Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][NH:9][C:10]([NH2:12])=S)=[O:7])=[CH:2]1.[OH-].[Na+].BrN1C(C)(C)C(=O)N(Br)C1=O.[I-].[K+].S(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(O)(C)C>[NH2:12][C:10]1[O:7][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[N:8][N:9]=1
Reactant: NC(=S)NNC(=O)c1ccoc1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: CC(C)O
Product: Nc1nnc(-c2ccoc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
An isopropanol (15 mL) solution of 1-(3-furoyl)thiosemicarbazide (1.50 g, 8.10 mmol), a 4 mol/L aqueous sodium hydroxide solution (3.04 mL, 12.2 mmol), and 1,3-dibromo-5,5-dimethylhydantoin (1.74 g, 6.09 mmol) were added to an aqueous (3 mL) solution of potassium iodide (403 mg, 2.43 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, a saturated aqueous solution of sodium bisulfite and a saturated aqueous solution of sodium chloride were added. The mixture was subjected to extraction with ethyl acetate and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was washed with water to obtain the title compound (686 mg, 4.54 mmol) (yield: 56%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[CH:5][C:4]=1[CH3:10].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[CH3:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH3:9])[C:3]=1[CH2:2][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1cncc(C)c1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2c(C)cncc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a 0° C. mixture of 4-(bromomethyl)-3,5-dimethylpyridine (18.6 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.7 g, 12 mmol) in absolute ethanol (170 mL) was added triethylamine (8 mL, 57.4 mmol). The mixture was stirred at room temperature overnight. The solid precipitate was removed by filtration. Diethyl ether (300 mL) was added to the filtrate. The precipitate was removed by filtration. The filtrate was recovered, evaporated, and co-evaporated with EtOAc (1×50 mL). The residue was treated with water (300 mL). The solid material was recovered by filtration, washed with water (4×30 mL), diethyl ether (3×30 mL) and hexanes (2×30 mL), and dried in vacuo, affording 2-{[(3,5-dimethylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.78 g, 57% yield). The product was used without further purification.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:31])[NH:10][C@@H:11]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:31])[CH2:27][CH:28]([CH3:29])[CH3:30])[S:16][CH:17]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Yield: 79.1 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 17d (203 mg, 0.45 mmol); LiOH (10.8 mg, 0.45 mmol); after extraction afforded the desired product as a white solid (150 mg, 78.8%). 1H NMR (DMSO-d6, 400 MHz): δ 12.51 (bs, 1H); 8.64-8.61 (d, 1H, J=12.0 Hz); 7.95-7.92 (t, 2H); 7.62 (s, 1H); 7.28-7.24 (t, 2H); 4.63-4.58 (m, 1H); 3.51-3.50 (d, 1H, J=1.60 Hz); 3.34-3.33 (d, 1H, J=1.60 Hz); 165-1.54 (m, 3H); 0.91-0.88 (t, 6H). 13C NMR (MeOD-d4, 100 MHz): 172.44, 165.32, 162.87, 159.37, 150.45, 132.60, 132.57, 129.14, 129.06, 116.56, 116.34, 108.69, 54.41, 53.55, 53.19, 41.79, 26.21, 23.54, 22.02. ESI-HRMS (m/z): [M+H+] calcd. for C19H20FN3O5S: 422.1180, observed: 422.1188. HPLC Method 1: Rt=24.6 min, purity=95.7%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[NH:3]1.[C:15](Cl)(=[O:19])[C:16](Cl)=[O:17].CCl>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4]3=[C:5]([C:15](=[O:19])[C:16](=[O:17])[N:3]13)[CH:6]=[C:7]([CH3:13])[CH:8]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=CC(C)(C)Nc2ccc(C)cc21
Agent: CCl
Solvent: ClCCl
Product: CC1=CC(C)(C)N2C(=O)C(=O)c3cc(C)cc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2-Dihydro-2,2,4,6-tetramethylquinoline (16.7 g., 0.09 mole) in 50 ml. dry methylene chloride was added slowly dropwise with stirring to oxalyl chloride (12.6 g., 0.1 mole) in 150 ml. dry methyl chloride under nitrogen at 30° C. Addition required 20 min., and when complete the very dark solution was stirred 15 min. at ambient temperature and one hour at a gentle reflux. The solvent was removed at reduced pressure and the dark red residue crystallized from methanol to yield a solid melting at 157°-161° C. Two additional recrystallizations from 25% chloroform in ligroine (60°-110° C.) gave a deep red crystalline solid melting at 163.5°-165.5° C. The yield was 44%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].Cl.[CH:12](OCC)(OCC)OCC>>[Cl:10][C:3]1[N:4]=[CH:5][N:6]=[C:7]2[C:2]=1[N:1]=[CH:9][N:8]2[CH3:12]
Reactant: CNc1ncnc(Cl)c1N
Reactant: CCOC(OCC)OCC
Agent: Cl
Product: Cn1cnc2c(Cl)ncnc21

Procedure:
To 5.0 g (31 mmol) of 5-amino-4-chloro-6-methylaminopyrimidine suspended in 200 ml of triethyl orthoformate was added 2.6 ml of concentrated HCl and the resultant mixture stirred overnight at room temperature (r.t.). The white precipitate was then collected, washed with ether which was then combined with the orthoformate which was concentrated to give pure 6-chloro-9-methylpurine by tlc (thin layer chromatography) (silica, 90:10 CHCl3 :CH3OH). The filtered solid was returned to 150 ml ethyl orthoformate, treated with 1.0 ml concentrated HCl and stirred at 60° C. for 18 hours. The solution was evaporated and the solids combined to give 5 g (94%) of 6-chloro-9-methylpurine, m.p. 205°-207° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13]Cl)([O-:3])=[O:2]>C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(SCl)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Sc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To 1.38 g. of 3-butenyltributyltin was added 0.936 g. of 2,4-dinitrobenzene sulfenyl chloride in 20 ml. glacial acetic acid at steam bath temperature. The reaction mixture was warned on the steam bath for 20 minutes, poured into ice water and filtered. The mixture was extracted with pentane, dried and recrystallized from ethanol to yield cyclopropylcarbinyl 2,4-dinitrophenyl sulfide; m.p. 80°-81° C. Analysis for C and H confirmed the composition of the reaction product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[CH2:24][CH:25]([OH:34])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[CH2:24][CH:25]([OH:34])[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:3]=2)[CH2:29][C:28]1=[O:33]
Reactant: O=C1CNCCN1CC(O)CN1CCc2ccccc2C1
Reactant: Brc1cncc(N2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: O=C1CN(c2cncc(N3CCOCC3)c2)CCN1CC(O)CN1CCc2ccccc2C1
Yield: 3.3 %

Procedure:
A solution of 4-(5-bromopyridin-3-yl)morpholine (100 mg, 0.413 mmol), 1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)piperazin-2-one (119 mg, 0.413 mmol), X-phos (20 mg, 0.042 mmol), Pd(dba)2 (10 mg, 0.017 mmol) and NaOtBu (59.0 mg, 0.615 mmol) in dioxane (5 mL) was heated at 120° C. 1 h under microwave conditions. The crude reaction mixture was filtered, concentrated, and purified by preparative HPLC purification. (6.10 mg, yield 3.3%) 1H NMR (MeOD, 400 MHz), δ ppm: 7.76 (d, J=2.3 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.17-7.07 (m, 3H), 7.07-7.01 (m, 1H), 6.89-6.80 (m, 1H), 4.28-4.18 (m, 1H), 3.93 (s, 2H), 3.89-3.82 (m, 4H), 3.82-3.72 (m, 4H), 3.71-3.63 (m, 1H), 3.59 (t, J=1.0 Hz, 2H), 3.32-3.28 (m, 1H), 3.27-3.16 (m, 4H), 2.99-2.90 (m, 2H), 2.90-2.81 (m, 2H), 2.68-2.58 (m, 2H).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc(Oc2ccc(I)cc2)n1
Temperature: 125 °C
Reaction time: 9 h
Yield: 95.1 %

Procedure:
Under an argon atmosphere, sodium hydride (108 mg) was added to a solution of 4-iodophenol (220 mg) and 2-chloro-4-methoxypyrimidine (168 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 9 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=5/1) to obtain 2-(4-iodophenoxy)-4-methoxypyrimidine (312 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40]CC2C=CC=CC=2)[C:35]=1[C:48](=[O:50])[CH3:49]>>[C:48]([C:35]1[C:36]([OH:40])=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:25](=[O:27])[CH2:24][CH2:23][C:11]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:21])=[O:22])=[C:9]([OH:8])[CH:10]=1)(=[O:50])[CH3:49]
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reactant: CC(=O)c1c(OCCCCN)cccc1OCc1ccccc1
Product: CC(=O)c1c(O)cccc1OCCCCNC(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared using (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid and 1-[2-(4-aminobutoxy)-6-benzyloxyphenyl]-ethanone analogous to Example 100 steps C and D: (M−1)−=504. HPLC retention time: 1.09 min. (Method A).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[CH2:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:25]=[CH:24]/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=Cc1cccnc1
Product: O=C1CN(c2ccc(/C=C/c3cccnc3)cc2OCc2ccccc2)S(=O)(=O)N1

Procedure:
The title compound is prepared using 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 3-vinylpyridine analogous to Example 2, step C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:28])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:27])=[C:5]([CH3:29])[CH:4]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl>[OH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9](=[O:28])[CH2:10][N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:27])=[C:5]([CH3:29])[CH:4]=2)[CH2:33][CH2:32]1
Reactant: OC1CCNCC1
Reactant: COc1ccc(COc2ccn(CC(=O)c3ccc(CBr)cc3C)c(=O)c2)nc1
Solvent: ClCCl
Product: COc1ccc(COc2ccn(CC(=O)c3ccc(CN4CCC(O)CC4)cc3C)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 11d, 129 mg, 0.28 mmol) in CH2Cl2 (2 mL) is added 4-hydroxypiperidine (85 mg, 0.84 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Waters Xbridge C18 5 μm, gradient 50%→95% methanol in water+0.1% NH4OH, 120 mL/min).
Reaction SMILES: C[N:2]([CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:15]=1)=[O:4].NCCOCCOCCOCCC(OC(C)(C)C)=O>>[CH3:55][N:12]([CH2:11][CH2:10][N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3](=[O:4])[NH:2][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:15]=1
Reactant: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: CC(C)(C)OC(=O)CCOCCOCCOCCN
Product: CN(CCN1CCC[C@H]1C(=O)NCCOCCOCCOCCC(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 2-Methyl-1-((S)-1-(2-(N-methyl-3-((4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzamido)ethyl)pyrrolidin-2-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oic acid Example 191, using tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate in place of tert-butyl 5,8,11-trioxa-2-azatetradecan-14-oate. MS (ES, m/z): 932.38 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[C:32]2=[C:33](Br)[CH:34]=[C:35]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[N:31]2[N:30]=[CH:29][N:28]=1>>[NH2:26][C:27]1[C:32]2=[C:33]([C:14]3[CH:15]=[CH:16][C:10]4[S:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:12][C:11]=4[CH:13]=3)[CH:34]=[C:35]([CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[N:31]2[N:30]=[CH:29][N:28]=1
Reactant: CC1(C)OB(c2ccc3sc(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 95.6 %

Procedure:
In a manner similar to the procedure described for step 7 of the preparation of Example 330 and using 2-benzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole and tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate as starting material, 411 mg (95.6%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.06 (s, 1H), 8.94 (s, 1H), 8.92 (d, 1 H), 7.49 (d, 1H), 7.37-7.45 (m, 5 H), 6.59 (s, 1H), 4.49 (s, 2 H), 4.25 (m, 2 H), 3.42 (m, 1H), 2.94 (m, 2H), 2.11 (m, 2H), 1.76-1.64 (m, 2 H), 1.48 (s, 9H); LC-MS m/z [M+H]+541.2, RT 3.37 min.
Reaction SMILES: N(OS(=O)(=O)O)=[O:2].[N+:8]([C:11]1[O:15][C:14]([C:16]2[C:20]([C:21](N)=[O:22])=[CH:19][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9].O>P(=O)(O)(O)O>[N+:8]([C:11]1[O:15][C:14]([C:16]2[C:20]([C:21]([OH:2])=[O:22])=[CH:19][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=NOS(=O)(=O)O
Reactant: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: O=P(O)(O)O
Solvent: O
Product: O=C(O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Yield: 98 %

Procedure:
Add 36 g of 98% nitrosylsulfuric acid (under cooling with ice) dropwise to a suspension of 50 g 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide in 830 ml of 89% orthophosphoric acid, whereupon the temperature rises from 0° C to 35° C. Stir the resulting reaction mixture for 18 hours at room temperature and pour the produced solution onto 5 kg of ice and water. Separate the formed precipitate and wash it with water until it is no longer acid to obtain a 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid [m.p. 264° to 265.5° C (with decomposition) from dioxane].
Reaction SMILES: [CH2:1]([C:4](=[CH:7][CH2:8]CCC)C=O)[CH2:2]C.C(#N)C=C.C(CCC(CCC)(C=CCCC)C=O)#N.C([C:34]1([CH:41]=[CH:42][CH2:43]CC)[CH2:40][O:39][C:37](=[O:38])[CH2:36][CH2:35]1)CC>>[CH2:41]([CH:34]1[CH:40]([CH:2]=[CH:1][CH2:4][CH2:7][CH3:8])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1)[CH2:42][CH3:43]
Reactant: CCCCC=C(C=O)CCC
Reactant: CCCC=CC1(CCC)CCC(=O)OC1
Agent: CCCC=CC(C=O)(CCC)CCC#N
Solvent: C=CC#N
Product: CCCC=CC1OC(=O)CCC1CCC

Procedure:
γ-Propyl-δ-1-pentenyl-δ-valerolactone was prepared from 2-propyl-2-heptenal and acrylonitrile analogous to Example 1. Yield of 2-(beta-cyanoethyl)-2-propyl-3-heptenal 38%, boiling at 118°-120° C. at 0.6 mm.; nD20 1.4640. Yield of γ-propyl-γ1-pentenyl-δ-valerolactone from this intermediate 40%, boiling at 107°-110° C. at 0.4 mm.; nD20 1.4749.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[NH:22][C@@H:21]([C@@H](O)C)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[N:22]3[C@@H:21]([C@H:9]([CH3:10])[O:8][C:1](=[O:7])[C:2]3=[O:4])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: C[C@H](O)[C@H]1CC[C@@H](c2ccc(Cl)cc2)N1
Product: C[C@@H]1OC(=O)C(=O)N2[C@@H]1CC[C@H]2c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Diethyl oxalate (5 mL) was added to (S)-1-[(2R,5S)-5-(4-chlorophenyl)pyrrolidine-2-yl]ethanol (570 mg). Stirring was continued for 2 hours at 120° C. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), and the title compound (470 mg) was obtained. The physical property values are as follows.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[N:19]([CH3:25])[CH:18]=2)=O)=[C:10]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)(C)(C)C.[C:35](O)(=[O:37])[CH3:36]>>[CH2:27]([N:26]1[C:10]2[CH:9]=[C:8]([NH:7][C:35](=[O:37])[CH3:36])[CH:13]=[CH:12][C:11]=2[N:14]=[C:15]1[C:17]1[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[N:19]([CH3:25])[CH:18]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(C(=O)Nc2ccc(NC(=O)OC(C)(C)C)cc2NCc2ccccc2)cn(C)c1=O
Reactant: CC(=O)O
Product: CC(=O)Nc1ccc2nc(-c3cc(C)c(=O)n(C)c3)n(Cc3ccccc3)c2c1
Temperature: 150 °C
Yield: 90 %

Procedure:
{3-Benzylamino-4-[(1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester I-9″ (4.000 g; 8.648 mmol) is suspended in acetic acid (5.190 g; 86 mmol) in a microwave vial and heated in the microwave at 150° C. for 1 h. The reaction mixture is then concentrated under reduced pressure. The residue is added to ice water, precipitation occurs. The precipitate is filtered off and dried under vacuum. The residue is used in the next step without further purification. (Yield: 90%, 3.000 g; 7.763 mmol)
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][O:17]C(=O)C(C)C)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[K+]>O1CCCC1.O>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][OH:17])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)OCc1ccccc1Oc1ccc2nnc(C(C)C)n2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(Oc3ccccc3CO)cn12
Temperature: 60 °C

Procedure:
A mixture of isobutyric acid 2-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-benzyl ester (130 mg, 0.37 mmol) and potassium hydroxide (103 mg, 1.84 mmol) in tetrahydrofuran (6 mL) and water (1 mL) was heated at 60° C. for 7 hours. The reaction was concentrated in vacuo to a solid. The residue was suspended in water, the solid filtered, then the material suspended in methylene chloride and filtered to give the above named compound as a tan solid (84 mg, 80%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:26])[C:8]2=O)[C:4]([CH3:28])=[N:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:26])[C:8]2=[S:38])[C:4]([CH3:28])=[N:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccnc4)cc3c21
Solvent: C1COCCO1
Product: Cc1nn(C)cc1-n1c(=S)n(C)c2cnc3ccc(-c4cccnc4)cc3c21
Temperature: 100 °C
Reaction time: 28 h

Procedure:
A mixture of a new batch of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 10.2, 8 mg, 0.219 mmol) and Lawesson's reagent (98 mg, 0.242 mmol) in dioxane (1 ml) was stirred in a seal vial for 28 h at 100° C. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was taken in NMP and purified by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.32 min (Method A); M+H=387 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.21 (s, 1H), 8.72-8.68 (m, 1H), 8.62-8.58 (m, 1H), 8.23-8.16 (m, 2H), 8.08-8.04 (m, 1H), 7.93-7.88 (m, 1H), 7.56-7.48 (m, 2H), 3.97-3.93 (m, 6H), 1.92 (s, 3H))
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:6]=1[F:15])[CH3:2].[CH3:17][NH2:18]>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([NH:18][CH3:17])=[CH:7][C:6]=1[F:15])[CH3:2]
Reactant: CN
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Yield: 69 %

Procedure:
Prepared analogously to example 156b from 2,4-difluoro-5-nitro-benzoic acid ethyl ester and 2 M methylamine solution in THF. Yield: 69%.