Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[C@H:7]([C:20]([O:22][CH3:23])=[O:21])[CH2:6]1)[CH:2]=[CH2:3].I[Si](C)(C)C.CO>C(#N)C>[CH2:1]([S:4][C@:5]1([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:9][NH:8][C@H:7]([C:20]([O:22][CH3:23])=[O:21])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: C=CCS[C@]1(c2ccc(-c3ccccc3)cc2)CN[C@H](C(=O)OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To an iced solution of (2S,4R)-1-benzyl 2-methyl 4-(allylthio)-4-(biphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (1.85 g, 3.79 mmol) in Acetonitrile (20 mL) was added Iodotrimethylsilane (0.810 mL, 5.69 mmol). The formed light brown solution was stirred at room temperature for 2 h. Cooled with ice bath, quenched with Methyl alcohol (7.68 mL, 190 mmol). The formed light brown solution was purified by prep-HPL, and the collected fractions were evaporated on speed-vac system. The yellow residue was taken up in DCM, washed with sat. Na2CO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (2S,4R)-methyl 4-(allylthio)-4-(biphenyl-4-yl)pyrrolidine-2-carboxylate (664 mg, 1.878 mmol, 49.5% yield) as a viscous oil. 1H NMR (500 MHz, MeOD) δ ppm 2.96-3.09 (m, 3 H) 3.15 (d, J=14.34 Hz, 1 H) 3.84 (d, J=12.21 Hz, 1 H) 3.96 (s, 2.5 H) 4.00 (s, 0.5 H) 4.04 (d, J=11.90 Hz, 1 H) 4.77 (dd, J=10.07, 3.05 Hz, 1 H) 5.02 (d, J=9.77 Hz, 1 H) 5.09 (d, J=17.09 Hz, 1 H) 5.54-5.68 (m, 1 H) 7.38 (t, J=7.48 Hz, 1 H) 7.44-7.54 (m, 4 H) 7.66 (d, J=7.32 Hz, 2 H) 7.71 (d, J=8.55 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.CC[N:12](C(C)C)C(C)C>>[Br:1][C:2]1[S:3][C:4]([C:7]([NH2:12])=[O:9])=[CH:5][N:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cnc(Br)s1
Product: NC(=O)c1cnc(Br)s1

Procedure:
Scheme 1 illustrates the synthesis of compounds of Formula 4 and 5. 2-Bromo-thiazol-5-carboxylic acid 1 is reacted with amine 2 in the presence of DMC and DIEA to afford 2-bromo-thiazol-5-carboxamide 3, which without separation is treated with arylboronic acid under Suzuki coupling conditions to give 2-aryl-thiozol-5-carboxamide 4. Reduction of amide 4 with Alane-N,N-dimethylethylamine complex produces compound 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.Cl.[I-:47].[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N+:58]=2[CH3:63])=[CH:52][CH:51]=1>ClCCCl>[I-:47].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][N+:58]=4[CH3:63])=[CH:52][CH:51]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: C[n+]1ccccc1Nc1ccc(CN)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3ccc(Nc4cccc[n+]4C)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AD using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.13 mmol), CDI (33 mg, 0.2 mmol), DIPEA (0.14 mL, 0.81 mmol) and 2-{[4-(aminomethyl)phenyl]amino}-1-methylpyridinium iodide hydrochloride (53 mg, 0.14 mmol) in DCE (1.0 mL).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[I:22][C:23]1[CH:24]=[C:25]([CH2:29][NH2:30])[CH:26]=[CH:27][CH:28]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:30][CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([I:22])[CH:24]=2)[N:3]=1
Reactant: NCc1cccc(I)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Solvent: CCCCO
Solvent: CC(C)O
Product: Clc1nc(NCc2cccc(I)c2)c2ncn(C3CCSC3)c2n1
Reaction time: 30 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.114 ml of 3-iodo-benzenemethanamine in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for approximately 30 hours, left to return to ambient temperature, diluted with 3 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum to a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion 90/10, 173 mg of expected product is thus obtained in the form of white-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.O[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[O:9][CH2:18][CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:23](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCOC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Yield: 56.3 %

Procedure:
A mixture of (4-Bromo-phenyl)-(4-chloro-phenyl)-methanol (2.3 g, 7.73 mmol), N-(2-hydroxyethyl)phthalimide (1.4 g, 7.36 mmol) and para-toluenesulphonic acid monohydrate (560 mg, 2.94 mmol) in toluene (50 ml) was heated to reflux under Dean-Stark conditions for 17 hours. Upon cooling, the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was then dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum ether (1:4), to yield the title compound (1.95 g). LC/MS. (PS-B3) Rt 4.07 no observable mass ion.
Reaction SMILES: [C:1]1(C=CC=C(O)C=1)O.COC1C=C(C=CC=1)C(Cl)=O.[OH:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=[O:29].CI>>[OH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:1])[CH:24]=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=[O:29]
Reactant: COc1cccc(C(=O)c2ccc(O)cc2O)c1
Reactant: Oc1cccc(O)c1
Agent: COc1cccc(C(=O)Cl)c1
Solvent: CI
Product: COc1cccc(C(=O)c2ccc(OC)cc2O)c1

Procedure:
Synthesized from resorcinol and 3-methoxybenzoyl chloride according to an analogous synthetic method to Preparation Example 66, (2,4-dihydroxyphenyl)(3-methoxyphenyl)methanone (14.7 g) and methyl iodide (9.4 g) were used according to an analogous synthetic method to Example 383 to provide the title compound (10.3 g).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(S([N:49]2[C:57]3[CH:56]=[CH:55][N:54]=[C:53](Br)[C:52]=3[CH:51]=[CH:50]2)(=O)=O)C=CC=CC=1>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[O:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:31][CH:32]([N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH2:33]4)=[CH:26][C:9]=3[N:10]=[C:11]([C:53]3[C:52]4[CH:51]=[CH:50][NH:49][C:57]=4[CH:56]=[CH:55][N:54]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: c1cc2[nH]ccc2c(-c2nc(N3CCOCC3)c3sc(CN4CC(N5CCOCC5)C4)cc3n2)n1
Temperature: 150 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A mixture of 4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)-2-(tributylstannanyl)thieno[3,2-d]pyrimidine (192 mg, 0.29 mmol), 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (117 mg, 0.35 mmol), tetrakis(triphenylphosphine)palladium (34 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (11 mg, 20 mol %) in dioxane (2.0 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH. The resulting residue was dissolved in IMS/dioxane (1:1 mL) and 12.5 M aqueous NaOH solution (0.1 mL) added. After stirring for 1 h the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, 2 M NH3 in MeOH:DCM, gradient 0:100 to 10:90) followed by trituration from diethyl ether to give 174 (38 mg, 27%) as a pale yellow solid. LCMS RT 4.52 min, [M+H]+ 492. 1H NMR (CDCl3, 400 MHz) δ 8.53 (m, 1 H), 7.45-7.35 (m, 4 H), 4.10 (t, J=4.7 Hz, 4 H), 3.97 (s, 2 H), 3.89 (t, J=4.7 Hz, 4 H), 3.72 (t, J=4.5 Hz, 4 H), 3.69-3.54 (m, 2 H), 3.08-3.01 (m, 3H), 2.33 (m, 4 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:18][C:19]1([CH3:22])[CH2:21][O:20]1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:18][C:19]1([CH2:22][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][O:20]1
Reactant: O=C(Nc1ccccc1O)c1ccccc1
Reactant: CC1(CCl)CO1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Product: CC1(COc2ccccc2NC(=O)c2ccccc2)CO1
Temperature: 72.5 °C
Reaction time: 6 h
Yield: 61.3 %

Procedure:
A mixture of N-(2-hydroxyphenyl)benzamide (159 mg, 0.75 mmol), 2-(chloromethyl)-2-methyloxirane (1.60 g, 15 mmol), and benzyltriethylammonium chloride (27 mg, 0.12 mmol) was stirred at 70-75° C. for 6 h. After cooling to room temperature, water (2 ml) was added and the mixture was vigorously shaken. It was extracted with dichloromethane (2×5 ml), and the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml). Drying with Na2SO4, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50%) afforded title compound as yellowish solid (131 mg, 0.46 mmol, 62%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18](F)[C:19]=3[F:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH2:10][CH2:9]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:18]2[C:19]([F:21])=[C:20]3[C:15]([C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12][N:11]3[CH:8]3[CH2:10][CH2:9]3)=[CH:16][C:17]=2[F:23])[CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: N[C@H]1CCCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N[C@H]1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 79.9 %

Procedure:
A suspension of (S)-3-aminopiperidine (4.0 g) obtained as described in the step (c) above 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(11.4 g) and triethylamine (8.4 g) in acetonitrile (250 ml) was refluxed for 3 hours with stirring. Then the mixture was cooled down and filtrationof the precipitated powder followed by treatment with a mixture of ethanol (550 ml) and water (250 ml) gave (S)-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (11.6 g) as colorless needles. m.p. 247.8° C. (decomposition).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[F:31])[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[F:31])[C:19]([NH:21][CH:22]1[CH2:23][CH2:24][N:25]([CH:1]([C:4]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]3)=[CH:6][CH:5]=2)[CH3:2])[CH2:26][CH2:27]1)=[O:20]
Reactant: O=C(NC1CCNCC1)c1ccc(F)c(Cl)c1
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CC2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(c1ccc2c(c1)NC(=O)CC2)N1CCC(NC(=O)c2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
To a MeOH solution (15 mL) of the compound (206 mg) obtained in Step 51-2, the compound (560 mg) obtained in Step 51-3 and AcOH (327 mg), NaBH3CN (274 mg) was added at room temperature and the mixture was refluxed for 12 hours. After the reaction mixture was cooled to room temperature, NaBH3CN (274 mg) was added and the mixture was refluxed for 72 hours. After a saturated aqueous NaHCO3 solution was added, a water layer and an organic layer were separated. The water layer was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography [(silica gel 60 N, mobile phase: MeOH/CHCl3=0/100 to 20/80; v/v) and (Chromatorex NH, mobile phase MeOH/CHCl3=0/100 to 10/90; v/v) in this order] to obtain the titled compound (7 mg, a colorless solid).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Brc1ccncn1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(-c2ccncn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 120 °C
Yield: 50.9 %

Procedure:
Into an appropriate sized reaction vessel, a mixture of (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (100.0 mg, 0.24 mmol), 4-bromopyrimidine (77.3 mg, 0.49 mmol), sodium carbonate (77.3 mg, 0.73 mmol) and Pd(PPh3)4 (14.04 mg, 0.01 mmol) was added Dioxane (8 ml), water (1 ml). The reaction mixture was stirred and heated at 120° C. for 3 h. Then, it was filtered through a pad of Celite and partitioned between EtOAc (2×30 mL) and brine (2×10 mL). The combined organic layers were washed with water (2×5 mL), concentrated, and purified by flash chromatography (100% EtOAc to 20% MeOH in EtOAc) to give 45.0 mg (50.9%) of (R)-4-((R)-1-((1-cyclopropyl-5-(pyrimidin-4-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 9.211 (d, J=1.2 Hz, 1H), 8.80 (d, J=5.1 Hz, 1H), 8.19 (dd, J=2.4, 0.9 Hz, 2H), 8.11 (s, 1H), 7.719 (s, 1H). 7.603 (s, 1H), 4.91-4.83 (m, 1H), 3.77-3.70 (m, 1H), 3.41 (t, J=9.2 Hz, 1H), 3.21 (dd, J=6.6, 6.9 Hz, 1H), 2.87-2.82 (m, 1H), 2.41-2.24 (m, 2H), 1.34 (d, J=6 Hz, 3H), 1.20-1.01 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C20H21N5O2: 363.17; found 364.04.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34][CH2:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:7]3[N:8]([CH3:11])[C:9]4[C:5]([C:6]=3[C:20]#[N:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH:17]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Product: Cn1c(-c2cncc(CN[C@H]3CCN(C(=O)OC(C)(C)C)C3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester are processed according to the method described in Example 170 to give (S)-3-{[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester. MS (ESI) m/z 466.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.O.[OH-].[K+]>C1CCCCC1.C(N)(=O)C1C=CC=CC=1>[Cl:9][CH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccnc1C
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: NC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: O
Product: Cc1cccnc1CCl
Reaction time: 7 h
Yield: 107.2 %

Procedure:
A mixture of 107.16 g (1 mole) of 2,3-dimethyl-pyridine and 5 g of benzamide in 400 ml of cyclohexane was heated to reflux while adding over 4 hours 130 g (0.56 mole) of trichloroisocyanuric acid (min. 90% available chlorine) in portions and the mixture was stirred for another 7 hours at reflux and then cooled. Under agitation mix with 500 ml of water and 150 ml of 50% potassium hydroxide were added with stirring to obtain a solution. The decanted organic phases were dried over MgSO4 and evaporated to dryness under reduced pressure to obtain 85 g (60%) of 2-chloromethyl-3-methyl pyridine which slowly colored red with a boiling point of 53° to 57° C. at 3 mm H
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:36]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][CH2:38][CH:37]1[CH2:46][NH2:47]>CN(C=O)C>[O:36]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][CH2:38][CH:37]1[CH2:46][NH:47][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: NCC1COc2ccccc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)OCC(CNCCCc1c[nH]c3ccccc13)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
3-Indolepropionic acid (1.1 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (2.3 ml, 14.4 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.2 g, 6.0 mmole) in 50 ml of DMF, and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (60%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-propanamide, as an oily solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([Cl:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:30][C:21]1[CH:20]=[C:19]([CH:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH3:18])[CH:24]=[CH:23][C:22]=1[C:25]([C:26]#[N:27])([CH3:29])[CH3:28]
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(Cl)c1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C(C)(C)C#N)c(Cl)c1
Yield: 53.3 %

Procedure:
To a solution of (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (285 mg, 1.35 mmol) prepared according to scheme 2, 2-[4-(1-aminoethyl)-2-chlorophenyl]-2-methylpropanenitrile (300 mg 1.35 mmol) prepared according to scheme 17 and DMAP (325 mg, 2.69 mmol) stirred in anhydrous DMF (3.0 mL) is added HATU (511 mg, 1.35 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (300 mg, 55%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.50 (d, J=7.03 Hz, 3H) 1.83 (s, 6 H) 5.02 (q, J=7.03 Hz, 1H) 5.14 (s, 2H) 7.17 (ddd, J=11.33, 8.98, 7.42 Hz, 1H) 7.33 (dd, J=8.20, 1.95 Hz, 1H) 7.43 (ddd, J=8.89, 3.81, 1.37 Hz, 1H) 7.47 (d, J=2.34 Hz, 1H) 7.51 (d, J=8.20 Hz, 1H) 8.13 (s, 1H), MS [M+H], calcd: 379.1. found: 379.3.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1)#[N:2].[C:19](O)([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1)#[N:2]
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC2(CCCCC2)O1
Temperature: 0 °C

Procedure:
(±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid 3.32 g (13.12 mmol), is dissolved in 15 mL of dichloromethane, cooled to 0° C. and 0.1 g of 4-dimethylaminopyridine (DMAP) added, followed by t-butyl alcohol, and followed by 3.25 g of dicyclohexylcarbodiimide (DCC). This solution is stirred and allowed to slowly warm to room temperature over a 16.5-hour period. TLC shows mainly product, and some slightly lower Rf by-product. The mixture is stirred one hour and 50 mL of dichloromethane is added and stirring continued four hours. One hundred mL of diethyl ether is added and then filtered. The filtrate is concentrated at reduced pressure. This crude concentrate is chromatographed on silica gel and eluted with 4:1 hexane:ethyl acetate to yield (±)-cis-1,1-dimethylethyl 4-(cyanomethyl)-1,5-dioxaspiro[5.5 ]undecane-2-acetate.