Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][C@H:9]([OH:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Solvent: CO
Product: O[C@H](COc1ccccc1)CN(Cc1ccccc1)Cc1ccccc1
Yield: 88 %

Procedure:
A reaction mixture containing (2S)-2-(phenoxymethyl)oxirane (Example 15, 20.6 mmol, 1.0 eq.) and dibenzylamine (22.7 mmol, 1.1 eq.) in MeOH (100 mL) was heated at reflux overnight. The resulting solution was concentrated in vacuo and the crude product was purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=10:1). The product was obtained as a colorless oil in 88% yield. MH+=348.3, Rf=0.42 (hexanes:EtOAc 6:1), retention time (LC-MS)=2.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Cc1ccc(CCl)cn1
Agent: Cl
Product: Cc1ccc(Cn2cc(C#Cc3cccc(Cl)c3)nc2C)cn1

Procedure:
The title compound, MS: m/e=322.5 (M+H30), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 5-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([PH:20](=[O:22])[OH:21])[NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=[C:24]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>C(OCC)(=O)C.O>[OH:22][P:20]([CH:8]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH2:23][CH:24]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:21]
Reactant: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Reactant: C=C(Cc1ccccc1)C(=O)OC
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(Cc1ccccc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 67 %

Procedure:
A solution of 1 g (3.31 mmol) of [2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinic acid, 0.66 g (3.75 mmol) of methyl α-methylenebenzenepropanoate and 3.1 ml of N,O-bis(trimethylsilyl)acetamide is maintained at 60° C. for 24 hours. After cooling, 60 ml of a 1/1 ethyl acetate/water mixture are added. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulphate, filtered and evaporated under vacuum. The residue is purified by recrystallization from a mixture of ethyl acetate and hexane. 1.04 g of product are recovered (yield=67%).
Reaction SMILES: O.Cl.C(OC([NH:10][C@@:11]1([C:35]([O:37]C(C)(C)C)=[O:36])[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C@@H:15]([OH:27])[C@@H:14]2[C@H:12]1[C@H:13]2[C:28]([O:30]C(C)(C)C)=[O:29])=O)(C)(C)C>O1CCOCC1>[ClH:25].[NH2:10][C@@:11]1([C:35]([OH:37])=[O:36])[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C@@H:15]([OH:27])[C@@H:14]2[C@H:12]1[C@H:13]2[C:28]([OH:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 186.3 %

Procedure:
A mixture of water (430 mL) and 37% HCl in water (299.9 mL, 3.65 mol) is added to a suspension of di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (215 g, 365.3 mmol) in 1,4-dioxane (73.1 mL). The resulting slurry is stirred at 100° C. for 4.5 hours, cooled to 25° C. and concentrated in vacuo to provide a white solid. Triturate sequentially with methyl tert-butyl ether (2 L) and hexanes (2 L) and then filter to collect the solids. Dry under vacuum for 16 hours. The solid is washed again with methyl tert-butyl ether (2×1 L) and hexane (1 L), then dried under vacuum at 50° C. overnight to yield the title compound as a white solid (140.4 g, 93% yield). MS (m/z): 376/378 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:27][NH2:28]>>[NH:27]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:28]
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: NNc1cc2c(nn1)CCN(Cc1ccc(-c3ccccc3)cc1)C2

Procedure:
9.0 g of 3-chloro-6-(p-phenylbenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 55 cc of hydrazine hydrate and stirred at a bath temperature of 100° for 51/2 hours. After cooling the mixture with ice the title compound precipitates and is recrystallized from 200 cc of dimethyl formamide. M.P. 241°-244° (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1ccc(F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2c1ccc(F)c(F)c1

Procedure:
The title compound was synthesized from methyl 4-(3,4-difluorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.333 g, 1.20 mmol) and lithium hydroxide (0.508 g, 12.1 mmol in 5 mL water), according to General Procedure 7. A 1:1 mixture of water and methanol (4 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound. 0.265 g. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.17 (ddt, J=12.70, 8.55, 6.38, 6.38 Hz, 1H), 2.67-2.94 (m, 3H), 4.15 (t, J=7.15 Hz, 1H), 6.53 (s, 1H), 6.93-6.98 (m, 1H), 7.01 (ddd, J=11.87, 7.77, 2.12 Hz, 1H), 7.11 (dt, J=10.59, 8.37 Hz, 1H); 19F NMR (376 MHz, METHANOL-d4) δ ppm −145.22-−145.11 (m, 1F) −141.41-−141.30 (m, 1F); LCMS (ESI−) 262.0 (M−H); HPLC (UV=99.7%), (ELSD=100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[O:15]1[CH2:16][CH2:17][CH:12]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:13][CH2:14]1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: OC1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1cc2[nH]ncc2cc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
To a solution of the 1H-indazol-5-ol (150 mg, 1.12 mmol) obtained in Reference Example 4 in tetrahydrofuran (6 ml) were added 4-hydroxytetrahydropyran (0.107 ml, 1.12 mmol), triphenylphosphine (293 mg, 1.12 mmol) and a 40%-diethyl azodicarboxylate-toluene solution (0.517 ml, 1.14 mmol) at 0° C. After 30 minutes, the mixture thus obtained was heated to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole (11.4 mg, 47%).
Reaction SMILES: C1[N:5]([CH2:6][O:7]CCO)[C:4]2NC(N)=[N:13][C:14](=O)[C:3]=2N=1.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=[CH:19][CH:18]=1>C(O)C>[NH2:13][C:14]1[CH:3]=[C:4]2[C:18]([CH2:19][C:6](=[O:7])[NH:5]2)=[CH:17][CH:22]=1
Reactant: Nc1nc(=O)c2ncn(COCCO)c2[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)C2
Yield: 3626.2 %

Procedure:
2,4-dinitrophenylacetic acic (10 g; 44 mmol) was dissolved in ethanol (200 mL) and purged with N2. 10% Pd/C (400 mg) was added and the reaction hydrogenated at 45 psi for 2 hours. The reacton was then transferred to a RBF and p-toluenesulfonic acid (150 mg) was added and the reaction heated at reflux overnight. The reaction was then filtered through celite to remove catalyst and concentrated. The product crashed out and was filtered as tan crystals 4.68 g (72% yield). 1H NMR (DMSO-d6, 400 MHz) δ 3.20 (s, 2H), 4.97 (br s, 2H), 6.07 (m, 2H), 6.76 (d, J=8.7 Hz; 1H), 10.05 (s, 1H); HPLC ret. time: 2.123 min. LRMS (M+) 148.7.
Reaction SMILES: CCCCC[C@H](O)CC[C@H]1[C@H]([OH:22])C[C@H]2[C@@H]1CC1C(C2)=C(OCC(O)=O)C=CC=1.[NH+]1C=CC=CC=1.C(CCOP([O-])([O-])=O)#N.[CH:44]1([N:50]=[C:51]=[N:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>N1C=CC=CC=1.O>[C:51]([NH:50][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1)([NH:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:22]
Reactant: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OCC(=O)O)c3C[C@H]2C[C@H]1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CCCOP(=O)([O-])[O-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The procedure was adapted after Steroids, 1963, 2(6), 567-603 and is the same for (8) and (10) starting from (6) and (5), respectively. The TBDMS protected methyl ester of treprostinil (6) (46 mg, 0.09 mmoles) was dissolved in 2 ml dry pyridine and a pyridinium solution of the previously prepared pyridinium solution of 2-cyanoethyiphosphate 1M (0.2 ml, 0.2 mmoles) (cf. Methods in Enzymology, 1971, 18(c), 54-57) were concentrated to dryness in vacuo at 40° C. Anhydrous pyridine was added and the reaction mixture was again concentrated; the operation was repeated twice in order to remove water completely. Finally the residue was dissolved in 2 ml anhydrous pyridine and 116 mg (0.56 mmoles) dicyclohexylcarbodiimide were added as a solution in 2 ml anhydrous pyridine. The reaction mixture in a closed flask was stirred magnetically for 48 hours at room temperature in the dark. 5 ml water were added and after one hour, the mixture was concentrated to a thick paste in vacuo. The reaction mixture was treated overnight at room temperature with 10 ml of a 1/9 water/methanol solution containing 100 mg sodium hydroxide. The white solid (dicyclohexylurea) formed was removed by filtration and it was washed well with water. The aqueous-methanolic solution was concentrated almost to dryness in vacuo, water was added and the solution was extracted with n-butanol (3×10 ml), then with methylene chloride (1×10 ml). The pH of the solution was adjusted to 9.0 by treatment with a sulfonic acid ion exchange resin (H+ cycle-Dowex); treatment with Dowex resin for a longer time (−˜12 hours) lead to both the cleavage of the TBDMS group and the recovery of the free carboxyl group. The resin was filtered and the solution was concentrated to dryness affording the corresponding monophosphate 8 (33 mg, yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:18]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH3:21])=[O:19]>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])/[CH:22]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC/C(=C\C=O)c1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-octenal (6 g) was treated with (carbomethoxymethylene)triphenylphosphorane (9.5 g) in carbon tetrachloride (60 mL) for 4 days at room temperature. The ester was isolated in the normal manner and purified by HPLC (ether-hexane; 1:7.5) to furnish 6.1 g of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: [CH:1]1([P:7]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:20]C>[I-].C[P+](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C1CCCCC1>[I-:20].[CH:14]1([PH+:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CI
Agent: C[P+](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: [I-]
Solvent: C1CCCCC1
Product: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1

Procedure:
This example shows the storage stability of precatalyzed resin containing methyl tricyclohexyl phosphonium iodide catalyst. Tricyclohexyl phosphonium iodide was prepared by reacting tricyclohexylphosphine with iodomethane. 3.95 g of tricyclohexyl phosphine was charged to a 200-ml flask. 70 ml of cyclohexane was added. The resulting solution was maintained with stirring under a nitrogen blanket and condenser. 2 g of iodomethane was added to the solution, resulting in the precipitation of a white solid. The reaction mixture was vacuum filtered and dried in a vacuum oven.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1c(Cl)cccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1c(Cl)cccc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 3-chloro-N1-phenylbenzene-1,2-diamine (1.72 g, 7.87 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.64 g, 8.65 mmol), HOAt (1.18 g, 8.65 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.66 g, 8.65 mmol) in DCM (40 mL) cooled to 0° C. under a nitrogen atmosphere was added Et3N (3.3 mL, 0.0236 mol). The reaction mixture was stirred at 0° C. for 5 min, then slowly warmed to RT and stirring was continued for 16 h. The resulting mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The residue thus obtained was purified column chromatography (Si—PCC, gradient 0-2% 2M NH3/MeOH in DCM) affording [(S)-1-(2-Chloro-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an off-white solid (1.60 g, 52% over three steps). LCMS: RT 3.75 min [M+H]+ 390.2.
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.CO.[C:34]([O:37][CH2:38]C)(=[O:36])C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:38][O:37][C:34](=[O:36])[C:2]1[CH:3]=[C:4]([Cl:31])[C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:28][C:29]=1[Cl:30]
Reactant: CCOC(C)=O
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Product: COC(=O)c1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 100 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
To a solution of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (100 mg, 0.19 mmol, 1.0 equiv; Example 163) in a 1:1 mixture of methanol and ethyl acetate (4 mL) was added 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (10.1 mg, 0.012 mmol, 0.064 equiv; [CAS RN 95464-05-4]) and the reaction mixture stirred under an atmosphere of carbon monoxide (70 bar) at 100° C. for 20 h. The crude reaction mixture was filtered over Celite® and purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to afford 50 mg (52%) of the title compound as a off-white solid. MS (ISN): 498.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:28](O)=[O:29])=[N:22][N:23]([CH:25]([F:27])[F:26])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH:25]([F:27])[F:26])[N:22]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Reactant: O=C(O)c1nn(C(F)F)cc1Cl
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2nn(C(F)F)cc2Cl)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=434.2 [M+H]+.
Reaction SMILES: C(N(C[CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10]1)CCC)CC.[NH3:18]>ClCCl.CO>[N:18]1([CH2:9][CH:14]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10]2)[CH2:10][CH2:9][CH2:14][CH2:13][CH2:12]1
Reactant: CCCN(CCC)CC1CCCN(CC#N)C1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: N#CCN1CCC(CN2CCCCC2)C1

Procedure:
2-[3-[(dipropylamino)methyl]-piperidin-1-yl]acetonitrile in a yield of 76% of theory, RF 0.545 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 89/10/1 v/v);
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][CH2:37][NH:38][C:15]2[N:14]=[C:13]([C:11]3[S:10][C:9]4[CH:21]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:6]=[CH:7][C:8]=4[CH:12]=3)[C:18]([CH3:19])=[CH:17][N:16]=2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CNC(=O)c1ccc2cc(-c3nc(Cl)ncc3C)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C(=O)OC(C)(C)C)CC4)ncc3C)sc2c1
Temperature: 95 °C
Yield: 43.9 %

Procedure:
A mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methylamide (263 mg, 0.830 mmol), 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (358 mg, 1.47 mmol) and diisopropylethylamine (0.44 mL) in 1,4-dioxane (10 mL) is heated at 95° C. for 20 hours. The solvent is removed after cooling and the residue is subjected to chromatography on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 0-10%, to give 4-{3-[5-methyl-4-(6-methylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (191 mg, 44% yield). The intermediate is dissolved in THF (8 mL) and 5 N hydrochloric acid (5 mL) is added. The solution is heated at 70° C. for 4.5 hours and then cooled before evaporating the solvent. Methanol is added to the residue and the mixture is sonicated for 30 minutes. The solid is filtered and washed with diethyl ether, then dried in a vacuum oven at 50° C. for 18 hours to give the title compound (129 mg, 66% yield). ES+(m/z) 425 [M(free base)+H].
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)=[O:4].[S:24]1[CH:28]=[C:27]([CH:29]=O)[N:26]=[CH:25]1.CN(C)C=O.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:18]1([CH2:17][C@H:2]([NH:1][CH2:29][C:27]2[N:26]=[CH:25][S:24][CH:28]=2)[C:3]([NH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:8][CH:7]=2)=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cnc(-c2ccncc2)s1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(-c2ccncc2)s1)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.3 %

Procedure:
To a mixture of (S)-2-amino-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)propanamide (0.075 g, 0.23 mmol), thiazole-4-carbaldehyde (0.026 g, 0.23 mmol) and N,N-dimethylformamide (0.500 ml, 0.23 mmol) in 1,2-dichloroethane (1.000 ml, 0.23 mmol) was added sodium triacetoxyborohydride (0.17 g, 0.81 mmol). The resulting mixture was allowed to stir at room temperature for 4 hours. Upon completion, the mixture was directly subjected to HPLC purification give 10 mg of (S)-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)-2-(thiazol-4-ylmethylamino)-propanamide 5.3. 400 MHz 1H NMR (CD3OD) δ: 9.30 (d, 1H), 8.81 (d, 2H), 8.07 (d, 2H), 7.95 (d, 1H), 7.76 (s, 1H), 7.28-7.37 (m, 3H), 7.24 (dd, J=8.0, 4.0 Hz, 2H), 4.49 (d, J=16 Hz, 1H), 4.44 (d, J=16 Hz, 1H), 4.43 (dd, J=12, 8.0 Hz, 1H), 3.49 (dd, J=12, 4.0 Hz, 1H), 3.23 (dd, J=12, 8.0 Hz, 1H). LCMS (ES+) m/z 422.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:17]1[N:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:19][CH:18]=1>>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][CH:24]([O:23][C:20]2[CH:21]=[N:22][C:17]([N:1]3[C:9]4[C:4](=[CH:5][C:6]([NH:10][C:11]([CH:13]5[CH2:14][CH2:15]5)=[O:12])=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[CH:18][CH:19]=2)[CH2:29][CH2:28]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(Nc1ccc2[nH]ccc2c1)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(NC(=O)C5CC5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using N-(1H-indol-5-yl)cyclopropanecarboxamide (intermediate-02) and tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06).
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13]1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH2:1]([NH:11][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCN
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCNC(=O)CCCO
Yield: 44.6 %

Procedure:
A mixture of 15 g of decylamine, 5.48 g of gamma butyrolactone, 100 ml of toluene, and 20 mg of zinc chloride was refluxed under nitrogen for 4 days. Upon cooling the reaction mixture formed a precipitate which was recrystallized from toluene to yield 6.91 g (44.6%) of N-decyl-4-hydroxybutyramide, m.p. 74-75° C.