Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=O)[C:9]2[CH2:8][CH2:7][CH2:6][C:5]([CH2:16][CH2:17][CH3:18])([CH2:13][CH2:14][CH3:15])[C:4]=2[N:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]([CH2:16][CH2:17][CH3:18])([CH2:13][CH2:14][CH3:15])[C:4]=2[N:3]=[C:2]([CH3:1])[N:11]=1
Reactant: CCCC1(CCC)CCCc2c1nc(C)[nH]c2=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC1(CCC)CCCc2c(Cl)nc(C)nc21
Yield: 87 %

Procedure:
2-Methyl-8,8-dipropyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (180 mg, 0.72 mmol) and POCl3 (3 mL) were combined and heated under reflux for 6 hrs. The excess POCl3 was evaporated under reduced pressure. The residue was taken up in CH2Cl2 (25 mL), washed with cold water, sat. NaHCO3 solution., brine and dried over MgSO4. The CH2Cl2 solution was passed through a short (22 mm×20 cm) SiO2 column, eluting with CH2Cl2. Evaporation afforded 169 mg (87%) of 4-chloro-2-methyl-8,8-dipropyl-5,6,7,8-tetrahydroquinazoline as a pale yellow viscous liquid. MS (ES+) 267 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].C(O)C.[H][H]>O.[Ni]>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)c(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
2,3-Dichloro-6-nitroaniline (20.11 g, 97.14 mmol), Raney-nickel (4.78 g of a 50% slurry in water), and ethanol (250 mL) were combined in an autoclave which was pressurized to 150 psig with hydrogen. The resulting reaction mixture was allowed to stir at RT overnight. The mixture was then filtered through a pad of celite, which was subsequently washed with several portions of methanol, and the solvents were removed by rotary evaporation to leave a dark brown solid. The solid was slurried and in hexanes and was collected on a Büchner funnel to afford 16.31 g (95%) of a brown solid. MS (EI): m/z 177.0 (M+H).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)=[CH:21][CH:20]=1
Reactant: Clc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 120 °C
Yield: 50 %

Procedure:
Sodium t-butylate (4.99 mmol, 3.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.66 mmol, 1.0 eq.) and 1-chloro-4-iodobenzene (1.66 mmol, 1.0 eq.) in toluene (12 ml) and the reaction mixture was degassed with N2. BINAP (0.099 mmol, 0.06 eq.) and Pd(OAc)2 (0.03 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 10% ethyl acetate in hexane), so that the desired product was achieved. Yield: 50%
Reaction SMILES: [Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:28]=1.C[O-].[Na+].C([NH2:35])=O>>[Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:35])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1C(O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 90 %

Procedure:
10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 131 mg (90% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1)[CH3:16]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1
Yield: 1492.2 %

Procedure:
3-Hydroxy-4-nitrobenzoic acid (20.0 g, 109 mmol) in ethanol (250 mg) was refluxed for 6 hr in the presence of dry hydrogen chloride (5 g). The solvent was evaporated and the residue was dissolved in methylene chloride. The solution was washed with sodium bicarbonate until the unreacted material was removed as a precipitate. The organic fraction was finally washed with brine, dried over magnesium sulfate to give a brown solid of 3- hydroxy-4-nitrobenzoic acid ethyl ester (17.1 g): mp 80°-81° C. (crystallized from diethyl ether-hexane); Anal. Calcd for C9H9NO5 : C, 51.19% H, 4.30% N, 6.63% and Found: C, 51.23% H, 4.30% N, 6.79%; ir(CHCl3) 3,260, 1,720, 1,535 and 1,320 cm-1 ; and nmr(CDCl3)δ 1.35 (3H, t), 4.3 (2H, q), 7.7 (3H, m) and 10.4 (1H, s).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH3:8].[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][C@@H:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:26])[CH3:8])=[O:25])=[CH:18][CH:19]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: Cc1ccccc1[C@@H](C)OC(=O)Nc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3C)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-o-tolyl-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[3-methyl-4-((R)-1-o-tolyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:4][C:3]=1[B:9]1[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[O:13]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NS(C)(=O)=O)cc1B1OC(C)(C)C(C)(C)O1
Yield: 84.2 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.14 mmol) was treated with methanesulfonyl chloride (162 μl, 2.10 mmol) according to the method described in Preparation 15b to give 550 mg (83% yield) of the title compound. Purity 98%.
Reaction SMILES: [N:1]1([C:6]2[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].NCCC(O)=O>C(O)CCC>[N+:13]([C:16]([CH3:17])=[CH:11][C:9]1[S:10][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)([O-:15])=[O:14]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(-n2ccnc2)s1
Agent: NCCC(=O)O
Solvent: CCCCO
Product: CC(=Cc1ccc(-n2ccnc2)s1)[N+](=O)[O-]

Procedure:
Similar to example 4(a), the reaction is carried out with 60 g 5-(1-imidazolyl)-thiophene-2-aldehyde (EPA No. 112 987), 23.1 g nitroethane, 2 4 g β-alanine and 210 ml n-butanol.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:15][C:14](=[O:16])[CH:13]2[CH:5]([C:6]3[CH2:7][CH2:8][C:9]4[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=4[C:11]=3[S:12]2)[N:4]=1.C(N(C(C)C)CC)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[OH:37][C:33]1[CH:32]=[C:31]([NH:30][CH2:2][C:3]2[NH:15][C:14](=[O:16])[CH:13]3[CH:5]([C:6]4[CH2:7][CH2:8][C:9]5[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=5[C:11]=4[S:12]3)[N:4]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1NC(CCl)=NC2C3=C(SC12)c1ccccc1CC3
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(CNc2cccc(O)c2)=NC2C3=C(SC12)c1ccccc1CC3
Yield: 31.4 %

Procedure:
A solution of EXAMPLE 12E (18 mg), diisopropylethylamine and 3-aminophenol (10 mg) in N,N-dimethylformamide (0.5 mL) were heated at 70° C. for 2 hours. The mixture was cooled and purified by HPLC on a C18 column using 0-70% acetonitrile/0.1% trifluoroacetic acid in water to provide 7 mg of the title compound as the trifluoroacetate salt. 1H NMR (DMSO-d6) δ 12.29 (s, 1H), 9.01 (s, 1H), 8.17 (bs, 1H), 7.53 (m, 1H), 7.31-7.38 (m, 3H), 6.86 (t, J=7.9 Hz, 1H), 6.11 (m, 1H), 6.06 (t, J=2.1 Hz, 1H), 6.03 (dd, J=7.9, 2.1 Hz, 1H), 4.22 (s, 2H), 3.01 (m, 2H), 2.94-2.96 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[N:7]([NH2:13])[C:6]=1[CH3:14])=[O:4].[CH:15](=O)[CH2:16][CH3:17].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[N:7]([NH:13][CH2:15][CH2:16][CH3:17])[C:6]=1[CH3:14])=[O:4]
Reactant: COC(=O)c1c(C)cc(=O)n(N)c1C
Reactant: CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNn1c(C)c(C(=O)OC)c(C)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-amino-2,4-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.8 g, 14 mmol), propionaldehyde (5.1 mL, 71 mmol) and molecular sieves (size 4 Å, 5 g) in methanol (50 mL) was stirred overnight at room temperature. The solution was cooled to 5° C. and sodium tetrahydroborate (2.2 g, 57 mmol) was added in small portions. It was stirred for 1 hour at 5° C., then filtered and evaporated. The residue was partitioned between water (100 mL) and ethyl acetate (3×100 mL). The combined organic solution was dried (MgSO4) and evaporated. The residue was treated with hot n-heptane, cooled to 10° C. and the unreacted starting material was removed by filtration. The heptane solution was purified by flash chromatography to give the title compound. LC-MS (m/z) 239.1 (MH+); tR=1.20 (method C). 1H NMR (600 MHz, CDCl3): 1.01 (t, J=7.4 Hz, 3H, Me of Pr), 1.61 (sextet, J=7.3 Hz, 2H, CH2 of Pr), 2.19 (d, J=0.9 Hz, 3H, Me), 2.53 (s, 3H, Me), 2.56-3.1 (very br. coalescing d, 2H, CH2N), 3.87 (s, 3H, OMe), 5.92 (t, J=7.3 Hz, 1H, NH), 6.35 (s, 1H, C5-H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1.C(OCC)(=O)C.[OH-].[Na+].[Br:40]Br>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:11]([C:17]([NH:18][CH:19]([CH:21]3[CH2:23][CH2:22]3)[CH3:20])=[O:24])=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=2[Br:40])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1
Reactant: BrBr
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1cc(Cl)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixed solution comprising 6.0 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide and 75 ml of ethyl acetate was cooled with ice, 1.4 g of sodium hydroxide (flakes) was added, and then 2.8 g of bromine was added over a period of 2 hours. After stirring at room temperature for 18 hours, 60 ml of water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with 20 ml of a mixed solution of ethyl acetate and hexane (1:5) and subjected to filtration to obtain 6.2 g of the desired product in the form of white crystals.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=3[S:22][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=4[S:22][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2c(sc3ncnc(Cl)c23)C1
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCCNC4)cc1Cl
Yield: 82 %

Procedure:
The title compound was synthesized in analogy to Example 12A from tert-butyl 4-chloro-5,6,7,9-tetrahydro-8H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepine-8-carboxylate from Example 80A (349 mg, 0.40 mmol) and 3-chloro-4-fluoroaniline (61 mg, 0.42 mmol) to yield 169 mg (68% purity, 82% yield), which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[K+]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)C)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(N)c([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 65 %

Procedure:
To a solution of N-(4-isopropyl-2-nitrophenyl)acetamide obtained in step II above (1.0 eq) in MeOH and water was added KOH (1.5 eq) at room temperature and stirred for 5 hrs. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired 4-isopropyl-2-nitroaniline. (Yield=65%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([N:12]([CH2:8][CH3:6])[CH2:11][CH3:10])=[O:17])=[CH:10][CH:9]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
To a solution of 6.1 g. (0.02 mole) of 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetic acid in 100 ml. chloroform is added 3.8 ml. (0.03 mole) thionyl chloride. The mixture is stirred and refluxed overnight. The solvent is then evaporated and the residue is added quickly to a solution of 22 ml. diethylamine in 50 ml. water while cooling externally with an ice-bath. A solid precipitates, 5-(p-chlorobenzoyl)-N,N-diethyl-1-methylpyrrole-2-acetamide, which is collected and purified by recrystallization from methylcyclohexane (with charcoal while in solution), m.p. 82°-85°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(F)c1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A mixture of 3-fluorophenol (3.36 g, 30.0 mmol), ethyl 2-bromo-2-methylpropanoate (8.78 g, 45.0 mmol) and K2CO3 (6.22 g, 45.0 mmol) in acetone (50 mL) was refluxed overnight. The mixture was cooled to rt and 60 mL of water was added. The resulting mixture was extracted with DCM (40 mL×2). The combined organic phases were washed with brine (40 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as colorless liquid (3.20 g, 47%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:6]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:6]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(azidomethyl)-4-chlorobenzylcarbamate (10.9 g, 36.73 mmol) in THF (60 ml) and water (6 ml) was added triphenylphospine (10.59 g, 40.40 mmol). The reaction was heated to 65 C. and stirred overnight at room temperature. The reaction was concentrated in vacuo and flashed with 4% (10% NH4OH/MeOH)/dichlor-omethane. A second purification using silica gel column chromatography with a careful gradient of 3 to 5% (10% NH4OH/MeOH)/dichloro methane gave the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]3[N:7]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>CC#N>[C:17]([C:16]1[CH:15]=[C:14]([C:13]2[N:8]3[N:7]=[C:6]([C:3]4([CH2:2][O:1][C:36](=[O:37])[NH:35][CH:32]([CH3:34])[CH3:33])[CH2:5][CH2:4]4)[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=2)[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: CC(C)N=C=O
Reactant: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(CO)CC3)nc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(COC(=O)NC(C)C)CC3)nc12
Temperature: 65 °C

Procedure:
Under an argon atmosphere 3-[2-(1-Hydroxymethyl-cyclopropyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzonitrile (compound 150) (0.03 g, 0.08 mmol) was dissolved in CH3CN (1 mL). Et3N (0.005 mL) and isopropyl isocyanate (0.04 mL) were added and the reaction mixture was shaken at 65° C. for 20 H. Et3N (0.005 mL) and isopropyl isocyanate (0.04 mL) were added again and the reaction mixture was shaken at 65° C. for another 24 H. The solvent was evaporated and the crude product was purified by flash chromatography on silica using DCM:MeOH 99:1 as eluent to afford the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>ClCCl>[CH2:15]([C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:17][CH2:30][C:31]4[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:16]
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(OCc4ccc(C(F)(F)F)o4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 31.8 %

Procedure:
A mixture of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (245 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 2-(Bromomethyl)-5-(trifluoromethyl)furan (252 mg, 1.1 mmol) was added in portions over a period of 30 minutes. The reaction mixture was stirred for 1 hour and then the heat source was removed. The reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-15 CMA in chloroform 700 mL and then with 15% CMA in chloroform over 200 mL. The resulting solid was recrystallized from acetonitrile to provide 125 mg of 2-ethyl-7-{[5-(trifluoromethyl)furan-2-yl]methoxy}thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 152-154° C. MS (ESI) m/z 394 (M+H)+; Anal. calcd for C18H14F3N3O2S: C, 54.96; H, 3.59; N, 10.68. Found: C, 54.90; H, 3.46; N, 10.52.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH:27]1[C:35]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[CH:29]=[CH:28]1>>[CH3:19][N:18]([CH3:20])[CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:3][C:2]([N:27]4[C:35]5[CH:34]=[CH:33][N:32]=[CH:31][C:30]=5[CH:29]=[CH:28]4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: c1cc2[nH]ccc2cn1
Product: CN(C)C1CCN(Cc2cc3nc(-n4ccc5cnccc54)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure I for Buchwald coupling, 1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine and 1H-pyrrolo[3,2-c]pyridine were reacted to give 149. MS m/e 478.6 [M+H]+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]1=[O:18].[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[NH:27][C:26]2=[O:34])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[O:34]=[C:26]1[N:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=4[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]3=[O:18])[CH2:24][CH2:23]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccc(C)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(C)n1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(C)cc21
Yield: 67 %

Procedure:
A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 4.3 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 6 parts (67%) of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].O>C(=O)([O-])[O-].[K+].[K+].ClCCl>[Cl:1][CH2:2][C:3]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 121.1 %

Procedure:
Chloroacetyl chloride (4.0 cm3, 50.18 mmol) was added dropwise to a vigorously stirred mixture of 4-amino-1-(2-[indol-3-yl]ethyl)piperidine (12.10 g, 49.8 mmol), potassium carbonate (7.0 g 50.72 mmol) water (100 cm3) and dichloromethane (300 cm3). After 3/4 hour more chloroacetyl chloride (0.5 cm3, 6.27 mmol) and potassium carbonate (0.5 g, 3.62 mmol) were added and stirring continued for a further 3/4 hour. The organic phase was separated, washed with water, dried over magnesium sulphate and evaporated to give 2-chloro-N-[1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]acetamide (19.29 g crude)