Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:35])[NH:17][C:18]1[S:19][C:20](C2C=CC=C(C(=O)NC3CC3)C=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]([C:40]1[O:41][C:42](C2N=C(N)SC=2)=[CH:43][CH:44]=1)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(OC(N1CCC[C@H]1C(O)=O)=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:35])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:42]2[O:41][C:40]([C:38]([O:37][CH3:36])=[O:39])=[CH:44][CH:43]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC1)c1cccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)c1
Reactant: COC(=O)c1ccc(-c2csc(N)n2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)o1

Procedure:
In a similar procedure as described for the synthesis of Compound 5312 (Example 312), 5-(2-amino-thiazol-4-yl)-furan-2-carboxylic acid methyl ester was treated with HATU (0.98 g, 2.38 mmol), DIEA (0.7 mL, 5.36 mmol), and (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.61 g, 2.45 mmol) to furnish (S)-2-[4-(5-Methoxycarbonyl-furan-2-yl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester; MS: 169.1 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:10])[C:6](Cl)=[N:7][OH:8])[CH2:3][CH2:2]1.[CH2:11]([O:13][C:14](=[O:20])/[CH:15]=[CH:16]/N(C)C)[CH3:12].C(OCC)(=O)C>C1COCC1>[CH2:11]([O:13][C:14]([C:15]1[C:6]([C:5](=[O:10])[NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:7][O:8][CH:16]=1)=[O:20])[CH3:12]
Reactant: CCOC(=O)/C=C/N(C)C
Reactant: O=C(NC1CC1)C(Cl)=NO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1conc1C(=O)NC1CC1
Temperature: 75 °C

Procedure:
A mixture of N-cyclopropyl-2-chloro-2-hydroxyimino-acetamide (2 g, 12.3 mmol) and (E)-3-(dimethylamino)-acrylic acid ethyl ester (1.76 ml, 12.3 mmol) in THF (25 ml) was heated at 75° C. for 2 h. The reaction was then cooled to r.t., poured into 100 mL ethyl acetate and extracted with 1 M HCl. The aqueous layers were back-extracted with ethyl acetate. The organic phase was washed with water and brine, dried and evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (1.6 g, 58%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][CH2:24][CH2:25][N:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9]([NH:31][C:28]2[CH:29]=[CH:30][N:26]([CH2:25][CH2:24][O:23][CH3:22])[N:27]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (60 mg, 0.21 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 0.031 g, 0.22 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.11 g, 0.25 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 70-100% ethyl acetate/hexanes) to give (S)-3-cyclohexyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (31 mg, 36%) as an off white solid: [α]28D=−69.7°, (c=0.31, chloroform); HR-ES(+) m/e calcd for C23H30N4O3 [M+H]+ 411.2391, observed 411.2389; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84-1.24 (m, 7H) 1.47-1.99 (m, 2H) 3.18 (s, 4H) 3.49-5.29 (m, 8H) 6.36 (s, 1H) 7.31-7.89 (m, 7H) 10.83 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([N+:12]([O-])=[O:13])([CH3:11])[CH3:10].C(O)(=O)C>C(O)C.[Zn]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N+:12]([C:9]([CH3:11])([CH3:10])[CH3:8])[O-:13]
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1cccs1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1cccs1

Procedure:
To a suspension of thiophene-2-carbaldehyde (296.7 mg, 2.65 mmol), 1,1-dimethylnitroethane (542.9 mg, 5.27 mmol) and zinc (516.3 mg, 7.90 mmol) in ethanol (3.0 ml) was added acetic acid (946.6 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=1/2).
Reaction SMILES: C(N1CC[CH2:6][CH:5](CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)[CH2:4]1)C.[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:53][CH3:54])[N:41]2[CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[C:37]([NH2:55])[N:36]=1)[CH2:31][CH2:32][CH3:33].IC(C)C>>[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:53][CH3:54])[N:41]2[CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([CH:5]([CH3:6])[CH3:4])[CH2:49][CH2:48]2)=[C:37]([NH2:55])[N:36]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Solvent: CC(C)I
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: COC1C=CC(C=[N:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=CC=1.ClC1C=C(C=CC=1)C(OO)=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.ON>O1CCCC1.C(OCC)(=O)C.O>[C:13]1([C@@H:11]([NH:10][OH:24])[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C=N[C@@H](C)c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](NO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A −78° C. solution of Example 2A (7.15 g, 30 mmole) in tetrahydrofuran (75 mL) was treated with a solution of 3-chloroperoxybenzoic acid (15 g, 60 mmol), warmed to 0 ° C., stirred for 2 hours, diluted with ethyl acetate (100 mL), washed sequentially with 10% (w/w) sodium thiosulfate, saturated sodium bicarbonate, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in tetrahydrofuran (100 mL), treated with p-toluene sulfonic acid monohydrate (8.15 g, 42.8 mmol), stirred for 2 hours, treated with a solution of N-hydroxylamine hydrochloride (8.7 g) in water (15 mL), and stirred for 16 hours. The mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:2 ethyl acetate/hexanes to provide 3.53g (86% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.36-7.20 (m, 5H), 4.09 (q, 1H, J=6.6 Hz), 1.48 (d, 3H, J=6.6 Hz).
Reaction SMILES: [C:1]([C:4](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:5]([O:7][CH2:8][CH2:9][O:10][CH3:11])=[O:6])(=O)[CH3:2].[NH2:20][C:21]([CH3:29])=[CH:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24].C1(C)C=CC=CC=1.C(OCC)(=O)C>C(O)(C)C>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[C:4]([C:5]([O:7][CH2:8][CH2:9][O:10][CH3:11])=[O:6])=[C:1]([CH3:2])[NH:20][C:21]([CH3:29])=[C:22]1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: CC(N)=CC(=O)OC(C)C
Reactant: COCCOC(=O)C(=Cc1ccccc1F)C(C)=O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1ccccc1F
Yield: 47.7 %

Procedure:
4.0 g (about 15 mmol) of the compound from Example I are heated to reflux overnight in 100 ml of isopropanol with 2.2 g (15 mmol) of isopropyl 3-amino-2-butenoate. After thin-layer chromatographic checking (SiO2, toluene/ethyl acetate 5:1) shows complete conversion, the reaction mixture is concentrated, the residue is-taken up with toluene, the solution is concentrated again and the residue is then purified by filtration on silica gel (eluent: toluene/ethyl acetate 100:1-5:1). A crystallizing yellow oil is obtained, which is recrystallized from methanol at about −15° C. 2.8 g (48%) of the target compound are obtained.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12]
Reactant: CCC1C(=O)Nc2ccccc21
Reactant: ClCCCCBr
Product: CCC1(CCCCCl)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chlorobutane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:8]([NH:22][C:23]2[CH:44]=[CH:43][CH:42]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=4)[CH:32]=3)[CH:24]=2)=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Cl)c(C(=O)O)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1cc(Cl)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n1
Yield: 45.2 %

Procedure:
In the same manner as in Example 18-4 and using 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (156 mg, 0.970 mmol), tetrahydrofuran (7 mL), oxalyl chloride (93.0 μL, 1.07 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (132 mg, 45%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:29](CS([O-])(=O)=O)([CH3:31])[CH3:30]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH:29]([CH3:31])[CH3:30])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)CS(=O)(=O)[O-]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C(C)C
Yield: 90.4 %

Procedure:
To a mixture of 5-benzyloxyindole-2-carboxylic acid ethyl ester (30 g, 1.0 eq.) and cesium carbonate (58. g, 1.75 eq.) in acetonitrile (200 mL), was added isopropylmethane sulfonate (24.8 g, 1.75 eq.). The reaction mixture was refluxed for 18 h and then concentrated in vacuo. The residue was partitioned between water and methyl-tert-butylether. The aqueous layer was extracted with methyl-tert-butylether and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and dried in vacuo. then purified on silica eluting with dichloromethane/methanol 98:2 v:v. The crude material was purified by crystallization in ethanol and dried in vacuo to yield 31 g (90%) of the desired product as an off-white oil. MS (m/e): 338.4 (MH+, 100%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([N:14]3[CH2:19][CH2:18][C@:17]([CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:16][C:15]3=[O:31])[CH3:13])=[CH:8][CH:7]=2)=[CH:2]1>O=[Pt]=O.C(O)C>[OH:30][C:27]([CH3:28])([CH3:29])[CH2:26][C@@:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:16][C:15](=[O:31])[N:14]([C@H:12]([C:9]2[CH:10]=[CH:11][C:6]([CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)=[CH:7][CH:8]=2)[CH3:13])[CH2:19][CH2:18]1
Reactant: C[C@@H](c1ccc(-c2ccoc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=[Pt]=O
Solvent: CCO
Product: C[C@@H](c1ccc(C2CCOC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-[(S)-1-(4-furan-3-yl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.12 g), PtO2 (50 mg), and ethanol (15 mL) was shaken under hydrogen atmosphere (3 bar) at room temperature for 4 h. Then, the catalyst was separated by filtration and the filtrate was concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20->0:100) to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]=2[Cl:34])[CH:5]=[CH:6][CH:7]=1.[CH3:35][NH:36][C:37]([C:39]1[CH:49]=[CH:48][C:42]([CH:43]=[CH:44][C:45](O)=[O:46])=[CH:41][CH:40]=1)=[O:38].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Si:17]([O:16][CH2:15][C:10]1[C:9]([Cl:34])=[C:8]([N:4]2[CH:5]=[CH:6][CH:7]=[C:3]2[CH2:2][NH:1][C:45](=[O:46])[CH:44]=[CH:43][C:42]2[CH:48]=[CH:49][C:39]([C:37](=[O:38])[NH:36][CH3:35])=[CH:40][CH:41]=2)[CH:13]=[CH:12][C:11]=1[Cl:14])([C:30]([CH3:31])([CH3:33])[CH3:32])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2CN)c1Cl)(c1ccccc1)c1ccccc1
Reactant: CNC(=O)c1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of 2-aminomethyl-1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (465 mg) in anhydrous dimethylformamide (7 ml) were added 4-(methylcarbamoyl)cinnamic acid (206 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (219 mg) and 1-hydroxybenzotriazole (185 mg). The mixture was stirred at ambient temperature for 3 hours and partitioned between ethyl acetate and water. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (622 mg) as a brownish powder.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[C:22]3[N:35](C)[CH3:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C1C=CC2N(C3CCCCC3)C(C3[CH:51]=[C:52]4C(=CC=3)N=[C:55](C3C=CC=CC=3)[CH:54]=[C:53]4[Cl:66])=NC=2C=1)=O)C.ClNC1C=CC=CC=1>>[Cl:66][C:53]1[CH:54]=[CH:55][C:36]([NH:35][C:22]2[C:21]3[C:26](=[CH:27][CH:28]=[C:19]([C:8]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:11]5[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=5[N:9]=4)[CH:20]=3)[N:25]=[C:24]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=2)=[CH:51][CH:52]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Reactant: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Agent: ClNc1ccccc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Nc4ccc(Cl)cc4)c3c1)n2C1CCCCC1

Procedure:
The title compound was prepared using the method described for Compound 481. In this reaction 102 mg (0.2 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used. The nucleophile used wasp-chlorophenylamine. Yield: 89 mg.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C@@H:6]1[C@@:10]2([CH3:28])[CH2:11][CH2:12][C@@H:13]3[C@@:18]4([CH3:27])[CH2:19][CH2:20][C@H:21]([O:23][C:24]([CH3:26])=[O:25])[CH2:22][C:17]4=[CH:16][CH2:15][C@H:14]3[C@@H:9]2[CH2:8][CH2:7]1)=[O:5]>C(O)C.C(Cl)Cl>[C:24]([O:23][CH:21]1[CH2:20][CH2:19][C@@:18]2([CH3:27])[C:17](=[CH:16][CH2:15][C@@H:14]3[C@@H:13]2[CH2:12][CH2:11][C@@:10]2([CH3:28])[C@H:9]3[CH2:8][CH2:7][C@@H:6]2[CH:4]([OH:5])[CH3:3])[CH2:22]1)(=[O:25])[CH3:26]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 4 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Sodium borohydride (21 gm) was added to a solution of pregnenolone acetate (100 g, 0.28 mol) in absolute ethanol (1 L) and methylene chloride (0.4 L) at -10° C. After stirring overnight at 4° C., another amount of sodium borohydride (10.5 gm) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched by pouring into 5% sodium phosphate monobasic (2 L) and extracted with methylene chloride. The organic extracts were dried over anhydrous magnesium sulfate and filtered through a pad of anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the title compound (97.6 gm, 87% yield).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH2:15][N:14]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:20][CH2:19]3)[C:13](=[O:30])[CH2:12]2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].O.[OH-].[Li+].[Cl-].[NH4+].CO>O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[CH2:15][N:14]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23]3)[C:13](=[O:30])[CH2:12]2)=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: CCOC(=O)CN1CCC(N2CC(=O)N(c3ccc(C(=N)N)cc3)CC2=O)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: N=C(N)c1ccc(N2CC(=O)N(C3CCN(CC(=O)O)CC3)CC2=O)cc1
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
0.089 g of ethyl 4-[4-(4-amidinophenyl)-2,5-dioxo-1-piperazinyl]-1-piperidineacetate hydrochloride was dissolved in 1 ml of water, and 0.017 g of lithium hydroxide monohydrate was added thereto with cooling with ice. This was stirred for 30 minutes still with cooling with ice, and an aqueous saturated solution of ammonium chloride was added thereto. Next, this was subjected to ODS column chromatography (H2O→H2 O/MeOH=3/2, v/v) to obtain 0.027 g of 4-[4-(4-amidinophenyl)-2,5-dioxo-1-piperazinyl]-1-piperidineacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.Cl.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.O>[CH:17]1([C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]3)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(O)C1CC1
Reactant: COC(=O)c1cnc2ccc(N)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cnc2ccc(NC(=O)C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of methyl 6-aminoquinoline-3-carboxylate.2 HCl (Int-3, 0.125 g, 0.524 mmol) and cyclopropanecarboxylic acid (45.7 μL, 0.576 mmol) in pyridine (1.98 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.301 g, 1.57 mmol). The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (hexanes to 40/60 hexanes/ethyl acetate gradient) to afford Int-4 (0.071 g, 50%). LC-MS: (FA) ES+ 271; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.65 (s, 1H), 9.17 (d, J=2.1 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.98 (dd, J=9.1, 2.3 Hz, 1H), 3.93 (s, 3H), 1.86 (tt, J=7.1, 7.1, 5.3, 5.3 Hz, 1H), 0.90-0.80 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]([C:31]#[N:32])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[CH3:33][C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:38]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:31]([C:23]1[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:36]4[S:35][C:34]([CH3:33])=[N:38][CH:37]=4)=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:32]
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(Br)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(-c4cnc(C)s4)c(C(OC)OC)nc32)ncc1C#N
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
A suspension of 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 315, 300 mg, 0.594 mmol), 2-methylthiazole-5-boronic acid pinacol ester (250 mg, 1.066 mmol), PdCl2(dppf) (43.4 mg, 59 μmol) and saturated aqueous Na2CO3 (0.7 ml) in DME (2.5 ml) was sealed in a vial and purged with argon. The reaction mixture was stirred at 120° C. for 20 min in a microwave. Additional methylthiazole-5-boronic acid pinacol ester (20 mg, x mmol), the reaction mixture was purged with argon and was stirred at 120° C. for 10 min in a microwave. The suspension was diluted with DCM and saturated aqueous Na2CO3, phases were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-10%) in DCM, followed by another purification eluting with a gradient of EtOAc (70-100%) in hexanes. Product containing fractions were combined, evaporated and dried to yield the title compound as a colorless solid. (UPLC-MS 3) tR 1.09 min; ESI-MS 524.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:5]2[N:6]=[C:7]([CH3:24])[C:8]([CH:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:25]=[C:5]2[N:6]=[C:7]([CH3:24])[C:8]([C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1
Reactant: COC(=O)C(O)c1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)C(=O)c1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (1.28 g, 3.11 mmol, 1 equiv) in DCM (16 mL) was added Dess-Martin periodindane (1.85 g, 4.36 mmol, 1.4 equiv). After 30 min, the reaction was added saturated aqueous NHCO3 and extracted with DCM (×3). The combined DCM extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-50% EtOAc/hexane) to provide methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate as a yellow solid (0.71 g, 56%). 1H NMR (400 MHz, CDCl3) δ 6.56 (s, 1H), 3.94 (s, 3H), 3.58-3.43 (m, 4H), 2.55 (s, 3H), 1.64-1.50 (m, 4H), 1.05 (s, 6H); LCMS (ESI, M+1): 409.2.