Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.CI.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][C:27]([S:33][CH3:34])=[N:28][CH:29]=2)[NH:24][C:23]1=[O:35].Cl>C(OCC)(=O)C.CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][C:27]([S:33][CH3:34])=[N:28][CH:29]=2)[N:24]([CH3:2])[C:23]1=[O:35]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
211 μL of 1,8-diazabicyclo[5,4,0]undec-7-ene and 105 μL of methyl iodide were added to an N,N-dimethylformamide (5 mL) solution of 500 mg of 3-(2,6-dichlorophenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-2,4(1H,3H)-dione obtained in Production Example 52, and stirred at room temperature for 1 hour. The reaction solution was added to ethyl acetate and aqueous 0.5 N hydrochloric acid solution with stirring, and the organic layer was separated. This was washed with saturated saline water, dried with anhydrous sodium sulfate, and the solvent was evaporated away. The crude product was solidified with methanol to obtain 420 mg of the entitled compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C#CCCCO)ccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc(CCCCCO)ccc21
Yield: 98.6 %

Procedure:
2.8 g (9.3 mmol) 5-(5-Hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 60 ml MeOH were subjected to hydrogenation with 10% Pd/C to yield 2.8 g (quantitative) 5-(5-Hydroxy-pentyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless viscous oil, MS: 305 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: Sc1ccccc1Cl
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
o-Chlorothiophenol (4.5 g., 31 mmoles) and cuprous oxide (2.2 g., 15.5 mmoles) in 100 ml. of dimethylformamide were heated in an oil bath at 170°-175° C. for 1.5 hours, during which time a precipitate formed. 5-Bromofuran-3-carboxylic acid (3 g., 15.7 mmoles) was added and heating continued for 2.5 hours. The reaction mixture was cooled to room temperature, filtered, diluted with 500 ml. of water, acidified with conc. hydrochloric acid and product extracted into 250 ml. of ethyl acetate. The ethyl acetate was back-washed with 150 ml. of water and insolubles removed by filtration. Product was extracted from the ethyl acetate into 150 ml. of 1 N sodium hydroxide, the aqueous phase acidified with conc. hydrochloric acid and product reextracted into 150 ml. of fresh ethyl acetate. The ethyl acetate was back-washed with water and concentrated to an oil (3.5 g.). Recrystallization from ether/hexane gave partially purified product in two crops (575 mg., 403 mg.). These were combined and chromatographed on approximately 150 ml. of silica gel with hexane/5% acetic acid as eluant. Middle fractions afforded purified 5-(2-chlorophenylthio)furan-3-carboxylic acid (490 mg., m.p. 146°-148° C., m/e 254).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:24])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:24])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A 1000 mL 3-necked round-bottom flask was charged with bis(4-chlorophenyl)methanol (49.6 g, 196 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), dichloromethane (100 mL). Liquid thionyl chloride (93.3 g, 790 mmol, 4.00 equiv) was added dropwise. The resulting solution was stirred overnight at 40° C. in an oil bath. The resulting mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/5) to provide 47.8 g (88% yield) of 1-chloro-4-[chloro(4-chlorophenyl)methyl]benzene as a gray solid. 1HNMR 300 MHz (CDCl3) δ 7.30-7.39 (m, 8H), 6.07 (s, 1H). GCMS (EI, m/z): 270 [M]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
To the carboxylic acid from step 2 (65 mg) was added 4.0 M HCl in dioxane (1.0 mL). After 3 h, the dioxane was removed to give 58 mg of product. 1H NMR (400 MHz, DMSO-d6) δ 3.11-3.28 (m, 2H), 4.20 (t, J=6.0 Hz, 1H), 6.94-7.15 (m, 9H), 7.27-7.32 (m, 2H), 7.36-7.42 (m, 2H); LCMS; 99%, ESI−, Calcd: 349.39 m/z. Found 348.5 (M−1) m/z.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]1([C:15](O)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:27]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][S:35][CH3:36])[NH2:32])[CH3:28].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:27]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][S:35][CH3:36])[NH:32][C:15]([C:10]1([CH2:9][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16])[CH3:28]
Reactant: CC(C)(C)OC(=O)C(CCc1ccccc1)CC1(C(=O)O)CCCC1
Reactant: CCOC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCSC)NC(=O)C1(CC(CCc2ccccc2)C(=O)OC(C)(C)C)CCCC1
Reaction time: 18 h

Procedure:
Combine the product of Step 1 (1.50 g, 4.33 mmol) with (S)-methionine ethyl ester hydrochloride (0.92 g, 4.33 mmol), triethylamine (0.65 g, 6.5 mmol), hydroxybenzotriazole (HOBT) (0.66 g, 4.33 mmol), and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (DEC) (0.91 g, 4.8 mmol) in 25 ml dimethylformamide (DMF). Stir 18 h., partition between EtOAc-H20, wash with 1N NaHCO3 and concentrate. Chromatograph the resultant residue on silica, eluting with hexane-ether 1:1 to obtain an oil, [α]D26 =-17.4° (EtOH).
Reaction SMILES: O=[C:2]([C:9]1SC=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7]C)=O.S1C=CC=C1C1C=CN=C(N)N=1.C[C:27]1([CH3:35])[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])O1.COC1C=C(C=CC=1)C(O)=O>>[O:34]=[C:29]([C:13]1[CH:9]=[CH:2][CH:3]=[C:4]([O:6][CH3:7])[CH:12]=1)[CH2:30][C:31]([O:32][CH2:27][CH3:35])=[O:33]
Reactant: CCOC(=O)CC(=O)c1cccs1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: COc1cccc(C(=O)O)c1
Agent: Nc1nccc(-c2cccs2)n1
Product: CCOC(=O)CC(=O)c1cccc(OC)c1

Procedure:
This material is prepared by a method analogous to that described for preparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D, starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and 3-methoxybenzoic acid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:22]3([CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH2:21][N:20]([C:35]3[C:36]4[C@H:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)[C:17]2=[CH:18][CH:19]=1.O.NN>CCO>[NH2:3][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:22]3([CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH2:24][CH2:23]3)[CH2:21][N:20]([C:35]3[C:36]4[C@H:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)[C:17]2=[CH:18][CH:19]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CCN5C(=O)c6ccccc6C5=O)ccc43)c21
Agent: NN
Solvent: O
Solvent: CCO
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CCN)ccc43)c21
Temperature: 40 °C
Yield: 84.4 %

Procedure:
To a solution of (R)-tert-butyl 5-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.014 g, 0.023 mmol) in EtOH (0.2 mL) was added hydrazine monohydrate (0.012 ml, 0.26 mmol). The solution was heated at 40° C. for 4 hours. After cooling, the solid was filtered and rinsed with EtOH. The filtrate was concentrated to dryness. The crude product was purified by column chromatography (10% MeOH/DCM then 10% MeOH/DCM+1% NH4OH) to yield (R)-tert-butyl 5-(2-aminoethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.009 g, 82%). LCMS (APCI+) m/z 464 [M+H]+; Rt=3.22 min.
Reaction SMILES: ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C2N=NN(CC(NCC)=O)C=2)C=CC=1C)=O.[Cl:37][C:38]1[CH:61]=[C:60]([NH:62][C:63]2[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:64]=2[F:70])[CH:59]=[CH:58][C:39]=1[C:40]([C:42]1[CH:43]=[C:44]([C:49]2[N:50]=[N:51][N:52]([CH2:54][C:55](O)=[O:56])[CH:53]=2)[CH:45]=[CH:46][C:47]=1[CH3:48])=[O:41].[NH2:71][C:72]([CH3:76])([CH3:75])[CH2:73][OH:74]>>[Cl:37][C:38]1[CH:61]=[C:60]([NH:62][C:63]2[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:64]=2[F:70])[CH:59]=[CH:58][C:39]=1[C:40]([C:42]1[CH:43]=[C:44]([C:49]2[N:50]=[N:51][N:52]([CH2:54][C:55]([NH:71][C:72]([CH3:76])([CH3:75])[CH2:73][OH:74])=[O:56])[CH:53]=2)[CH:45]=[CH:46][C:47]=1[CH3:48])=[O:41]
Reactant: Cc1ccc(-c2cn(CC(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CC(C)(N)CO
Agent: CCNC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Product: Cc1ccc(-c2cn(CC(=O)NC(C)(C)CO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 112, using compound 111 (0.08 mmol) and 2-amino-2-methyl-1-propanol (0.08 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 50:50 to 100:0 as the eluent to afford the title compound as almost yellow solid. 13C NMR (DMSOd6) δ 8.74 (s, 1H), 8.50 (s, 1H), 7.90 (dd, 1H), 7.85 (bs, 1H), 7.75 (d, 1H), 7.50-7.33 (m, 4H), 7.11 (m, 1H), 6.83 (m, 1H), 6.78 (m, 1H), 5.07 (s, 2H), 4.80 (t, 1H), 3.40 (d, 2H), 2.33 (s, 3H), 1.21 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH3:27])[N:9]=1.ON1C2C=CC=CC=2N=N1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:22])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH3:27])[N:9]=1
Reactant: C1COCCN1
Reactant: Cc1nnc2n1-c1sc(CCC(=O)O)cc1C(c1ccccc1Cl)=NC2C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1sc(CCC(=O)N3CCOCC3)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
To a solution of 1.4 g of 3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid in 20 ml of dimethylformamide are added 0.5 g of N-hydroxybenzotriazole and 0.35 g of morpholine and stirred at room temperature for 10 minutes. To the mixture is added 0.9 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 3 hours and furthermore stirred at room temperature for 18 hours. The resulting dicyclohexylurea is filtered off, the filtrate is concentrated under reduced pressure and then the residue is dissolved in 100 ml of chloroform. The solution is washed with 50 ml of 5% aqueous sodium hydrogencarbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from isopropyl ether. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 1 g of 3-[4 -(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid morpholide as colorless crystals, melting at 162°-163° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@@H:2]([C:8]([NH:10][CH2:11][C:12]([N:14]([CH3:30])[C@H:15]([C:23]([NH:25][NH:26][C:27]([CH3:29])=[O:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[O:9])[CH2:3][CH2:4][S:5]([CH3:7])=[O:6].CC(OC(N[C@H](C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)CC1C=CC(O)=CC=1)=O)(C)C.[NH:68]([C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[C@H:69]([C:78]([NH:80][C@@H](C(NCC(O)=O)=O)CCSC)=[O:79])[CH2:70][C:71]1[CH:76]=[CH:75][C:74]([OH:77])=[CH:73][CH:72]=1>CN(C=O)C>[NH:68]([C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[C@H:69]([C:78]([NH:80][C@@H:2]([C:8]([NH:10][CH2:11][C:12]([N:14]([CH3:30])[C@H:15]([C:23]([NH:25][NH:26][C:27]([CH3:29])=[O:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[O:9])[CH2:3][CH2:4][S:5]([CH3:7])=[O:6])=[O:79])[CH2:70][C:71]1[CH:72]=[CH:73][C:74]([OH:77])=[CH:75][CH:76]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
Using 0.54 g of BOC-(D)-Met(O)-Gly-MePhe-NHNH-CO-CH3 and 0.46 g of BOC-Tyr-ONB in a similar manner to (III) of Example 36 is obtained (0.46 g) of the desired product, m.p. 141°-142° C., [α]D22 -25.4° (c=0.48, DMF), Rf1 =0.22.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:29][C:30](O)=[O:31]>>[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:29][C:30]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:31]
Reactant: COc1cccc(CC(=O)O)c1OC
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: COc1cccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c1OC

Procedure:
The product of Example 1B and 2-(2,3-dimethoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (d, J=7.9 Hz, 1H), 7.97-8.04 (m, 2H), 7.89-7.92 (m, 1H), 7.04 (t, J=7.8 Hz, 1H), 6.93-6.99 (m, 2H), 3.84-3.81 (d, J=4.2 Hz, 4H), 3.81 (s, 3H), 3.77 (s, 3H), 3.64 (s, 2H), 3.06-3.10 (m, 4H); MS (ESI+) M/Z 425 (M+H)+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1.[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>COCCOC>[NH:15]1[CH2:16][CH2:17][CH:12]([O:11][C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=2)[CH2:13][CH2:14]1
Reactant: OC1CCNCC1
Reactant: Clc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(OC2CCNCC2)nc1
Temperature: 82 °C
Reaction time: 0.5 h

Procedure:
NaH (2.88 g, 66 mmol, 55% dispersion in mineral oil) was stirred in dry DME (200 ml), under Argon. A mixture of 2,5-dichloropyridine (8.87 g, 60 mmol) and 4-hydroxypiperidine (6.67 g, 66 mmol) dissolved in dry DME (200 ml) was added to the NaH suspension dropwise, over a period of 30 minutes. After complete addition the reaction is heated to 82° C. for 48 hrs, maintaining the Argon blanket. The reaction was slowly quenched with water before removing most of the THF. Extracted the aqueous with DCM (×3). The organic layers were dried with Na2SO4 and evaporated in vacuo to afford 2-(4-piperidinyloxy)-5-chloropyridine as a yellow oil (12.7 g, quantitative). 1H NMR (DMSO): 8.17 (d, 1H), 7.76 (dd, 1H), 6.81 (d, 1H), 4.96 (m, 1H), 2.93 (m, 2H), 2.53 (m, 2H), 1.91 (m, 2H), 1.46 (m, 2H); MS (ES+): 213.3 (MH+), 225.3 (MNa+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]2([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=4)[CH2:17][CH2:16][N:15]=3)[CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1.[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33]Br)([CH3:28])([CH3:27])[CH3:26]>CCCCC.CN(C)C=O.O>[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33][O:24][C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][N:15]=[C:14]2[C:10]2([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([Cl:3])[N:9]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:19][CH:20]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCC
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Temperature: 40 °C

Procedure:
90% suspension of sodium hydride in oil (37 mg, 1.387 mmol) was washed with n-pentane and suspended in dry dimethylformamide (5 ml). (1-[1-(6-Chloropyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (217 mg, 0.69 mmol) dissolved in dimethylformamide (1 ml) was added dropwise. After stirring at room temperature for 1 hour a solution of tert-butyl-2-bromoethylcarbamate (466 mg, 2.08 mmol) in dimethylformamide (2 ml) was added dropwise. The reaction mixture was heated to 40° C. for 4 hours. The reaction mixture was diluted with water (30 ml) and extracted with dichloromethane (3×). The combined organic extracts were washed with brine twice, dried (MgSO4) and concentrated in vacuo. The crude product was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:4]=1.CO[C:31](OC)([N:33]([CH3:35])[CH3:34])[CH3:32]>>[CH3:34][N:33]([CH3:35])[C:31](=[N:14][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:7]2[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)[CH3:32]
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(N)=O)c3)nc(OC)n2)cc1
Reactant: COC(C)(OC)N(C)C
Product: COc1ccc(CCNc2cc(-c3cccc(C(=O)N=C(C)N(C)C)c3)nc(OC)n2)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzamide [50 mg, 0.132 mmol, Example 35(g)] and dimethylacetamide dimethylacetal (2 mL) in a sealed tube and heated to 110° C. for 45 minutes. The mixture is concentrated by rotary evaporator to provide N-(1-dimethylamino-ethylidene)-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzamide [Intermediate (46)] in quantitative yield.
Reaction SMILES: CC(C)CCN1C2C=CC(C#N)=CC=2N=C1CN1C2C=CC=CC=2NC1=O.[OH:28][NH:29][C:30]([C:32]1[CH:59]=[CH:58][C:35]2[N:36]([CH2:53][CH2:54][CH:55]([CH3:57])[CH3:56])[C:37]([CH2:39][N:40]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42](C(C)=C)[C:41]3=[O:52])=[N:38][C:34]=2[CH:33]=1)=[NH:31]>>[OH:28][NH:29][C:30]([C:32]1[CH:59]=[CH:58][C:35]2[N:36]([CH2:53][CH2:54][CH:55]([CH3:56])[CH3:57])[C:37]([CH2:39][N:40]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[NH:42][C:41]3=[O:52])=[N:38][C:34]=2[CH:33]=1)=[NH:31]
Reactant: C=C(C)n1c(=O)n(Cc2nc3cc(C(=N)NO)ccc3n2CCC(C)C)c2ccccc21
Agent: CC(C)CCn1c(Cn2c(=O)[nH]c3ccccc32)nc2cc(C#N)ccc21
Product: CC(C)CCn1c(Cn2c(=O)[nH]c3ccccc32)nc2cc(C(=N)NO)ccc21

Procedure:
N-Hydroxy-1-(3-methyl-butyl)-2-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1H-benzoimidazole-5-carboxamidine was prepared from 1-(3-Methyl-butyl)-2-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1H-benzoimidazole-5-carbonitrile as described for N-hydroxy-2-(3-isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.C[Si]([CH:44](O[Si](C)(C)C)[C:45]([O-:47])=[O:46])(C)C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.C(Cl)Cl>C(OCC)(=O)C>[O:33]=[C:31]1[O:30][N:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][C:12]3[C:13](=[O:14])[N:8]([CH:5]4[CH2:6][CH2:7][C:2]5([O:47][C:45](=[O:46])[CH2:44][O:1]5)[CH2:3][CH2:4]4)[C:9]4[N:10]([N:37]=[CH:38][N:39]=4)[C:11]=3[CH2:34][CH2:35][CH3:36])=[CH:21][CH:20]=2)[NH:32]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: C[Si](C)(C)OC(C(=O)[O-])[Si](C)(C)C
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCC(=O)O3)c2ncnn12
Temperature: -78 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), trimethylsilyl[(trimethylsilyl)oxy]acetate (0.16 mL), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.18 mL) and methylene chloride (5 mL) was stirred at −78° C. for 1 hr, and then at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.066 g, 26%).
Reaction SMILES: C1(C[O:5][C:6]2[C:7]([O:26][CH3:27])=[CH:8][CH:9]=[C:10]3[C:15]=2[NH:14][C:13](=[O:16])[CH:12]=[C:11]3[NH:17][C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[CH:20][C:19]=2[CH3:25])CC1.Cl.P([O-])([O-])([O-])=O.[OH-].[Na+]>>[CH3:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH3:24])[C:18]=1[NH:17][C:11]1[C:10]2[C:15](=[C:6]([OH:5])[C:7]([O:26][CH3:27])=[CH:8][CH:9]=2)[NH:14][C:13](=[O:16])[CH:12]=1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCC1CC1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of 8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (1.1 g, 3.0 mmol) and conc. HCl (6 mL) was maintained at room temperature for 3 h and then cooled to 0° C. This cold solution was poured into a solution of 0.5 M pH 7 phosphate buffer (75 mL) and 10N NaOH (7.5 mL) at 0° C. The resulting mixture was stirred vigorously at 0° C. for 15 min, filtered, washed with water (0° C., 75 mL), and then dried under vacuum to give 0.92 g of 4-(3,5-dimethylpyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one. 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.37 (s, 1H), 8.40 (s, 2H), 8.35 (s, 1H), 7.65 (d, 1H), 6.98 (d, 1H), 4.50 (s, 1H), 3.88 (s, 3H), 2.12 (s, 6H); MS (ESI): 312.6.