Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:31])[C:5](=[O:30])[N:6]2[C@H:22]1[CH2:27][CH2:26][C@H:25]([O:28]C)[CH2:24][CH2:23]1.I[Si](C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:31])[C:5](=[O:30])[N:6]2[C@H:22]1[CH2:23][CH2:24][C@H:25]([OH:28])[CH2:26][CH2:27]1
Reactant: CO[C@H]1CC[C@H](n2c(=O)n(C)c3c(Cl)nc(-n4cnc5ccc(C#N)cc54)nc32)CC1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(-n3cnc4ccc(C#N)cc43)nc(Cl)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an oven dried flask under Argon flow was added 3-(6-chloro-9-(trans-4-methoxycyclohexyl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile (0.55 g, 1.25 mmol) in chloroform, followed by iodotrimethylsilane (0.1 mL, 1.25 mmol, 1 equiv.) The reaction mixture was stirred at room temperature for 4 h. Upon completion (HPLC monitoring), the reaction was slowly quenched with water. The organic layer was separated and the aqueous layer extracted with CHCl3 (15 ml×3) and with EtOAc (15 mL×3). The combined organic layers were dried (MgSO4), and concentrated in vacuo to give a dark solid (66% crude yield). MS (EI) m/z 424 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Borane tetrahydrofuran complex (15.4 mL, 15.4 mmol) was added to a stirred solution of 5,6-dichloronicotinic acid (2.46 g, 12.8 mmol) in anhydrous THF (15 mL) at 0° C. The mixture was stirred at 0° C. for 30 min while the mixture became orange in color and then at RT for 3 h. An additional portion of borane tetrahydrofuran complex (15.4 mL, 15.4 mmol) was added and the mixture was stirred at RT for 16 h. The mixture was then carefully poured into a cold 1 N aqueous HCl solution and extracted with DCM. The organic layer was dried (Na2SO4), filtered and the solvents evaporated to yield 5,6-dichloro-pyridin-3-yl)-methanol (1.64 g, 68%) as a pale yellow wax which was used in next reaction without further purification.
Reaction SMILES: B.[BH4-].[Na+].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]([CH:36]([CH3:38])[CH3:37])([C:34]#[N:35])[CH2:16][CH2:17][CH2:18][C:19]2[CH2:28][C:27]3[C:22](=[CH:23][C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[CH:26]=3)[CH2:21][N+:20]=2[CH3:33])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]([CH:36]([CH3:38])[CH3:37])([C:34]#[N:35])[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:28][C:27]3[C:22](=[CH:23][C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[CH:26]=3)[CH2:21][N:20]2[CH3:33])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C(C#N)(CCCC2=[N+](C)Cc3cc(OC)c(OC)cc3C2)C(C)C)cc1OC
Agent: B
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC
Reaction time: 1 h

Procedure:
The dihydroisoquinolinium salt of formula 34 is then hydrogenated to produce a compound of formula 1 (step 6). This reaction is performed using a suitable hydrogenating agent, preferably a boron hydride derivative, particularly NaBH4. The solvent used is preferably a lower alkanol, particularly MeOH. The reaction is carried out at a temperature of about -10° C. to about 50° C., preferably about 0° C., over about 10 minutes to about 3 hours, preferably 1 hour. For example, 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,4-dihydroisoquinolinium chloride (34) is suspended in MeOH at 0° C., then treated with NaBH4 for about 1 hour to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[C@:10]2([N:14]([CH3:15])[C:13](=[O:16])[N:12]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:11]2=[O:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn](C)(C)[C:37]1[CH:38]=[N:39][CH:40]=[N:41][CH:42]=1>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([C:37]3[CH:38]=[N:39][CH:40]=[N:41][CH:42]=3)=[CH:30][CH:29]=2)[C@:10]2([N:14]([CH3:15])[C:13](=[O:16])[N:12]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:11]2=[O:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1ccccc1)C[C@H]2c1ccc(Br)cc1
Reactant: C[Sn](C)(C)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1ccccc1)C[C@H]2c1ccc(-c2cncnc2)cc1
Temperature: 25 °C

Procedure:
A mixture of Example 65 (2 g, 3.58 mmol), 5-trimethylstannyl-pyrimidine (1.3 g, 5.35 mmol, prepared according to patent WO 95/06636) and tetrakis(triphenylphosphine)palladium(0) (620 mg, 0.54 mmol) in toluene (50 ml) was refluxed for 10 h under a nitrogen atmosphere. After cooling to room temperature, the insoluble material was filtered off and washed twice with toluene. The toluene layers were concentrated in vacuo. The resulting orange oil (3.1 g) was chromatographed over silica gel (eluent: EtOAc) to yield the above-titled compound as a white solid after crystallization from MeOH (430 mg), mp=228° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cccc(-c2cc3cnc(N)nc3nc2N)c1C
Product: Cc1cccc(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1C

Procedure:
The title compound was prepared from 0.5007 g of 6-(2,3-dimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 92 and 0.23 mL tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with a gradient of CHCl3 :EtOAc (2:1) to CHCl3 :EtOAc (1:1); mp 326-330° C., MS(CI)
Reaction SMILES: [C:1]1([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:19]1([Mg]Br)[CH2:21][CH2:20]1>>[CH:19]1([CH:15]([C:14]2[CH:13]=[N:12][C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[CH:18][CH:17]=2)[OH:16])[CH2:21][CH2:20]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(-c2cccc3ccccc23)nc1
Product: OC(c1ccc(-c2cccc3ccccc23)nc1)C1CC1

Procedure:
Synthesized using compound 54b (253 mg, 1.09 mmol) and cyclopropylmagnesium bromide (4.34 mL, 2.17 mmol, 0.5 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Light yellow solid. Yield: 239 mg, 80%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.39-0.54 (m, 2H), 0.60-0.72 (m, 2H), 1.22-1.29 (m, 1H), 4.04-4.14 (m, 1H), 7.42-7.60 (m, 5H), 7.86-7.92 (m, 3H), 8.04-8.08 (m, 1H), 8.77 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=3.3, 3.9, 14.4, 60.6, 125.0, 125.5, 125.9, 126.1, 126.7, 127.7, 128.6, 129.1, 134.2, 137.8, 138.5, 147.8, 158.5, 171.4; MS (ESI): m/z=276.34 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][C:11]2[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=2)=[C:4]([OH:25])[CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH2:10][C:11]3[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[N:16]=3)[O:25][C:4]=2[CH:3]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(Br)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccc(Br)cc3o2)[nH]1
Yield: 23.2 %

Procedure:
The product is prepared according to the procedure described in Example 2, using 316 mg of N-(4-bromo-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide and 73 mg of 4-methylbenzenesulphonic acid hydrate, and replacing the toluene with xylene. After recrystallization from 30 ml of ethanol, 5 ml of methanol and 5 ml of dichloromethane and then purification of the formed precipitate by silica column chromatography, eluent: CH2Cl2/MeOH: 90/10, 70 mg of 2-[(6-bromo-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13]#[N:14])=[C:6]2[CH:7]=[N:8][CH2:9][CH2:10][O:11][C:5]2=[C:4]([CH:15]([OH:17])[CH3:16])[CH:3]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[C:12]([C:13]#[N:14])=[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][O:11][C:5]2=[C:4]([CH:15]([OH:17])[CH3:16])[CH:3]=1
Reactant: CC(O)c1cc(Cl)c(C#N)c2c1OCCN=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1cc(Cl)c(C#N)c2c1OCCNC2
Reaction time: 1 h
Yield: 41 %

Procedure:
The crude 7-chloro-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-6-carbonitrile was taken up in ethanol (30 mL) cooled in an ice bath and the sodium tetrahydroborate (0.16 g, 4.4 mmol) was added. The reaction was allowed to stir for 1 h, and water was added to quench the remaining hydride and the reaction was concentrated to remove most of the ethanol. The residue was dissolved with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated to give 7-chloro-9-(1-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile as an oil (0.45 g, 41%). LCMS calculated for C12H14ClN2O2(M+H)+: m/z=253.1; found: 253.0.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:53]1[CH:54]=[N:55][N:56](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:57]=1)CCC>>[NH:24]1[CH:25]=[C:21]([C:17]([C:12]2[CH:11]=[CH:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:53]4[CH:57]=[N:56][NH:55][CH:54]=4)[CH:8]=3)[CH:13]=2)([OH:45])[CH:18]([CH3:20])[CH3:19])[N:22]=[CH:23]1
Reactant: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CC(C)C(O)(c1ccc2cc(-c3cn[nH]c3)ccc2c1)c1c[nH]cn1
Yield: 233.1 %

Procedure:
In a similar manner to that described in Example 2-(i), the reaction was carried out by using 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthyl trifluoromethanesulfonate (3.0 g) and 4-tributylstannyl-1-trityl-1H-pyrazole (5.48 g) to give the titled compound (3.54 g) as a pale brown powder.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH3:35])[CH2:30][C:29]2=[O:36])[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH2:34]([N:31]1[CH2:32][CH2:33][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([NH:21][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:23]=2)[C:29](=[O:36])[CH2:30]1)[CH3:35]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CCN1CCN(c2cccc(N)c2)C(=O)C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CCN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)C(=O)C1

Procedure:
205 d) 4-Ethyl-1-{3-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-2-one was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 1-(3-amino-phenyl)-4-ethyl-piperazin-2-one (79.0 mg, 0.360 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (27.0 mg, 0.0494 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.059 g, 37%). MP=210-212° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 8.24 (d, J=8.0 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H), 7.76 (s, 1H), 7.65 (d, J=6.9 Hz, 1H), 7.42-7.34 (m, 2H), 7.04 (t, J=6.5 Hz. 1H), 6.96-6.92 (m, 2H), 3.80-3.75 (m, 2H), 3.36 (s, 2H), 3.10 (s, 3H), 2.88-2.83 (m, 2H), 2.58 (q, J=7.0 Hz, 2H), 1.18 (t, J=6.4 Hz, 3H). MS=491 (MH)+.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:16])[C:4]([N:6]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.CCOCC>[C:17]1([NH:23][C:24]([S:1][CH2:2][CH:3]([CH3:16])[C:4]([N:6]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(CS)C(=O)N(CC(=O)O)C1CCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(CSC(=O)Nc1ccccc1)C(=O)N(CC(=O)O)C1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4.9 g (0.02M) of N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine and 8 ml of phenyl isocyanate in 5 ml methylene chloride was stirred at room temperature for 72 hours. The mixture was diluted with ether and filtered. The ether solution was washed with water, dried over MgSO4 and evaporated to dryness. The crude residue was dissolved in acetonitrile, treated with charcoal and crystallized by addition of ether, m.p. 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=O)=[O:9])=[CH:4][CH:3]=1.[CH:12](I)(I)[I:13]>O1CCCC1.[Cl-].[Cl-].[Cr+2]>[O:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:10]=[CH:12][I:13]
Reactant: O=CC(=O)c1ccc(Cl)cc1
Reactant: IC(I)I
Agent: [Cr+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(C=CI)c1ccc(Cl)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 4, using 6.7 grams (0.04 mole) of 4-chlorophenylglyoxal (prepared by the method of Kornblum et al., JACS, (1957), 79, 6562), 29.5 grams (0.24 mole) of anhydrous chromium(II) dichloride, and 31.5 grams (0.08 mole) of iodoform in 600 mL of tetrahydrofuran, yielding 1-oxo-1-(4-chlorophenyl)-3-iodo-2-propene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:42]([O:46][C:47](=[O:62])[NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51](CN2C=CC(N)=N2)[CH:50]=1)([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[C:42]([O:46][C:47](=[O:62])[NH:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)[CH:54]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(N)n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 500 mg, 1.52 mmol) was suspended in methylene chloride (7.6 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (760 μL, 1.52 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (354 μL, 3.04 mmol) was added. The reaction continued to stir at 0° C. for 15 min. [3-(3-Amino-pyrazol-1-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (437 mg, 1.52 mmol) was dissolved in methylene chloride (7 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (300 mL), washed with water (2×50 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate and concentrated in vacuo to a yellow foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 5% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded (3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-phenyl)-carbamic acid tert-butyl ester (539 mg 59%) as a pale pink powder: ESI-LRMS m/e calcd for C30H37ClN4O5S [M+] 600.22, found 601.50 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.23 (m, 2H, CH2), 1.45-1.93 (m, 8H, 4×CH2), 1.51 (s, 9H, 3×CH3), 2.15-2.30 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.8 Hz, 1H, CH), 5.11 (s, 2H, NCH2), 6.49 (brs, 1H, NH), 6.71 (d, J=2.5 Hz, 1H, Ar), 6.82 (m, 1H, Ar), 7.19-7.25 (m, 2H, Ar), 7.26-7.29 (brs, 1H, Ar), 7.31 (d, J=2.5 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.6 Hz, 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 8.08 (d, Jo=8.2 Hz. 1H, Ar), 8.17 (brs, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](N)=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.BrC1C(N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)=NC=NC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([N:14]3[CH2:15][CH2:16][CH:17]([C:20]4[N:21]([CH3:36])[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:33])([F:34])[F:35])[CH:26]=5)[N:24]=4)[CH2:18][CH2:19]3)=[N:12][CH:11]=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Agent: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncncc2Br)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncncc2-c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 5-bromo-4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine instead of 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine. LC-MS: (M+1=500, obsd.=500).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[F:15][C:16]([F:25])([F:24])[C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:4][C:3]1[N:1]=[CH:2][O:23][C:22]=1[C:20]1[O:21][C:17]([C:16]([F:24])([F:15])[F:25])=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(C(F)(F)F)o1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (0.893 g, 4.27 mmol), 5-(trifluoromethyl)furan-2-carbaldehyde (0.70 g, 4.3 mmol), and K2CO3 (1.18 g, 8.53 mmol) in MeOH (25 mL) was heated to reflux. After 2.5 hr the reaction mixture was cooled to ambient temperature and stirred overnight. The reaction mixture was extracted with EtOAc (2×200 mL) and washed with water (2×200 mL), then washed with brine and dried over Na2SO4, filtered, and concentrated to an orange solid. The crude product was chromatographed on silica gel (Analogix® SF25-40G column, 0%-25% EtOAc/hexanes, 30 mL/min) to yield 709 mg (77%) of the title compound as a light yellow solid. 1H NMR (300 MHz, MeOH-d4) δ 8.19 (s, 1H), 7.12 (m, 1H), 6.80 (dd, J=3.7, 0.6 1H), 2.41 (s, 3H). MS (DCI+) m/z 218 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7](=[CH:22][N:23](C)[CH3:24])[C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)=[CH:4][CH:3]=1.[O-]CC.[Na+].C(O)C.C(O)(=O)C.C(N)=[NH:40]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]([C@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[N:40][CH:24]=[N:23][CH:22]=2)=[CH:26][CH:27]=1
Reactant: N=CN
Reactant: CN(C)C=C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ncncc1Cc1ccc(Cl)cc1
Temperature: 90 °C
Yield: 57.1 %

Procedure:
To a solution of (R)-tert-butyl 2-(2-(4-chlorobenzyl)-3-(dimethylamino)acryloyl)pyrrolidine-1-carboxylate (1.5 mmol) in n-butanol (10 mL) was added sodium ethoxide in ethanol (5.6 mL, 21 wt. %, 15 mmol) and formamidine acetate (1.56 g, 15 mmol). The reaction mixture was heated at 90° C. for 12 h. After removal of the solvents in vacuo, the residue was dissolved in ethyl acetate. The organic layer was washed with brine three times, dried over sodium sulfate and the solvent was removed in vacuo. Purification by silica gel column chromatography (ethyl acetate/hexane gradient, 10-100% EtOAc) afforded the desired product (320 mg, combined yield for step B and step C was 57%). MS: calculated: 373.16 found (MH+): 374.4.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[C:15]([C:18]1[CH:19]=[C:20]([CH:48]=[CH:49][CH:50]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([N+:31]([O-])=O)=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=1)=[O:35])(=[NH:17])[NH2:16].C(O)(=O)C>C(O)C.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[C:15]([C:18]1[CH:19]=[C:20]([CH:48]=[CH:49][CH:50]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([CH3:45])([CH3:46])[CH3:47])=[CH:40][CH:39]=1)=[O:35])(=[NH:16])[NH2:17]
Reactant: C[N+](C)(C)c1ccc(CNC(=O)c2cc3cc([N+](=O)[O-])ccc3n2Cc2cccc(C(=N)N)c2)cc1
Agent: [Pd]
Agent: O=C([O-])C(F)(F)F
Solvent: CC(=O)O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: C[N+](C)(C)c1ccc(CNC(=O)c2cc3cc(N)ccc3n2Cc2cccc(C(=N)N)c2)cc1
Yield: 70 %

Procedure:
This compound was prepared from [4-({[1-(3-amidino-benzyl)-5-nitro-1H-indole-2-carbonyl]-amino}-methyl)-phenyl]-trimethyl-ammonium trifluoroacetate trifluoroacetic acid salt (example 36) by hydrogenation in ethanol with 3 equivalents of acetic acid, catalyzed by Pd/C (10%). Yield: 70%. M.p. 114° C. (dec.). MS: 455.3 (M+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][CH3:21])[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([NH2:35])=[CH:33][C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:26]1([C:29]2[C:34]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[S:20][CH3:21])[C:3]=3[CH3:22])=[CH:33][C:32]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:31][N:30]=2)[CH2:25][CH2:24][O:23][CH2:28][CH2:27]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Nc2cc(N3CCOCC3)cnc2N2CCOCC2)c1C

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline (75.0 mg, 0.22 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-(methylsulfanyl)phenyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 7.83 (1H, d, J=12.1 Hz), 7.64 (1H, d, J=9.0 Hz), 7.61 (1H, d, J=2.7 Hz), 7.64 (1H, d, J=9.4 Hz), 7.43-7.50 (1H, m), 7.37-7.42 (1H, m), 7.34 (1H, td, J=7.2, 1.2 Hz), 7.25-7.30 (1H, m), 7.03 (1H, ddd, J=13.5, 8.5, 2.5 Hz), 6.42 (1H, br. s.), 3.92 (4H, br. s.), 3.73-3.83 (4H, m), 3.39 (2H, br. s.), 3.03-3.12 (4H, m), 2.85-3.03 (2H, m), 2.41 (3H, s), 1.97 (3H, s). Mass Spectrum (ESI) m/e=564.3 (M+1).