Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:25])[CH3:24])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[C:23]([CH3:25])([O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15](=[O:31])[NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:17]=1)[CH3:24])[CH3:30]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCNCC2)c1
Reaction time: 5 h
Yield: 71.8 %

Procedure:
2.08 g (5.0 mmol) of 4-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester was dissolved under argon in 80 mL of MeCl2; to the stirred solution, 3.66 mL (5.46 g=10 eq.) of TFA was added drop by drop and stirring continued at rt for 5 h. Then, the reaction mixture was evaporated i.V., the residue was dissolved in MeCl2 and water, the pH was adjusted to ˜10 with sodium carbonate solution and the mixture was extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. The crude product was purified by chromatography (silicagel, eluent:gradient of MeCl2/MeOH) to yield 1.20 g of the title compound as colorless oil. MS: 335.2 (MH+).
Reaction SMILES: [CH:1]1([C:6]#[CH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.C([Li])CCC.CCCCCC.Cl[C:25]([O:27][CH3:28])=[O:26]>>[CH:1]1([C:6]#[C:7][C:25]([O:27][CH3:28])=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cl
Reactant: C#CC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C#CC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a stirred solution of cyclopentylacetylene (7, 17.49 mL, 150.0 mmol) in anhydrous tetrahydrofuran (THF, 200 mL, 2466 mmol) at −78° C. was added 2.50 M of n-butyllithium in hexane (66.0 mL, 165 mmol, 1.1 equiv). The resulting milky suspension was stirred at −78° C. for 30 min. Methyl chloroformate (17.6 mL, 225 mmol, 1.5 equiv) was then added. The reaction mixture became a clear solution. The cooling bath was then removed, and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture became a suspension again. When TLC (5% EtOAc/hexane, KMnO4 stain) showed the reaction was deemed complete, the reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL) and extracted with diethyl ether (Et2O, 2×200 mL). The combined organic layers were washed with saturated aqueous NaCl solution, dried over magnesium sulfate (MgSO4), filtered and concentrated under the reduced pressure. The residue was distilled under vacuum (99-101° C./16 mbar) to afford methyl 3-cyclopentylpropiolate (18, 21.856 g, 22.83 g theoretical, 96% yield) as a colorless oil. For 18: 1H NMR (CDCl3, 400 MHz) δ ppm 3.74 (s, 3H), 2.73 (m, 1H), 1.95 (m, 2H), 1.72 (m, 4H), 1.57 (m, 2H).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].O.Cl.Cl[CH2:16][C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1>CN(C=O)C>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:16][C:17]2[N:18]=[C:19]([CH3:22])[S:20][CH:21]=2)[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(CSc2nc(N)cc(=O)[nH]2)cs1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimidine hydrate (16.1 g) and powdered sodium hydroxide, (8.0 g) was stirred in dry DMF (100 ml) for 20 mins. 4-Chloromethyl-2-methylthiazole hydrochloride monohydrate (20 g) was added portionwise and the resulting suspension stirred 18 hrs. The mixture was poured onto water and the solid collected, washed with water and dried to afford the sub-title compound (24.3 g)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:39]=[CH:38][CH:37]=[CH:36][C:11]=1[C:12]([NH:14][CH:15]([C:17]1[N:22]=[N:21][C:20]([NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)=[N:19][CH:18]=1)[CH3:16])=O)#[N:2].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:16][C:15]1[N:14]=[C:12]([C:11]2[CH:36]=[CH:37][CH:38]=[CH:39][C:10]=2[S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[N:22]2[C:17]=1[CH:18]=[N:19][C:20]([NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)=[N:21]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Sc3ccccc3C#N)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4Sc4ccccc4C#N)n3n2)cc(OC)c1OC
Yield: 37 %

Procedure:
In a similar manner as described for Example 9, 2-[(2-cyanophenyl)thio]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 39) (269 mg, 0.49 mmol), and 1,2,4-triazole (210 mg, 2.94 mmol) in pyridine (3 mL) and phosphorous oxychloride (0.14 mL, 1.5 mmol) gave 2-[(2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)thio]benzonitrile (95 mg, 37%) as a yellow solid. 1H NMR (CDCl3): δ8.77 (s, 1H), 7.70 (m, 1H), 7.57 (m, 1H), 7.42-7.47 (m, 3H), 7.10-7.23 (m, 3H), 6.85 (s, 1H), 6.79 (s, 2H), 3.80 (s, 3H), 3.63 (s, 6H), 2.57 (s, 3H). MS m/z 524 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)CC)(C)C.[NH:35]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:42].ClCl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:38]1[CH2:39][CH2:40][CH2:41][NH:35][C:36](=[O:42])[CH2:37]1)=[O:5])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: O=C1CNCCCN1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCCNC(=O)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 63 %

Procedure:
Prepared analogously to Example 1d from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, PFTU, diisopropylethylamine, and [1,4]diazepan-2-one in dimethylformamide. Yield: 63%; C22H21Cl2N5O3 (474.346); mass spectrum: (M+H)+=474/476 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]3[N:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH3:20])=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][N+:23]1([O-])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC(CC(C)=O)=O.CC(CC(C)=O)=O.O=[V].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]3[N:15]=[C:16]([Cl:19])[CH:17]=[C:18]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:13]3=[N:12][C:11]=2[CH3:20])=[O:9])=[C:4]([F:21])[CH:3]=1
Reactant: Cc1nc2ccc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[V]
Solvent: CC(=O)CC(C)=O
Solvent: CCO
Product: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F

Procedure:
Add ethanol (12 L), (4-chloro-2-fluorophenyl)(6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)methanone (897.70 g, 2.77 mol) and bis(2,4-pentanedionato)oxovanadium (IV) (146.81 g, 553.67 mmol) to a reaction vessel with a nitrogen atmosphere. Add an ethanol (6 L) solution of 4-methylmorpholine 4-oxide (3.89 kg, 33.21 mol) drop-wise over 150 min keeping the reaction temperature at 23-33° C.; then heat the reaction at 40° C. for 48 h. Cool the reaction and concentrate by removal of solvent (13 L). Filter the resulting mixture, rinse the filter cake with hexane (1 L) and then dry. (728 g, 66.25%; mp 145-147° C.; M+=423).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3ncccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2ncccc12
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a mixture of methyl 4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}benzoate (975 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), 1N hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (701 mg, 75%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]=[CH:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1.N1CCCCC1>CO>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1C=CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C\CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-enyl]piperidine-1-carboxylate (0.0265 g, 0.0660 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.00964 g, 0.0660 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperidine-1-carboxylate (0.0293 g, 84%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:36]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)[C@H](C)O)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)O)=[O:4].[NH2:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.CN1C(N)=CC(C)=N1.ClC(N(C)C)=C(C)C>CCOC(C)=O.CCN(CC)CC>[Br:10][C:8]1[N:7]([CH:11]([CH3:12])[CH3:13])[C:6]2[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=3)[N:24]([C:25]3[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=3)[C:3](=[O:4])[C:5]=2[CH:9]=1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)c(F)c1
Reactant: Cn1cc(N)cc(Cl)c1=O
Agent: CC(C)=C(Cl)N(C)C
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cc1cc(N)n(C)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)c(F)c1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate AW but in the step corresponding to Step AW2, 5-bromo-2-[(4-chloro-3-fluoro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step AZ1) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 2,5-dimethyl-2H-pyrazol-3-ylamine respectively. Moreover, in this step, the procedures described for Steps H3 and H2 using 1-chloro-N,N,2-trimethylpropenylamine and Et3N were used. The title compound (containing some of the corresponding 2-chloro analog) was obtained as a white foam. tR: 1.18 min (HPLC 3); ESI-MS: tR=1.10 min, [M+H]+ 512/514/516 (LC-MS 1); TLC: Rf=0.19 (EtOAc).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:17]([O:24][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: Clc1nc(SCOCc2ccccc2)ns1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCSc2nsc(OCc3ccccc3)n2)cc1
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
Into 3 g of N,N-dimethylformamide were dissolved 350 mg of 5-chloro-3-benzyloxymethylthio-1,2,4-thiadiazole and 153 mg of benzyl alcohol, 68 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes. After stirring for 2 hours at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 260 mg of 5-bezyloxy-3-benzyloxymethythio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (43)).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH:10]([O:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)([CH3:12])[CH3:11]>C(N(C(C)C)C(C)C)C.C(#N)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:24][CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:16]3[CH:15]=[C:14]([O:13][CH:10]([CH3:11])[CH3:12])[CH:27]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:25]=3)[CH2:19][CH2:20]2)[C:7]=1[NH2:8]
Reactant: CC(C)Oc1cc(CN2CCC(N)CC2)cc(OC(C)C)c1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(CN2CCC(Nc3ncnc(Cl)c3N)CC2)cc(OC(C)C)c1
Yield: 20 %

Procedure:
A solution of 4,6-dichloro-pyrimidin-5-ylamine (19.7 mg, 0.12 mmol, 1.0 equiv; commercially available) and 1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamine (46.0 mg, 0.15 mmol, 1.25 equiv; intermediate A3) in N-ethyl diisopropylamine (1.0 mL) and acetonitril (1.0 mL) was heated by microwave irradiation to 160° C. for 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.6 mg (20%) of the title compound. MS (ISP): 434.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:13]([O:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=2)[N:24]=[C:23]([NH:35][NH2:36])[C:22]1=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCCC1>[CH2:13]([O:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=2)[N:24]=[C:23]([NH:35][NH:36][C:10](=[O:11])[CH2:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[C:22]1=[O:37])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNc1nc2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)NNc1nc2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A solution of (diethoxyphosphoryl)acetyl chloride (5.8 g, 27 mmol) in 40 ml of dry tetrahydrofuran was added to a solution of 1-benzyloxy-3-hydrazino-7-trifluoromethylquinoxalin-2(1H)-one (8.75 g, 25 mmol) and dry triethylamine (3.6 ml, 27 mmol) in 200 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 3 h and filtered. The filtrate was evaporated to dryness, and the residue was crystallized by trituration with water (200 ml) to give 12.85 g (97%) of the title compound. M.p. 163°-166° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:19]=[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=3)[C:21]([OH:34])=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:23]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:46]([C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[C:51]([OH:58])[CH:50]=1)(=[O:48])=[O:47].[K+].[Br-]>>[OH:58][C:51]1[CH:50]=[C:49]([S:46]([O:34][C:21]2[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=3)=[CH:19][C:18]([C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:23][C:22]=2[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)(=[O:48])=[O:47])[CH:57]=[CH:56][C:52]=1[C:53]([OH:55])=[O:54]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared as an white foam (0.541 g, 78%) from 2′-Hydroxy-3,3″-bis-trifluoromethyl-[1,1′;3′1″]terphenyl-5′-carboxylic acid (8-phenyl-octyl)-amide and 4-chlorosulfonyl-2-hydroxy-benzoic acid using a procedure similar to step 3 of Example 179. 1H NMR (DMSO-d6) δ 11.60 (bs, 2H); 8.70 (t, 1H); 7.94 (s, 2H); 7.88-7.80 (m, 4H); 7.69-7.57 (m, 5H); 7.26-7.10 (m, 5H); 6.68 (dd, 1H); 6.57 (d, 1H); 3.25 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.28 (m, 8H); IR (KBr) 3400, 2950, 2840, 1690, 1640, 1600, 1550, 1460, 1380, 1320, 1280, 1200, 1170, 1120, 1080 cm−1; mass spectrum [(−)ESI], m/z 812 (M−H)−; Anal. Calcd. for C42H37F6NO7S: C, 61.99; H, 4.58; N, 1.72, Found: C, 61.40; H, 4.80; N, 1.68.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.[CH3:12][N:13](C)[CH2:14][CH2:15][CH2:16]N=C=NCC.[CH2:23]([O:25][C:26]([C@@H:28]1[CH2:30][C@H:29]1[C:31]([OH:33])=O)=[O:27])[CH3:24].C(N(CC)CC)C.CNCCC>CN(C)C=O>[CH2:23]([O:25][C:26]([C@@H:28]1[CH2:30][C@H:29]1[C:31](=[O:33])[N:13]([CH3:12])[CH2:14][CH2:15][CH3:16])=[O:27])[CH3:24]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(C)C(=O)[C@@H]1C[C@H]1C(=O)OCC
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Add 1-hydroxybenzotriazole (HOBT) (1.46 g, 10.8118 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.07 g, 10.8118 mmol) to a solution of crude trans-cyclopropane-1,2-dicarboxylic acid monoethyl ester (1.71 g, 10.8118 mmol) in N,N-dimethylformamide (11 mL). Stir for 30 minutes. Add triethylamine (2.26 mL, 16.2177 mmol) and methylpropylamine (1.11 mL, 10.8118 mmol) and stir for 16 hours. Quench with 10% aqueous potassium carbonate (10 mL) and extract with ethyl acetate (3×50 mL). Combine the organic extracts, wash with 0.1 N aqueous citric acid (30 mL) and 1 N lithium chloride, dry (magnesium sulfate), concentrate and crystallize with xylenes to give the desired compound (1.02 g, 50%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N2CCN(c3ccccn3)CC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 1-(2-pyridyl)-piperazine (3.5 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature and poured into water. The crude yellow solid was collected by vacuum filtration, air dried, and recrystallized from CHCl3 (0.36 g, 17%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([O:12][C:13](=[O:17])[CH:14](Br)[CH3:15])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:10]([O:12][C:13](=[O:17])[CH:14]([O:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:9])=[CH:5][CH:6]=1)[CH3:15])[CH3:11]
Reactant: Oc1ccc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ccc(Cl)nc1Cl

Procedure:
164 g (1 mole) of 2,6-dichloro-3-pyridinol, 1500 ml of acetonitrile, 253.4 g (1.4 moles) of 2-bromopropionic acid ethyl ester and 127.2 (1.2 moles) of sodium carbonate are refluxed for 3 hours. The reaction mixture is then cooled, filtered, and concentrated in a rotary evaporator. The residue is taken up in ether and washed with 2N sodium hydroxide solution. After drying with magnesium sulphate, the solution is concentrated by evaporation and distilled in vacuo; a clear oil distills at 110°-140°/0.1 torr; yield: 200 g; i nD25 : 1.5200. Crystallisation from benzene/petroleum ether yields a product having a melting point of 41°-46°;
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O>[CH3:13][O:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[N:6]=[CH:7][C:2]([NH:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: COC(=O)/C=C/c1cnc(Cl)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cn1
Temperature: 92.5 °C
Reaction time: 6 h
Yield: 60.7 %

Procedure:
A mixture of methyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (10.00 g), tert-butyl (3R)-3-amino-1-pyrrolidinecarboxylate (14.01 g) and potassium phosphate (21.30 g) in DMA (25 mL) was stirred at 90-95° C. for 6 hours under nitrogen atmosphere. After addition of water, the reaction mixture was extracted with AcOEt. Water was added to the organic layer and the mixture was adjusted to pH 8 with 1N HCl aq., washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel (chromatorex NH) (hexane-AcOEt 60:40 v/v) to give tert-butyl (3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate as a solid (10.64 g).