Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([OH:23])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21]C)=[O:20])[CH:13]=2)=[C:4]([NH2:24])[N:3]=1.Cl>[OH-].[Na+].CO>[C:19]([CH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:8]1[C:7]([OH:23])=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[NH2:24])([OH:21])=[O:20]
Reactant: COC(=O)Cc1cccc(Cn2c(O)nc3c(N)nc(Cl)nc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(Cl)nc2c1nc(O)n2Cc1cccc(CC(=O)O)c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 51.4 %

Procedure:
2-Chloro-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine (50 mg, 0.14 mmol) obtained by Example 98 was dissolved in a mixed solvent of 1N sodium hydroxide solution (5 ml) and methanol (5 ml), and the solution was stirred at 100° C. for 5 minutes. The solution was neutralized with 12N hydrochloric acid and the solvent was removed. The residue was added to water, the resulting solid was filtered and washed with water to give the captioned compound (24 mg, 0.072 mmol, yield: 50%) as a pale red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23](O)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[CH3:27][O:28][C:29]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:29]=4[O:28][CH3:27])[CH2:34]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Reactant: COc1cc2c(c(OC)c1)CCNC2
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccccc13)C2
Yield: 33.3 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 92 (33.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.81 and 2.99 (2t, 2H), 3.45 (s, 1H), 3.49 and 4.04 (2t, 2H), 3.73-3.77 (m, 6H), 3.86 and 3.92 (m, 8H), 4.24 and 4.79 (2s, 2H), 6.33-6.50 (m, 2H), 7.72-8.17 (m, 6H); MS (ESI) m/z 516 ([M+H]+).
Reaction SMILES: [Fe:1](Cl)(Cl)Cl.N.[OH-].[Fe+3].[OH-].[OH-].[C:10]([CH2:13][C:14](=[O:16])[CH3:15])(=[O:12])[CH3:11]>O>[CH3:15]/[C:14](/[O-:16])=[CH:13]/[C:10]([CH3:11])=[O:12].[CH3:15]/[C:14](/[O-:16])=[CH:13]/[C:10]([CH3:11])=[O:12].[CH3:15]/[C:14](/[O-:16])=[CH:13]/[C:10]([CH3:11])=[O:12].[Fe+3:1]
Reactant: Cl[Fe](Cl)Cl
Reactant: CC(=O)CC(C)=O
Agent: [Fe+3]
Agent: N
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C(/C)[O-]

Procedure:
20.3 g of anhydrous iron (III) chloride (0.124 mol) was dissolved in 30 g of demineralised water with gentle warming. To this was added 45 ml of ammonia solution (SG. 0.880). The mixture was then heated on a steam bath for 30 minutes. The precipitate of iron (III) hydroxide was filtered and washed free of chloride. The moist iron (III) hydroxide and 60 g of acetylacetone (0.6 mol) were mixed together and heated for 30 minutes. Crystals of Fe(acac)3 were deposited and were recrystallised from ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-])=[C:4]2[CH2:9][CH2:10][CH2:11][C:3]=12.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH:9]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[CH2:11][CH2:10]1)(=[O:14])[CH3:13]
Reactant: [O-][n+]1cnc(Cl)c2c1CCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCc2c(Cl)ncnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
The solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (2.93 g, 17.2 mmol) in acetic anhydride (50 mL) was added dropwise to the acetic anhydride (50 mL) at 50° C. After addition, the mixture was stirred at 110° C. for 2 hour. After cooling, the solvent was removed and the residue was treated with toluene and hexanes (1:1, 200 mL). The mixture was stirred and then the solvent was removed. The residue was subject to chromatography on silica gel, eluted by hexanes/ethyl acetate (4:1-3:1) to afford the 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (2.3 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 8.92 (s, 1H), 6.20-6.16 (m, 1H), 3.20-3.10 (m, 1H), 3.03-2.93 (m, 1H), 2.76-2.67 (m, 1H), 2.20-2.05 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]>COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:13]([C:15]2[N:20]3[N:21]=[CH:22][N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(OC(C)c2ccnc3ncnn23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-methoxyphenol (1,24 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature, filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by flash chromatography using as eluent a mixture of ethyl acetate and petroleum ether, followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 1.67 g (mp 112°-114° C.)
Reaction SMILES: C1(C(=[N:14][C:15]2[N:20]=[CH:19][C:18]([CH:21]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]3)=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.NO.O>CO>[NH2:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]2[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(N=C(c3ccccc3)c3ccccc3)nc2)C1
Agent: NO
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(N)nc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 117b (2.44 g, 5.91 mmol), methanol (80 mL), 50% hydroxylamine in water (390 mg, 11.8 mmol) and the reaction was stirred at room temperature for 4 h. After this time, the reaction mixture was concentrated, and the resulting residue was purified by column chromatography to afford an 86% yield (1.27 g) of 117c as a yellow solid: mp 103-104° C.; 1H NMR (500 MHz, CDCl3) δ 7.94 (d, 1H, J=2.0 Hz), 7.49 (dd, 1H, J=8.5, 2.5 Hz), 6.53 (d, 1H, J=8.5 Hz), 4.48 (br s, 2H), 4.30 (t, 2H, J=8.5 Hz), 3.88 (dd, 2H, J=8.5, 4.5 Hz), 3.62 (m, 1H), 1.44 (s, 9H); MS (ESI+) m/z 249.9 (M+H).
Reaction SMILES: [C:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:10]=2[CH:9]=[C:8]([C:23]([O:25]C)=[O:24])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[OH-].[Na+]>CO.C1COCC1>[C:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:10]=2[CH:9]=[C:8]([C:23]([OH:25])=[O:24])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc2c(c1)C=C(C(=O)OC)CCN2C(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc2c(c1)C=C(C(=O)O)CCN2C(=O)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 1-propionyl-7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g), and to the solution was added 1N sodium hydroxide solution (5 ml). The mixture was stirred at room temperature overnight, concentrated, and then neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-propionyl-7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].O.[NH2:13][NH2:14]>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:13][NH2:14])=[O:5]
Reactant: COC(=O)c1ccccc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccccc1F
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Methyl 2-fluorobenzoate (27) (25 g, 160 mmol) was dissolved in ethanol (200 mL) and hydrazine monohydrate (11.8 mL, 240 mmol) was added. The mixture was heated to reflux for 4 hr then allowed to cool to room temperature overnight. The reaction was incomplete. After heating for a further 2 hr, starting material still remained. Additional hydrazine monohydrate (4 mL) was added. After heating for 2-3 hr the reaction was nearly complete. The mixture was cooled and concentrated under reduced pressure. Water (50 mL) was added to the residue and the aqueous layer was saturated with solid NaCl. The product was extracted with EtOAc (3×100 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with heptane (100 mL), filtered, and dried to provide 23.8 g (95%) of 13 as a pinkish solid.
Reaction SMILES: [CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29].N1CCCCC1>CO>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:22]3/[C:21](=[O:29])[NH:20][C:28]4[C:23]/3=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2c(/C=C/c3ccccc3)n[nH]c2c1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccccc3)n[nH]c2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 11.9 %

Procedure:
A solution of (E)-3-styryl-1H-indazole-6-carbaldehyde (27 mg, 0.109 mmol) and oxindole (15 mg, 0.109 mmol) in MeOH (1.0 mL) was treated with piperidine (1 uL. 0.011 mmol) and the reaction stirred at 60° C. for 4 hours. The MeOH was removed and the residue purified by prep-HPLC to give 4.7 mg, 12% of a yellow powder. 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J=8.38 Hz, 2H), 7.91-7.86 (m, 2H), 7.71-7.64 (m, 3H), 7.60-7.49 (m, 2H), 7.42 (t, J=7.41 Hz, 2H), 7.31 (t, J=7.49 Hz, 1H), 7.26 (t, J=7.89 Hz, 1H), 6.94 (d, J=7.75 Hz, 1H), 6.89 (t, J=6.86 Hz, 1H); MS ESI 364.2 [M+H]+, calcd for [C24H17N3O+H]+ 364.14.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([NH:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:7]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C.[Na+].[Cl-]>[C:18]([O:17][C:15]([NH:14][CH2:13][CH2:12][NH:11][C:10]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:9]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1NCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 103.2 %

Procedure:
To a solution of 4-(2-tert-butoxycarbonylaminoethylamino)-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (I-4b, 900 mg) in ethanol (50 ml) at room temperature was added 1 N KOH (25 ml). The reaction mixture was heated at 50° C. for 2 hours, cooled to room temperature, diluted with saturated aqueous NaCl, and acidified to pH 3 with 3N HCl. The aqueous solution was extracted with EtOAc (2×) and the combined organic extracts were dried and concentrated in vacuo to give the product I-4c as an amorphous glass (879 mg): +ES MS (M+1) 491.5.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.C(=O)C.[N:30]([CH2:33][C:34]([C:36]1[CH:37]=[CH:38][C:39]2[N:43]=[C:42]([C@@H:44]3[CH2:48][CH2:47][CH2:46][NH:45]3)[NH:41][C:40]=2[CH:49]=1)=[O:35])=[N+:31]=[N-:32].Cl.[CH3:51][N:52]([CH3:63])[C@H:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:54](O)=[O:55].CCN(C(C)C)C(C)C>CN(C=O)C>[N:30]([CH2:33][C:34]([C:36]1[CH:37]=[CH:38][C:39]2[N:43]=[C:42]([C@@H:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:54](=[O:55])[C@H:53]([N:52]([CH3:51])[CH3:63])[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[NH:41][C:40]=2[CH:49]=1)=[O:35])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NCC(=O)c1ccc2nc([C@@H]3CCCN3)[nH]c2c1
Reactant: CN(C)[C@@H](C(=O)O)c1ccccc1
Agent: CC=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@@H](C(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CN=[N+]=[N-])cc2[nH]1)c1ccccc1
Reaction time: 6 h
Yield: 50.1 %

Procedure:
To a solution of J4 (1.8 g, 4.86 mmol) in EtOAc (5 mL) was added HCl/Dioxane (10 mL of 4N), and the reaction was stirred 4 hr. The solvents were removed in vacuo, and the HCl salt was exposed to high vacuum for 18 h to give (S)-2-azido-1-(2-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone 2HCl as a yellow solid. HATU (1.94 g, 5.10 mmol) was added to the HCl salt of (S)-2-azido-1-(2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone (1.8 g, 4.86 mmol), (R)-2-(dimethylamino)-2-phenylacetic acid HCl salt (1.05 g, 4.86 mmol), and Hunig's base (3.4 mL, 19.4 mmol) in DMF (50 mL) while being rapidly stirred 6 h. The solvent was removed in vacuo and the reside was partitioned into two lots and separately pre-absorbed onto SiO2 (CH2Cl2), and subjected to flash chromatography on a 40 M Biotage silica gel column pre-equilibrated 2% B, and eluted with 2% B (150 mL); Segment 2: 2-40% B (1200 mL); Segment 3: 40-80% (600 mL). A=CH2Cl2; B=25% MeOH/CH2Cl2 to give J4.a (R)-1-((S)-2-(6-(2-azidoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-(dimethylamino)-2-phenylethanone (combined lots: (1.05 g, 50%)) as a yellow foam. 1H NMR (500 MHz, DMSO-d6) δ: 8.16 (s, 1H), 7.82 (dd, J=8.8, 1.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.60-7.56 (m, 5H), 5.51 (s, 1H), 5.22 (dd, J=8.2, 2.8, 1H), 4.95 (m, 2H), 4.09-4.05 (m, 1H), 3.17-3.12 (m, 1H), 2.90/2.84 (br. s, 6H), 2.23-2.19 (m, 1H), 2.21-1.89 (m, 3H). LC (D-Cond. 2): RT=1.53 min; LC/MS: Anal. Calcd. for [M+H]+ C23H26N7O2: 432.22. found: 431.93. HRMS Anal. Calcd. for [M+H]+ C23H26N7O2: 432.2148. found: 432.2127.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:22]([CH2:21][N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:19])[N:7]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Product: CCOC(=O)Cn1c2ccccc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(Carboethoxymethyl)-3-methylbenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-methylbenzimidazo[2,1-b]quinazoline-12(6H)one and ethyl bromoacetate.
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:32])[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13][N:14]2[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)C1C=CC=CC=1>CC(O)=O.[Pd]>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:32])[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13][N:14]2[CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cn(C2CCOCC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CCOCC2)c2cc(F)c(F)c(N)c2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a suspension of ethyl 5-benzylamino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylate (112 mg, 0.252 mmol) in AcOH (5 mL), was added 10% Pd—C (11.2 mg), the whole mixture was stirred at room temperature for 4 h under H2 atmosphere (1 atm). After insoluble materials were filtered off, the filtrate was concentrated in vacuo. Flash chromatography of the residue (EtOAc) gave ethyl 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylate (76.5 mg, 86%) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]2[NH:9][CH:10]=[N:11][C:3]=12.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[N:5]=[C:4]2[NH:9][CH:10]=[N:11][C:3]2=[C:2]([Cl:1])[CH:7]=1
Reactant: [O-][n+]1ccc(Cl)c2nc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(Cl)c2nc[nH]c2n1

Procedure:
7-Chloro-3H-imidazo[4,5-b]pyridine-4-oxide (15 g, 88.5 mMol) and 300 mL phosphorus oxychloride were heated at 110° C. under a nitrogen atmosphere. After 4 hours the excess phosphorus oxychloride was removed in vacuo. The residue was dissolved in water and the solution was neutralized by the addition of aqueous ammonium hydroxide. The suspension was cooled and the solid isolated. After drying, the product, 5,7-dichloro-3H-imidazo[4,5-b]pyridine, weighed 10.5 g (54.5 mMol, 61.6%); m.p. 263° C.; NMR (DMSO-d6): 8.58 δ (s, 1H, H2); 7.58 (s, 1H, H5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[O:14]1CCCO[CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:34][C:33]3[C:28](=[N:29][CH:30]=[CH:31][C:32]=3[O:35][C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=3[F:43])[CH:27]=2)=[N:24][CH:25]=1.[N-]=C=S>C1(C)C=CC=CC=1.C(O)C.C(O)C.C1(C)C=CC=CC=1.C(O)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([NH:40][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[S:13])[CH:41]=[CH:42][C:36]=1[O:35][C:32]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:27]=[C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH:15]=[O:14])=[CH:25][N:24]=3)[S:34][C:33]=12
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Agent: [N-]=C=S
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a solution of 2 (5.27 g, 27.0 mmol) in toluene (50.0 mL) and ethanol (50.0 mL) was added a suspension of intermediate 31 (9.52 g, 22.5 mmol) in toluene (20 mL) and ethanol (20 mL) over 30 min. After few minutes, more of isothiocyanate (1 g) in ethanol/toluene (5 mL/5 mL) mixture was added over 1 min. The reaction mixture was stirred at r.t. for an additional 30 min and concentrated under reduced pressure. The residue was triturated with toluene (70 mL), filtered and washed with toluene (20 mL) to afford a beige solid material that was suspended in 80% acetic acid (204 mL) and heated at 90° C. overnight. The reaction mixture was cooled down to r.t., and the precipitate was collected by filtration, washed with 80% AcOH (2×30 mL) to afford compound 33 (8.24 g, 72% yield) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][O:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9].[C:12](Cl)([Cl:14])=[O:13]>C(Cl)Cl>[CH3:2][N:3]([CH2:4][CH2:5][O:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9])[C:12]([Cl:14])=[O:13]
Reactant: C=C(C)C(=O)OCCNC
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)OCCN(C)C(=O)Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
N-Methyl-N-(2-methacryloyloxyethyl)amine hydrochloride (95.0 g, 0.529 mol) produced in Example 1 was suspended in methylene chloride (300 ml) and heated to 50° C. Phosgene (7.85 g, 0.793 mol) was introduced into the resultant suspension over two hours. The resultant reaction mixture was further stirred for one hour, and then the methylene chloride was removed from the mixture to produce N-methyl-N-(2-methacryloyloxyethyl)carbamoyl chloride (106.6 g, almost quantitative yield, purity: 98%) as a colorless transparent liquid. The product was analyzed through gas chromatography (column: silicone SE-30 20% glass column (2 m), injection temperature: 220° C., detection temperature: 230° C.). FIGS. 3 and 4 show the infrared spectrum and NMR spectrum of the product, respectively.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:5](=[O:20])[N:4]([CH2:21][C:22](O)=[O:23])[C:3]=1[CH3:25].[CH3:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:36][NH2:37])[CH:34]=2)[NH:29][CH:28]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH:17]2[CH2:18][CH2:19]2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([NH:37][CH2:36][C:33]2[CH:34]=[C:35]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[C:27]3[CH3:26])=[O:23])[C:3]=1[CH3:25]
Reactant: Cc1c[nH]c2ccc(CN)cc12
Reactant: Cc1c(Cl)nc(NC[C@H]2CCCCN2CC2CC2)c(=O)n1CC(=O)O
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)c(Cl)nc(NC[C@H]4CCCCN4CC4CC4)c3=O)cc12

Procedure:
The title compound was prepared by a similar method to preparation 45 from 2-[3-chloro-5-({[(2R)-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetic acid [see preparation 72] and (3-methyl-1H-indol-5-yl)methylamine (preperation 36) to afford the product as a white solid, (14%). LRMS: m/z=511 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6].C1C(=O)N([Cl:25])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cnc(N)c1Cl
Temperature: 50 °C
Yield: 86.8 %

Procedure:
A mixture of 2-amino-5-(2,4-dichloro-phenyl)-isonicotinonitrile (300 mg, 1.14 mmol, prepared according to Example 15, Step 6.1) and NCS (159 mg, 1.19 mmol) in DMF (4 mL) was stirred and heated at 50° C. for 3 h. The reaction mixture was cooled to RT, poured into AcOEt (40 mL) and washed with water (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/TBME 95:5→100% TBME) to yield the title compound (310 mg, 0.99 mmol, 87%) as a yellow solid. MS: 296 [M−1]+; HPLC: AtRet=2.43; TLC: RF 0.33 (hexane/TBME 1:1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=O)C.C(C1C=CC(C)=NC=1)C.C(OCCOCCO)C.CO.C[O-].[Na+]>O.CCCCCCC>[O:16]=[C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:12]#[N:13]
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: CCc1ccc(C)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCCOCCO
Solvent: CCCCCCC
Solvent: O
Product: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 92.5 °C
Yield: 92.3 %

Procedure:
In a 300 mL-reaction flask equipped with a rectification column and a separating tank, 11.3 g (65.2 mmol) of 4-tert-butylphenylacetonitrile, 10.8 g (59.5 mmol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 100 g of heptane, 10.0 g of 5-ethyl-2-picoline, and 3.0 g of diethylene glycol monoethyl ether were added, the atmosphere was substituted with nitrogen, then azeotropic dehydration was carried out by heating at 90 to 95° C. for 1 hour. The temperature was maintained, 13.8 g (71.5 mmol) of 28% sodium methoxide methanol solution was added dropwise over 5 hours, and the resulting mixture was further reacted for 5 hours. After cooling to 30° C. or less, 108 g of water was added to separate out heptane phase and obtain an aqueous phase. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 17.0 g (yield 92.1%) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl)propionitrile.