Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([NH:19][O:20]C4CCCCO4)=[O:18])[CH:13]=3)[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl>O.CO>[CH:1]1([C:5]([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([NH:19][OH:20])=[O:18])[CH:13]=3)[CH2:8]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)C1CCC1)C2
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)C1CCC1)C2

Procedure:
160 mg of 2-(cyclobutylcarbonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide and 2 ml of a 0.1M solution of HCl in water in 2 ml methanol are stirred overnight at ambient temperature. The reaction mixture is evaporated and the residue is treated with acetonitrile. 53 mg of nearly colorless crystals are obtained. MH+=275.1
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C:5]2[C:14]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:16]=[C:17]([Cl:18])[C:4]=2[N:3]=1.[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=1[NH2:27].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:18][C:17]1[C:4]2[N:3]=[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:25]=3[Cl:24])[N:6]([CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C:5]=2[C:14]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:16]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CC(=O)OC(C)C)c12
Temperature: 100 °C
Reaction time: 15 h
Yield: 20.6 %

Procedure:
A mixture of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 10; 1.96 g, 5.49 mmol), 2,4-dichloroaniline (2.67 g, 16.5 mmol) and N-methyl-2-pyrrolidinone (1.5 mL) was stirred at 100° C. for 15 hr. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 3-15% ethyl acetate/n-hexane gradient mixture to give the title compound (546 mg, 1.13 mmol, 21%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:13]=[C:12]([NH2:14])[S:11][C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1.[H-].[Na+].C(N(CC)C(C)C)(C)C.[OH:26][C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:32][CH2:31][N:30]([C:33](Cl)=[O:34])[CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]2[N:13]=[C:12]([NH:14][C:33]([N:30]3[CH2:29][CH2:28][C:27]([OH:26])([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:43])[F:45])[CH:37]=4)[CH2:32][CH2:31]3)=[O:34])[S:11][C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1
Reactant: COc1nc(SC)nc2sc(N)nc12
Reactant: O=C(Cl)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1nc(SC)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
A magnetically stirred mixture of 7-Methoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-2-ylamine (500 mg, 2.19 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere at 25° C. was treated with sodium hydride (60% suspension in mineral oil, 265 mg, 6.58 mmol). The reaction mixture was stirred at 50° C. for 1 h. At this time, the reaction was cooled to room temperature and was treated with N,N-diisopropylethylamine (850 mg, 6.58 mmol) and 4-hydroxy-4-[3-(trifluoromethyl)phenyl]piperidine-1-carbonyl chloride (810 mg, 2.63 mmol). The reaction mixture was stirred at room temperature for 3 d. At this time, the reaction was concentrated in vacuo, poured into water and extracted with ethyl acetate. The organics were washed with a 2N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98:2 methylene chloride/methanol) afforded 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-2-yl)-amide (375 mg, 34%) as a red solid. LRMS for C20H20F3N5O3S2 (M+H)+ at m/z=499. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(OCCN3CCCCC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Yield: 49 %

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.4 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 g (77%); off white powder; mp 174° C.; MS: 517.6 (M+H)+.
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH3:15])[C:8]=1B(O)O)=[O:6])([CH3:3])[CH3:2].I[C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:24]1[CH:23]=[CH:29][C:28]([F:30])=[CH:27][C:26]=1[C:8]1[C:9]([O:13][CH2:14][CH3:15])=[N:10][CH:11]=[CH:12][C:7]=1[C:5]([N:4]([CH:19]([CH3:21])[CH3:20])[CH:1]([CH3:3])[CH3:2])=[O:6]
Reactant: Nc1ccc(F)cc1I
Reactant: CCOc1nccc(C(=O)N(C(C)C)C(C)C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1nccc(C(=O)N(C(C)C)C(C)C)c1-c1cc(F)ccc1N
Temperature: 100 °C

Procedure:
To a solution of {4-[(diisopropylamino)carbonyl]-2-ethoxypyridin-3-yl}boronic acid (8.19 g, 27.8 mmol) in THF (45 mL), were added 2-iodo-4-fluoro-aniline (3 g, 12.7 mmol), sodium carbonate (2.0 M, 10 mL), and tetrakis(triphenylphosphine)palladium (2.93 g, 2.53 mmol). The solution was degassed by bubbling nitrogen through the flask and subsequently heated to 100° C. for 2 hr. The solution was cooled and worked up with EtOAc and water, dried over MgSO4, filtered, and concentrated. Column chromatography on silica gel (100% hexanes to 100% EtOAc) provided the title product.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[N:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.CCN(C(C)C)C(C)C.[NH:27]1[C:31]([CH2:32][C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)=[N:30][N:29]=[N:28]1>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][C:31]4[NH:30][N:29]=[N:28][N:27]=4)[CH:34]=3)[N:12]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: Clc1ncnc(-n2c(Cl)nc3ccccc32)n1
Reactant: Nc1cccc(Cc2nnn[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2n1-c1ncnc(Nc2cccc(Cc3nnn[nH]3)c2)n1
Temperature: 67.5 °C

Procedure:
To crude 2-chloro-1-(4-chloro-[1,3,5]triazin-2-yl)-1H-benzimidazole was added DIEA (381 μl, 2.184 mmol) and then a solution of DMF (1 ml) and 3-(1H-tetrazol-5-ylmethyl)phenylamine (382.7 mg, 2.1845 mmol). The reaction was heated at 60-75° C. for 18 h. The reaction was cooled to RT and concentrated to a small volume. The crude was eluted on a silica gel column with a MeOH/CH2Cl2 elution gradient, giving [4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3-(1H-tetrazol-5-ylmethyl)-phenyl]amine.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[CH:28]=1>>[CH3:24][O:23][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([NH:33][C:29]2[CH:28]=[C:27]([O:26][CH3:25])[N:32]=[CH:31][N:30]=2)=[O:16])=[CH:6][CH:5]=1
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Reactant: COc1cc(N)ncn1
Product: COc1cc(NC(=O)N2CCCc3ccc(C(OC)OC)nc32)ncn1

Procedure:
From intermediate 3 and 6-methoxypyrimidin-4-amine, reacted in an analogous manner to the preparation of intermediate 6. (UPLC-MS 1) tR 1.06 min; ESI-MS 360.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:4][C:3]=1[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[K+].C(O)C.O.Cl>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:4][C:3]=1[CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)O)c(F)c1

Procedure:
A mixture of 6.0 g. of ethyl 2-fluoro-4-(hexadecylamino)phenylacetate, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with conc. hydrochloric acid. The mixture is diluted with water, cooled and filtered. Recrystallization of the precipitate yields 2-fluoro-4-(hexadecylamino)phenylacetic acid.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>CN(C)C=O>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:51][C:50]4[CH:52]=[CH:53][C:47]([F:46])=[CH:48][CH:49]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(F)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg), along with 1-hydroxybenzotriazole, was dissolved in N,N-dimethylformamide (1.0 mL). While the solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.4 mg) was added and the mixture was allowed to warm to room temperature and was stirred for 1 hour. Subsequently, 4-fluoroaniline (17.8 μL) was added and the mixture was stirred for additional 2 hours. The solvent was evaporated under reduced pressure and the resulting residue was purified by preparative thin-layer chromatography (solvent:dichloromethane:methanol=4:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-fluorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.6 mg).
Reaction SMILES: II.[F:3][C:4]([F:37])([F:36])[CH2:5][CH2:6][CH:7]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:8][O:9][C:10]1[C:11]([CH:26]=O)=[CH:12][C:13]2[C:22]3[C:17](=[CH:18][N:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH3:24])[C:14]=2[CH:25]=1.[NH3:38].[O-]S([O-])(=S)=O.[Na+].[Na+]>O1CCCC1>[C:26]([C:11]1[C:10]([O:9][CH2:8][CH:7]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:6][CH2:5][C:4]([F:36])([F:37])[F:3])=[CH:25][C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17]3[C:22]([C:13]=2[CH:12]=1)=[CH:21][CH:20]=[N:19][CH:18]=3)#[N:38]
Reactant: Cn1c(=O)c2cnccc2c2cc(C=O)c(OCC(CCC(F)(F)F)NC(=O)OC(C)(C)C)cc21
Reactant: N
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2cnccc2c2cc(C#N)c(OCC(CCC(F)(F)F)NC(=O)OC(C)(C)C)cc21
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Iodine (0.047 g, 0.184 mmol) was added to a stirred solution of tert-butyl (5,5,5-trifluoro-1-((9-formyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.165 g, 0.167 mmol) in aqueous ammonia (4 mL, 48.1 mmol) and tetrahydrofuran (6 mL) at room temperature. The dark solution became light gray after stirring for 3 h, an indication that the reaction was complete. The reaction mixture was charged with aqueous Na2S2O3 (25 mL of 5% solution) and extracted with ethyl acetate (3×30 mL). The combined the organic layers were dried over sodium sulphate and concentrated under reduced pressure to afford tert-butyl (1-((9-cyano-6-methyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-5,5,5-trifluoropentan-2-yl)carbamate (0.14 g, 0.143 mmol, 85% crude yield) as a pale yellow solid. The material was carried forward without further purification. LC/MS (ESI) m/e 491.5 (M+H)+, calcd for C24H26F3N4O4, 491.2]; LC/MS retention time (method D): tR=0.87 min.
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:24][CH2:25][C:26]1[C:27](=[O:32])[NH:28][CH:29]=[CH:30][CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:33][C:34]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:35]=1F.O>CN(C=O)C>[Si:7]([O:24][CH2:25][C:26]1[C:27](=[O:32])[N:28]([C:35]2[CH:36]=[CH:37][C:38]([N+:40]([O-:42])=[O:41])=[CH:39][C:34]=2[Cl:33])[CH:29]=[CH:30][CH:31]=1)([C:20]([CH3:23])([CH3:21])[CH3:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCc1cccn(-c2ccc([N+](=O)[O-])cc2Cl)c1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 0.500 g (4.46 mmol) of potassium tert-butoxide is added to 1.08 g (2.97 mmol) of the compound from Example 3A in 21 ml of DMF, and the mixture is stirred at room temperature for 30 min. 0.571 g (3.27 mmol) of 2-chloro-1-fluoro-4-nitrobenzene is added, and the mixture is stirred at RT. After 4.5 h, 200 ml of water are added, and the mixture is then extracted three times with ethyl acetate. The combined organic phases are washed with water and then dried over sodium sulphate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1). This gives 872 mg (56% of theory) of the desired compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:31])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol (450 mg, 1.71 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (386 ml, 2.56 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (515 mg, 72%).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C>C(#N)C>[N:16]1[C:17]2[C:12](=[CH:11][C:10](/[CH:9]=[C:5]3/[C:6](=[O:8])[N:7]=[C:3]([NH:26][CH2:25][C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)[S:4]/3)=[CH:19][CH:18]=2)[CH:13]=[N:14][CH:15]=1
Reactant: NCc1cccs1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1N=C(NCc2cccs2)S/C1=C\c1ccc2ncncc2c1
Temperature: 145 °C

Procedure:
The suspension of 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one (example 1c, 58 mg, 0.2 mmol), thiophene methyl amine (45.3 mg, 0.4 mmol) and diisopropylethylamine (DIEA) (70 uL, 0.4 mmol) in acetonitrile (1 mL) was heated to 145° C. by microwave for 20 min. After cooling to room temperature, the solid was collected by filtration, washed with a small amount of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a light yellow solid: LC-MS m/e 353 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15][O:14][C@H:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CO[C@H]1CCCN(C(=O)OC(C)(C)C)C1)C3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CO[C@H]1CCCNC1)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A mixture of (S)-3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzyloxy]-piperidine-1-carboxylic acid tert-butyl ester (50 mg; 0.09 mmol; 1 eq.) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 30 minutes then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in to afford the title compound (40 mg, 98%) as an off-white solid. 1H NMR (CDCl3) δ 7.39-7.26 (m, 4H), 5.03-4.88 (m, 2H), 4.63-4.47 (m, 4H), 3.63-3.30 (m, 1H), 2.94-2.71 (m, 5H), 2.62-2.53 (m, 3H), 1.83-0.72 (m, 7H). HPLC (max plot) 100%, Rt 2.63 min. UPLC/MS: (MS+) 440.2 ([M+H]+).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3].[C:43]([NH:53][C@H:54]([C:66](O)=[O:67])[CH2:55][C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].N>ClCCl.CO>[C:43]([NH:53][C@H:54]([C:66]([NH:1][C@@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3])=[O:67])[CH2:55][C:56](=[O:57])[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:44]
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](C)N
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](C)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Yield: 63 %

Procedure:
from N-(2D-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-4-O-benzyl-L-aspartic acid. Yield 63%. Rf 0.57 (dichloromethane/methanol/conc. ammonia 15:1:0.1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:41][CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the general procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.73 (m, 11 H), 1.88-2.21 (m, 8 H) 2.78 (br. s., 2 H) 3.73 (br. s., 1 H) 3.91 (s, 3 H) 4.08 (t, J=13.8 Hz, 2 H) 4.81 (d, J=8.1 Hz, 1 H) 7.18 (d, J=6.6 Hz, 1 H) 7.91 (br. s., 1 H) 8.04 (s, 1 H) 8.24 (d, J=13.4 Hz, 1 H) 8.30 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.
Reaction SMILES: [CH2:1]1COCC1.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl.CCCCCC>[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=[CH2:1])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: C=C1CCC(C(C)(C)C)CC1
Reaction time: 8 h
Yield: 70 %

Procedure:
BDAM (3.00 grams) was suspended in 40 milliliters of methylene chloride and 2 molar equivalents of THF were added at 0° C. After a homogeneous solution was formed, 1 molar equivalent of TEAL in 10 milliliters of hexane was added followed by 2.20 grams of 4-tert-butylcyclohexanone. After overnight stirring, reaction mixture was hydrolyzed and worked up as described in Example 1. A total of 1.50 grams of 4-tert-butyl-1-methylenecyclohexane was isolated (70% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CI.[CH3:15][N:16]([CH:18]=[O:19])C>C1COCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:16]1[CH2:15][CH2:5][CH2:4][CH2:3][CH2:2][C:18]1=[O:19]
Reactant: CN(C)C=O
Reactant: BrCc1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CI
Product: O=C1CCCCCN1Cc1ccc2ccccc2c1
Yield: 97 %

Procedure:
Following the procedure described in Example 122, step 1, but substituting respectively 2-bromomethylnaphthalene for methyl iodide, and DMF for THF, the title compound 217 was obtained in 97% yield. MS (ESI)=254 (MH+).