesulfonyl chloride (4.0 g, 18.29 mmol) was then added as a solid, and the resulting dark solution was stirred for 10 minutes. The volatiles were then removed, and the resulting residue was suspended in THF. Excess Et3N was then added, and the mixture was stirred for several minutes before the solids were filtered. The mother liquor was then evaporated to a solid which was purified by flash chromatography (EtOAc/hexanes) to yield the desired compound as a white solid. (5.5 g (15.31 mmol, 84%).
Reaction SMILES: CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.Br[C:18]1[CH:39]=[C:38]2[C:21]([CH2:22][C:23]3([C:31]42[N:35]=[C:34]([NH2:36])[C:33]([CH3:37])=[N:32]4)[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]3)=[CH:20][CH:19]=1.[Cl:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[N:45][CH:46]=1.C([O-])([O-])=O.[K+].[K+]>CC1CCCO1.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.O>[Cl:40][C:41]1[CH:42]=[C:43]([C:18]2[CH:39]=[C:38]3[C:21]([CH2:22][C:23]4([C:31]53[N:35]=[C:34]([NH2:36])[C:33]([CH3:37])=[N:32]5)[CH2:24][CH2:25][C:26]([F:30])([F:29])[CH2:27][CH2:28]4)=[CH:20][CH:19]=2)[CH:44]=[N:45][CH:46]=1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Reactant: OB(O)c1cncc(Cl)c1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[PH+](CCCS(=O)(=O)[O-])C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC1CCCO1
Product: CC1=NC2(N=C1N)c1cc(-c3cncc(Cl)c3)ccc1CC21CCC(F)(F)CC1
Temperature: 100 °C
Yield: 38 %

Procedure:
Sodium tetrachloropalladate(II) (7.70 mg, 0.03 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (7.02 mg, 0.03 mmol), 6′-bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 27, 100 mg, 0.26 mmol) and 5-chloropyridin-3-ylboronic acid (52.0 mg, 0.31 mmol) were added to a microwave vial and dissolved in 2-methyl-tetrahydrofuran (1 mL). K2CO3 (2M aq) (0.392 mL, 0.78 mmol) was added and the vial was flushed with Ar (g) and capped. The mixture was heated in a microwave reactor at 100° C. for 45 min. Additional sodium tetrachloropalladate(II) (7.70 mg, 0.03 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (7.02 mg, 0.03 mmol) and 0.5 equiv. 5-chloropyridin-3-ylboronic acid was added to the reaction mixture and it was heated to 90° C. for 1 h. Water was added and the residue was extracted with EtOAc (×3). The organic phases were dried with MgSO4 and concentrated. The crude product was purified on a silica gel column (4 g SiO2, 7 M NH3 in MeOH in DCM 1:9/DCM 0-100%) to give the title compound (41 mg, 38% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23-1.32 (m, 1 H), 1.52 (br. s., 2 H), 1.72 (br. s., 1 H), 1.79-1.98 (m, 4 H), 2.19 (s, 3 H), 3.08 (d, 1 H), 3.16 (d, 1 H), 6.62 (br. s., 2 H), 6.90 (d, 1 H), 7.43 (d, 1 H), 7.60 (dd, 1 H), 8.10 (t, 1 H), 8.57 (d, 1 H), 8.72 (d, 1 H). MS (APCI+) m/z 415.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:33]([F:36])([F:35])[F:34])[C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:22][CH2:21]1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:70]1([C:73]2[O:74][CH:75]=[C:76]([C:78](O)=[O:79])[N:77]=2)[CH2:72][CH2:71]1.[Cl-].[Li+]>CN(C=O)C>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH2:10][CH2:9][CH2:8][NH:7][C:5]([C:4]1[CH:17]=[C:18]([C:33]([F:36])([F:35])[F:34])[C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:22][CH2:21]2)=[C:2]([NH:1][C:78]([C:76]2[N:77]=[C:73]([CH:70]3[CH2:72][CH2:71]3)[O:74][CH:75]=2)=[O:79])[CH:3]=1)=[O:6]
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccccc1N1CCN(c2c(N)cc(C(=O)NCCCN3CCCC3=O)cc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2c(NC(=O)c3coc(C4CC4)n3)cc(C(=O)NCCCN3CCCC3=O)cc2C(F)(F)F)CC1
Reaction time: 0.07 h

Procedure:
To a solution of 3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-5-trifluoromethyl-benzamide 4d (87.0 mg, 0.173 mmol) in DMF (3.0 mL) was added HATU (131.4 mg, 0.346 mmol) and stirred for 4 min. N,N-diisopropylethylamine (0.11 g, 0.86 mmol) was added to this and the solution was stirred for another 4 min. 2-Cyclopropyl-oxazole-4-carboxylic acid 1h (39.6 mg, 0.26 mmol) was added to this and the reaction was stirred at 25° C. for 16 h. A saturated solution of lithium chloride was added and extracted with ethyl acetate. Organic layer was washed with brine and dried on anhydrous sodium sulfate, concentrated and the crude 4e was dissolved in methanol and purified on preparative HPLC using water/methanol as eluent.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][CH2:17][O-:18].[Na+]>>[CH2:17]([O:18][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1)[CH3:16]
Reactant: CC[O-]
Reactant: COc1ccc2c(O)nc(Cl)nc2c1C
Agent: [Na+]
Product: CCOc1nc(O)c2ccc(OC)c(C)c2n1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
The quinazolinol (140) (530 mg, 2.36 mmol) was added in small portions to freshly prepared EtONa (740 mg of Na added in 20 mL EtOH). The resulting solution was heated to reflux and after 24 h, the reaction mixture was cooled down to room temperature and evaporated. The residue was re-dissolved in water (10 mL) and the pH of the resulting solution was adjusted to 5 with AcOH. The precipitate was collected by filtration, washed with ice-cooled water and dried to give the title compound (534 mg, 96.6%) as a white solid, m/z=235 (M+H)+.
Reaction SMILES: [I-:1].[CH2:2]([C:4]1[CH:13]=[CH:12][C:11]2[N+:10]3[CH:14]=[C:15]4[CH:24]=[CH:23][C:22]5[CH:21]=[C:20](F)[CH:19]=[CH:18][C:17]=5[N:16]4[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:5]=1)[CH3:3].[NH:26]1[CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[I-:1].[N:26]1([C:20]2[CH:19]=[CH:18][C:17]3[N:16]4[C:9]5[CH:8]=[CH:7][C:12]6[CH:13]=[C:4]([CH2:2][CH3:3])[CH:5]=[CH:6][C:11]=6[N+:10]=5[CH:14]=[C:15]4[CH:24]=[CH:23][C:22]=3[CH:21]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CCc1ccc2c(ccc3n4c(ccc5cc(F)ccc54)c[n+]23)c1
Reactant: C1CNC1
Agent: [I-]
Solvent: CN(C)C=O
Product: CCc1ccc2c(ccc3n4c(ccc5cc(N6CCC6)ccc54)c[n+]23)c1
Reaction time: 168 h

Procedure:
A stirred mixture of 2.21 g. of 3-ethyl-10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 15 ml. of dimethylformamide and 1.0 ml. of azetidine is heated at 72° C. for 3 days in a pressure vessel, then cooled, treated with 0.5 ml. of azetidine and allowed to stand at 20°-25° C. for 7 days, with occasional agitation. The resulting precipitate of 10-(1-azetidinyl)-3-ethylimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with water and dried; m.p. 270°-275° C., after crystallization from methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][N:13]1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(OCc2ccccc2)c1
Agent: O=C1NC(=O)c2ccccc21
Product: NCc1cccc(OCc2ccccc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 74 using N-(3-benzyloxy-benzyl)phthalimide instead of N-(2-methoxybiphenyl-4-yl-methyl(phthalimide.