Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:2]2[S:3][C:4]3[C:9]([N:1]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:12][CH:13]=1
Reactant: OCc1ccc(Oc2nc3cccnc3s2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(Oc2nc3cccnc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.7 %

Procedure:
To a solution of [4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenyl]methanol (140 mg, 0.542 mmol) in CH2Cl2 (3.6 mL) was added SOCl2 (43 μL, 0.596 mmol, 1.1 equiv.). The solution was allowed to stir under N2 at rt for 4 h. The reaction mixture was then concentrated to afford the desired product as a cream-colored solid (157 mg, 92%). MS (ESI): mass calcd. for C13H9ClN2OS, 276.0; m/z found, 277.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.47 (dd, J=4.4, 1.5, 1H), 8.11 (dd, J=8.2, 1.5, 1H), 7.65-7.57 (m, 2H), 7.56-7.47 (m, 3H), 4.85 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)([CH3:5])[CH2:3]O.Cl>COCCOC>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[O:15][CH2:3][C:2]([CH3:1])([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(CO)NC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: COCCOC
Product: CC1(C)COC(c2ccc(N)cc2)=N1
Temperature: 5 °C
Reaction time: 48 h

Procedure:
To a solution of 9.5 g. of N-(1,1-dimethyl-2-hydroxyethyl)-4-aminobenzamide in 100 ml. of DME was added gaseous HCl such that all of the starting amide came out of solution. The solvent was removed and 30 ml. of thionyl chloride added. This solution was stirred for 2 days at 5° C. The excess thionyl chloride was removed. The amber liquid was then poured into 200 ml. of CH2Cl2 and neutralized with 20% NaOH with cooling. The solution was extracted with diethyl ether and the ether layer dried over MgSO4. The combined ether layer was filtered and concentrated to a solid; 5.75 g. This solid was preabsorbed on 25 g. of silica III and placed on 425 g. of silica (in a column). Elution with ether gave 3.7 g. of product which was recrystallized from CH2Cl2 -hexane (1:1) and acetonitrile, m.p. 227°-230° C.
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[C:13]([NH:15][NH2:16])=[O:14].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][N:19]=1.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:20][N:19]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (5.00 g, 23.0 mmol) in dichloromethane (100 mL) was added 6-chloronicotinic acid (4.71 g, 29.9 mmol) and 2-chloro-1,3-dimethylimidazolium chloride (8.56 g, 50.6 mmol). After the suspension was stirred for 15 min at ambient temperature, it was cooled to 0° C. and N,N-diisopropyl ethyl amine (19.7 mL, 115 mmol) was added slowly. The reaction mixture was stirred for 18 h while warming to ambient temperature. It was washed with aqueous sodium carbonate (saturated) and the aqueous layers were extracted with dichloromethane. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 50:50) afforded the title compound (4.78 g, 61%) as a light yellow solid. MS: m/e=339.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH2:16]([Sn](CCCC)(CCCC)CC=C)[CH2:17][CH2:18]C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1)[CH:17]=[CH2:16]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)Cn1nc(C(F)(F)F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(C(F)(F)F)nn1CC(=O)OC
Temperature: 120 °C
Yield: 38.4 %

Procedure:
Methyl 2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (420 mg, 1.47 mmol), tri n-butyl allyltin (729 mg, 2.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) were dissolved in DMF (10 mL). The solution was degassed with argon for 10 min and then heated at 120° C. overnight. After the solution was cooled to room temperature, the volatiles were removed under vacuum. The resulting residue was purified by silica gel chromatography (loading with toluene, eluting with dichloromethane/hexanes) to afford methyl 2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (140 mg, 38%) as a clear oil. MS (m/z): 249.1 [M+H]+; HPLC retention time 3.51 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:24][O:25][C:26](=[O:40])[C@H:27](OS(C)(=O)=O)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[CH3:24][O:25][C:26](=[O:40])[C@@H:27]([N:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[C:5]1=[O:8])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)OS(C)(=O)=O
Reactant: O=C(Nc1cc(Br)cnc1O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)n1cc(Br)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of N-(5-bromo-2-hydroxypyridin-3-yl)-4-trifluoromethyl-benzamide from Step D (760 mg, 2.1 mmol) in tetrahydrofuran (10 mL) was added 95% sodium hydride (80 mg, 3.15 mmol) at room temperature. After the reaction mixture was stirred at room temperature for 30 min, (R)-2-methanesulfonyloxy-3-phenylpropionic acid methyl ester from Step B (820 mg, 3.15 mmol) was added and the reaction was stirred and heated at 50° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with saturated ammonium chloride solution and brine. The organic layer was separated, dried with sodium sulfate, filtered and concentrated in vacuo. Purification by medium pressure liquid chromatography on silica gel (1:6 ethyl acetate/hexanes) gave 770 mg (70%) of the title compound as a semisolid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27]([CH2:56][CH:57]1[CH2:61][CH2:60][CH2:59][O:58]1)[S:28](C1C=CC(C2C=C3N=C(CCC4CCCCC(=S)N4)NC3=NC=2)=CC=1)(=[O:30])=[O:29].N>CO>[NH2:25][C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:14]2[NH:13][C:10]3=[N:11][CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([S:28]([N:27]([CH3:26])[CH2:56][CH:57]5[CH2:61][CH2:60][CH2:59][O:58]5)(=[O:29])=[O:30])=[CH:5][CH:6]=4)[CH:8]=[C:9]3[N:15]=2)[N:24]=1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Reactant: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Agent: N
Solvent: CO
Product: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(N)=N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 114 mg of N-methyl-N-(tetrahydro-furan-2-ylmethyl)-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound A10) and 5.0 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 64 hours. Purification by flash chromatography on RP-C8 resin (eluent: acetonitrile/water 2:1 parts by volume) and lyophilization from 1.0 ml of water and 3.0 ml of dioxane afford 14 mg of the title compound as an amorphous, colorless solid of m.p. 260° C. ESI-MS: 511.4 (MH+). TLC: Rf=0.17 (HPTLC RP-C18, acetonitrile/water 2:1 parts by volume).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.[OH-].[Ca+2].[OH-].[OH:23][CH2:24][CH:25]([CH2:37][OH:38])[CH2:26][CH2:27][N:28]1[CH:35]=[C:34](I)[C:32](=[O:33])[NH:31][C:29]1=[O:30].C(OC=C)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[OH:23][CH2:24][CH:25]([CH2:37][OH:38])[CH2:26][CH2:27][N:28]1[CH:35]=[C:34]([CH:1]=[CH2:2])[C:32](=[O:33])[NH:31][C:29]1=[O:30]
Reactant: O=c1[nH]c(=O)n(CCC(CO)CO)cc1I
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: C=COC(C)=O
Solvent: CCN(CC)CC
Product: C=Cc1cn(CCC(CO)CO)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 6 h
Yield: 475.7 %

Procedure:
A mixture of palladium (II) acetate (79 mg, 0.35 mmol), triphenylphosphine (185 mg, 0.7 mmol) and triethylamine (5 ml), (dried over calcium hydroxide) in dry DMF (80 ml) was maintained at 70° C. with stirring until an intense red color appeared. Compound 19 (2.36 gm, 6.95 mmol) and vinyl acetate (30 ml, 330 mmol) were then added, and the reaction was allowed to proceed at 70° C. for 6 h with stirring. The solvent was removed in vacuo and the residue obtained was extracted with water (2×50 ml). The water layer was washed with dichloromethane, evaporated in vacuo, and the residue obtained was purified by elution from a silica gel column using ethyl acetate-methanol (95:5, v/v) as eluent to give 20 as a viscous oil (800 mg, 48%).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:45])([CH3:44])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[S:43][N:42]=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)([OH:32])[CH3:31])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:45])([CH3:44])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[S:43][N:42]=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)([OH:32])[CH3:31])[NH:8][CH:9]=1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(C)(O)c2ccc(-c3ccns3)cc2)n1
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1c[nH]c(CC(C)(O)c2ccc(-c3ccns3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 mL, 0.5 mmol) was added to an ambient temperature solution of 1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-2-(4-isothiazol-5-ylphenyl)propan-2-ol (103 mg, 0.17 mmol) in methanol (4 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was basified with 10% aqueous sodium hydroxide and extracted with ethyl acetate. Combined extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. LCMS: 356 (M+H). Individual enantiomer (E1 or E2) was obtained by HPLC separation on a chrial column.
Reaction SMILES: C(N(CC)CC)C.CN(C=O)C.[NH2:13][CH2:14][C:15]1[N:16]2[CH:23]=[N:22][CH:21]=[C:17]2[S:18][C:19]=1[CH3:20].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25]>O.C(=O)([O-])O.[Na+]>[NH2:25][S:24]([NH:13][CH2:14][C:15]1[N:16]2[CH:23]=[N:22][CH:21]=[C:17]2[S:18][C:19]=1[CH3:20])(=[O:27])=[O:26]
Reactant: Cc1sc2cncn2c1CN
Reactant: NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1sc2cncn2c1CNS(N)(=O)=O
Temperature: -25 °C
Reaction time: 3 h
Yield: 22.4 %

Procedure:
Under an argon atmosphere at -40° C., 0.84 ml of triethylamine was added dropwise to 5 ml of a dry DMF solution containing 334 mg of 3-aminomethyl-2-methylimidazo[5,1-b]thiazole, and 347 mg of sulfamoyl chloride was further added, followed by stirring at -40 to -10° C. for 3 hours. After the reaction solution was diluted with water, sodium hydrogencarbonate was used to adjust the pH of the solution to about 7.5, and the thus adjusted solution was directly subjected to Diaion HP-20 Resin to obtain 110 mg of the title compound as a light green powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Br:9]Br.[OH-].[Na+]>>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: BrBr
Reactant: Cc1ccncc1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cncc(Br)c1C
Temperature: 155 °C

Procedure:
3,4-Dimethylpyridine (20 g, 0.186 mol) was added slowly to ice cold oleum (400 mL) with vigorous stirring. The solution was heated to 155° C. and bromine (12.2 mL, 0.223 mol) was added drop wise very slowly. The reaction mass was heated at 155° C. for 24 h. After cooling to room temperature, the mixture was carefully poured into ice water and basified using 10% aqueous sodium hydroxide solution. The compound was then extracted with ethyl acetate (2×500 mL). The organic solution was dried over sodium sulphate and evaporated to yield oil which was purified by column chromatography (20% ethyl acetate/hexane) to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.22 (s, 1H), 2.36 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH:33]([CH3:35])[CH3:34])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH:33]([CH3:34])[CH3:35])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: CC(C)Oc1ccc2cc(C3(O)CCNCC3)ccc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Product: CC(C)Oc1ccc2cc(C3(O)CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)ccc2c1
Yield: 69.5 %

Procedure:
Beginning with 0.099 gm (0.50 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.150 gm (0.50 mMol) 4-hydroxy-4-(6-isopropoxynaphth-2-yl)piperidine, 0.165 gm (66%) of the title compound were recovered as a white solid by the procedure described in Example 9.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Yield: 79.8 %

Procedure:
As described for example 91a, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.4 g, 4.2 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, to the title compound (1.1 g, 78%) which was obtained as a white solid. MS: m/e=327.3 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[N:14]=[CH:15][N:16](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:17]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1.COC1C=C(C(C)C(C2N=CNC=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCC(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: COc1cccc(C(C)C(=O)c2c[nH]cn2)c1
Product: COc1cccc(CCC(=O)c2c[nH]cn2)c1

Procedure:
Using the same procedure as in Example 2.4.a and starting with 10.28 g (0.0217 mole) of 3-(3-methoxyphenyl)-1-(1-triphenylmethyl-1H-imidazol-4-yl)-1-propanone prepared in Example 2.3.b, 3.68 g of 3-(3-methoxyphenyl-1-(1H-imidazol-4-yl)-1-propanone are obtained after crystallization from ethyl acetate.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.C>CO.O.[Pd]>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(C(=CCN2CCN(Cc3ccccc3)CC2)c2ccc(F)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Fc1ccc(C(CCN2CCNCC2)c2ccc(F)cc2)cc1
Yield: 99.8 %

Procedure:
A mixture of 32,5 g of 1-[3,3-bis(4-fluorophenyl)-2-propenyl]-4-(phenylmethyl)piperazine dihydrochloride and 3,3 g of 5% Pd at activated charcoal in 150 ml of methanol and 100 ml of water was hydrogenated under 60 psi. The catalyst was filtered off and after evaporation of the solvent basification with sodium hydroxide was achieved. The base was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to yield 21,5 g (90,7%) of crude 1-[3,3-bis(4-fluorophenyl)propyl]piperazine.
Reaction SMILES: [ClH:1].Cl.[C:3]1([N:9]([CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>>[ClH:1].[C:3]1([N:9]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)-amide-dihydrochloride and sodium hydroxide solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:5][C:6]([N+:15]([O-])=O)=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:8]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[N:15]=[C:13]([NH2:14])[C:9]12[CH2:12][CH2:11][CH2:10]1
Reactant: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCCCN1CCCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OCCCN1CCCC1)N=C(N)C21CCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 28.1 %

Procedure:
A solution of 1-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)cyclobutanecarbonitrile (0.063 g, 1.742 mmol), from Step 4, in acetic acid (10 mL), was treated with 10% Pd/C (0.56 g, 0.523 mmol). The mixture was stirred under an atmosphere of hydrogen at 80° C. for 5 hours. The catalyst was filtered off and washed with EtOH. The filtrate was concentrated and resulting crude product was purification by flash chromatography (silica gel, 15-25% 3N methanolic ammonia/dichloromethane) to afford 0.161 g (28%) of 5′-methoxy-6′-(3-(pyrrolidin-1-yl)propoxy)spiro[cyclobutane-1,3′-indol]-2′-amine 1H NMR (400 MHz, METHANOL-D4) δ 7.28 (s, 1H), 6.71 (s, 1H), 4.11 (t, J=5.7 Hz, 2H), 3.88 (s, 3H), 3.27-3.19 (m, 6H), 2.63 (t, J=9.9 Hz, 2H), 2.52-2.42 (m, 1H), 2.38 (dd, J=13.0, 10.4 Hz, 2H), 2.31-2.22 (m, 1H), 2.17 (dt, J=12.8, 6.2 Hz, 2H), 2.04 (t, J=6.8 Hz, 6H). MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])(C)(C)C.CCCCC.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([C:30](OCC)=[O:31])[N:21]=1.[Cl-].[NH4+]>C(OCC)C.C(OCC)C.C(Cl)Cl>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([C:30]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=2)=[O:31])[N:21]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCCCC
Solvent: CCOCC
Product: O=C(c1ccc(F)cn1)c1nc(Cl)c2ccccc2n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 24.7 %

Procedure:
To a stirred solution of 2-bromo-5-fluoropyridine (237 mg, 2.11 mmol) in anhydrous diethyl ether (7 mL) at −78° C. was added dropwise 1.7 M tert-butyl lithium/pentane (4 mL, 6.8 mmol). The brown mixture was stirred at −78° C. for 20 min, then ethyl 4-chloroquinazoline-2-carboxylate (500 mg, 2.11 mmol) in 3:1 diethyl ether/DCM (4 mL) was added to the mixture over 40 min. The resulting mixture was stirred at −78° C. for 1 h and then at −40° C. for 4 h. Then 10% aq ammonium chloride was added and the mixture was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexane to afford (4-chloroquinazolin-2-yl)(5-fluoropyridin-2-yl)methanone (150 mg, 25%). 1H NMR (300 MHz, CDCl3) δ 8.50 (d, J=3 Hz, 1H), 8.37-8.28 (m, 2H), 8.17 (d, J=8.4 Hz, 1H), 8.04 (t, J=8.4 Hz, 1H), 7.83 (t, J=8.4 Hz, 1H), 7.63 (td, J=3 Hz, J=8.4 Hz, 1H); LC-MS (ESI) m/z 288 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([F:24])[CH:16]=1)([CH2:11][CH:12]([CH3:14])[CH3:13])C(OCC)=O)C>CC(O)=O.O.OS(O)(=O)=O>[F:24][C:17]1[CH:16]=[C:15]([CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:25])=[O:3])[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CC(C(=O)O)c1ccc([N+](=O)[O-])c(F)c1

Procedure:
2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl ester (92.0 g, 0.26 mol) was dissolved in AcOH/H2O/H2SO4 (96%) (500 mL/200 mL/70 mL) and the reaction mixture was refluxed for 24 h. After cooling and evaporation, water (300 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). The evaporation of solvent under reduced pressure gave a brown oil (61 g, quantitative), which was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.07-8.01 (m, 1H), 7.33-7.26 (m, 2H), 3.79-3.73 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 178.3, 156.0 (d, 1JCF=232.5 Hz), 147.0, 136.0, 126.2, 124.3, 118.1 (d, 2JCF=30 Hz), 49.3, 42.0, 25.8, 22.4, 22.0.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[NH:2]2.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28](O)=[O:29])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28]([N:2]2[C@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:29])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide with 5-(3-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (acidic): tR=0.99 min; [M+H]+=444.1.