Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:10][NH:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN)Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H](CNC[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
The product from Example 1B (0.54 g, 2.16 mmol) and the product from Example 1C (0.50 g, 2.14 mmol) in isopropanol (5 mL) were placed in a sealed tube and heated at 100° C. for 18 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel (24:1 CHCl3:methanol) to provide the title compound as a colorless solid (0.44 g, 42%). Rf=0.55 (CHCl3:methanol, 9:1); 1H NMR (CDCl3) δ 7.30-7.14 (m, 10H), 4.61 (br s, 2H), 3.87 (m, 2H), 2.87-2.77 (m, 2H), 2.72 (dd, J=7.4, 13.6 Hz, 2H), 2.57 (d, J=5.8 Hz, 4H), 1.41 (s, 18H); MS (APCI+) m/z 484 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].[Na+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[N:6]([CH2:20][CH3:21])[C:5]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CCI
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)Oc2ccc(C(=O)OC)cc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 2,2-dimethyl-6-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine [prepared in Preparation 6(1)] (1.50 g) in dimethylformamide (20 ml) were added 60% sodium hydride (in oil) (0.3 g) and ethyl iodide (1.1 g) and the mixture was stirred at 50° C. for 1 hour. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 2,2-dimethyl-4-ethyl-6-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.6 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][C:6]=1[CH3:23])=O.[NH2:24][C:25]([NH2:27])=[S:26]>CCO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:24]=[C:25]([NH2:27])[S:26][CH:2]=3)=[C:6]([CH3:23])[CH:7]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: NC(N)=S
Reactant: COc1ccc(S(=O)(=O)c2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)c2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 64.7 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(4-methoxyphenylsulfonyl)-2,6-dimethylphenyl)ethanone (1.33 g, 3.4 mmol, 1.0 equiv) and thiourea (254.8 mg, 3.4 mmol, 1.0 equiv) in EtOH (5.0 mL) was heated at reflux for 1.0 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The resultant solids were washed with hexanes to give 4-(4-(4-methoxyphenylsulfonyl)-2,6-dimethylphenyl)thiazol-2-amine (839.2 mg, 2.2 mmol) as yellow solids in 65% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.89 (d, J=8.9 Hz, 2 H), 7.61 (s, 2 H), 7.13 (d, J=8.9 Hz, 2 H), 6.95 (brs, 2 H), 6.43 (s, 1 H), 3.83 (s, 3 H), 2.16 (s, 6 H); ESI-MS: m/z 375.6 (M+H)+.
Reaction SMILES: I[C:2]1[CH:22]=[N:21][C:5]2[NH:6][CH2:7][C:8](=[O:20])[N:9]([CH2:10][C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[O:31])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:22]=[N:21][C:5]4[NH:6][CH2:7][C:8](=[O:20])[N:9]([CH2:10][C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=5[F:19])[C:4]=4[CH:3]=3)=[CH:34][CH:33]=2)=[O:31])[CH2:26][CH2:25]1
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1cc(F)c(F)cc1F
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(F)c(F)cc3F)C(=O)CN4)cc2)CC1
Yield: 32 %

Procedure:
7-Iodo-1-(2,4,5-trifluorobenzyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (42 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a white solid (32% yield). M.p. 238° C., LCMS: m/z=496.00 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.35-2.53 (m, 4H), 3.43-3.58 (m, 2H), 3.72-3.84 (m, 2H), 4.33 (s, 2H), 5.11 (s, 1H), 5.30 (s, 2H), 6.97-7.03 (m, 1H), 7.05-7.14 (m, 1H), 7.21 (s, 1H), 7.45 (dd, J=8.1 Hz, 4H), 8.02 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]=[N+:11]=[N-:12])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 4-bromobenzyl bromide (54) and sodium azide (2.0 equiv.) in DMF was stirred at 50° C. for 3 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography to yield 55 as colorless oil in 92% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[CH:2].[CH3:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1)=[O:31].C(N(CC)CC)C>CN(C)C=O.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>[C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([C:13]3[N:14]=[C:15]([CH2:18][N:19]4[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]4)[S:16][CH:17]=3)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=2)=[CH:34][CH:33]=1)(=[O:31])[CH3:29]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C#Cc1cc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(C#Cc4ccc(C(C)=O)cc4)cc(C(F)(F)F)c3)cs2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
In the same manner as in Example 98c, to a solution (3 mL) of the compound (200 mg, 0.49 mmol) obtained in Example 98b, 4-bromoacetophenone (150 mg, 0.74 mmol), triethylamine (0.14 mL, 0.98 mmol) and copper iodide(I) (19 mg, 0.10 mmol) in N,N-dimethylformamide was added tetrakistriphenylphosphinepalladium (58 mg, 0.050 mmol), and the mixture was stirred at 90° C. overnight. The palladium catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound (97 mg, 38%) as a pale-yellow solid.
Reaction SMILES: ClC(N(C)C)=C.[CH3:7][O:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O.[NH2:14][C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([NH:33][C:34]([NH:36][C:37]3[N:41]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)[N:40]=[C:39]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:38]=3)=[O:35])=[CH:25][CH:24]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.N.CO>[C:49]([C:39]1[CH:38]=[C:37]([NH:36][C:34](=[O:35])[NH:33][C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([O:22][CH2:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:10](=[O:12])[C@@H:9]([O:8][CH3:7])[CH3:13])[CH:20]=3)=[CH:24][CH:25]=2)[N:41]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:40]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CO[C@@H](C)C(=O)O
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)c3)c3ccccc23)cc1
Agent: C=C(Cl)N(C)C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CO[C@@H](C)C(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
1-Chloro-N,N-dimethylethenamine (50 μL, 0.48 mmol) was added to a stirring solution of (S)-2-methoxypropionic acid (50 mg, 0.48 mmol) in DCM (1.0 mL) and the resulting yellow solution was stirred at RT for 1 hr. The solution was added dropwise to a stirring mixture of 1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate A) (50 mg, 0.10 mmol) and DIPEA (167 μl, 0.96 mmol) in DCM (1.0 mL). Stirring was continued overnight. The reaction mixture was stirred in 1% NH3 in MeOH (20 mL), evaporated in vacuo, pre-adsorbed on silica and purified by column chromatography (12 g, 10-50% EtOAc in iso-hexane, gradient elution) to give (S)—N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxypropanamide (Example 4) as a colourless solid (18 mg, 30%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, d), 1.31 (3H, s), 2.38 (3H, s), 3.30 (3H, s), 4.02 (1H, q), 5.39 (2H, s), 6.37 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.45 (2H, m), 7.56-7.64 (3H, m), 7.93 (1H, m), 8.30-8.37 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 10.06 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[C:5]([F:10])=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:3]=1.[CH:18]1([CH2:23][C@H:24]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:25](O)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:25](=[O:26])[C@H:24]([CH2:23][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:28][N:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:37]=[O:38])[C:5]([F:10])=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:3]=1
Reactant: CN1CCN(c2nc(Cl)nc(NN)c2F)CC1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC1
Yield: 46.1 %

Procedure:
A mixture of 2-chloro-5-fluoro-4-hydrazino-6-(4-methyl-1-piperazinyl)pyrimidine (31 mg, 0.12 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (36 mg, 0.12 mmol), HOAt (20 mg, 0.144 mmol), EDC (28 mg, 0.144 mmol) and NMM (26 uL, 0.144 mmol) in DMF (2 mL) was stirred until the reaction was complete (2 h). The reaction mixture was then purified via RP-HPLC to provide [(2R)-3-{2-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (30 mg, 46%). LCMS: (M+H)+: 542.3; (M+Na)+: 564.3.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][C:9]=2[O:18][CH3:19])=[C:5]([CH3:7])[N:6]=1.Br[CH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]1=O>C(O)C>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][C:29]4[CH2:30][CH2:31][CH2:32][CH:27]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:21][CH:22]=5)[C:28]=4[N:17]=3)=[CH:10][C:9]=2[O:18][CH3:19])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: COc1cc(NC(N)=S)ccc1-c1sc(C)nc1C
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1sc(C)nc1C
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of [4-(2,4-dimethyl-thiazol-5-yl)-3-methoxy-phenyl]-thiourea (88 mg, 0.30 mmol) and 2-bromo-6-phenyl-cyclohexanone (80 mg, 0.32 mmol) in ethanol (3 ml) was heated to reflux over night. The precipitated solid was filtered off after cooling to room temperature and dried to yield the title compound (100 mg, 100%) as a yellow solid. MS ISP (m/e): 448.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.27 (br s, 1H, NH), 7.59 (s, 1H), 7.28 (t, 2H), 7.12-7.19 (m, 4H), 6.85 (d, 1H), 4.00 (m, 1H), 3.37 (s, 3H), 2.74 (m, 2H), 2.66 (s, 3H), 2.20 (s, 2H), 2.13 (m, 1H), 1.70-1.93 (m, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[CH:10][C:3]=12.[C:30](=[O:32])=[O:31].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[C:11]([N:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:30]([OH:32])=[O:31])[C:3]=2[CH:10]=[N:9]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=O
Reactant: Ic1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of Isopropylmagnesium chloride-lithium chloride complex (21.99 mL of 14% w/v, 21.20 mmol) in THF (2.5 mL) was cooled to below −20° C. This was treated with 4-iodo-1-trityl-pyrazolo[5,4-b]pyridine (9.84 g, 20.19 mmol) under nitrogen and allowed to stir for 30 minutes. The reaction was then treated with 3 pellets of CO2 and allowed to warm up. After a further hour the mixture was diluted with EtOAc and acidified with saturated aqueous ammonium chloride. The layers were separated, dried (MgSO4), filtered and concentrated in vacuo. The mixture was purified by column chromatography (1:1 Petroleum ether/EtOAc moving to 10% MeOH/EtOAc) to give the product as an off-white oil (7.0 g, 86% Yield). 1H NMR (DMSO, 400 MHz) δ 7.17-7.26 (15H, m), 7.47-7.49 (1H, m), 8.18 (1H, d), 8.56-8.58 (1H, m).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1>COCCOC.C(O)C.C([O-])([O-])=O.[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][C:10]1[CH:15]=[C:14]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1cccc(-c2ccc(C=O)s2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
5-Bromo-2-thiophenecarboxaldehyde (5.09 g, 26.2 mmol) was added to a suspension of 907 mg (0.78 mmol) of tetrakis(triphenylphosphine) palladium (0) in 50 mL of DME, and the resulting mixture was stirred at room temperature for 15 min. To this mixture was added a solution of the 3-methylphenyl boronic acid (prepared above) in 10 mL of ethanol and 26 mL of 2M aqueous Na2CO3. The reaction was stirred at reflux for 24 hours, then cooled to room temperature, diluted, and extracted with ether. The organic extract was washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 5% ethyl acetate in hexane, to give 4.75 g (90% yield) of 5-(3-methylphenyl)-2-thiophenecarboxaldehyde. MS: 203 (M+H)+ 220 (M+NH4)+. NMR (CDCl3) d: 9.89 (s, 1H), 7.74 (d, 1H, J=5 Hz), 7.55-7.20 (m, 5H), 2.42 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([F:25])([F:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([F:25])([F:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(F)(F)CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(F)(F)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 5-(4-bromo-phenyl)-4-(1,1-difluoro-4-phenyl-butyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([N:5]1[CH2:11][C@@H:10]2[C@@H:7]([CH2:8][C@H:9]2[C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH2:6]1)(=O)CC.Cl>C(O)CCC>[CH:7]12[CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([NH:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:10]1[CH2:11][NH:5][CH2:6]2
Reactant: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)cc3)[C@@H]2C1
Agent: Cl
Solvent: CCCCO
Product: O=S(=O)(Nc1ccc(C2CC3CNCC32)cc1)c1ccc(OC(F)(F)F)cc1
Yield: 98 %

Procedure:
N-[4-((1R,5S,6R)-3-Propionyl-3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (100 mg, 0.21 mmol) was dissolved in n-butanol (10 ml) followed by the addition of concentrated HCl (2 ml). The solution was refluxed for 3 hours, cooled and concentrated. The residue was washed with ethyl acetate, treated with NaOH (2M) and extracted with ethyl acetate (3×10 ml). The alkaline organic extracts were dried over MgSO4, filtered and concentrated to give N-[4-(3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide as an oil (amount 389 mg, yield 98%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[CH:2].C1C(=O)N([Br:28])C(=O)C1>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:28][C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([CH3:20])([S:16]([CH3:19])(=[O:17])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=1
Reactant: C#Cc1ccc(CCC(C)(C(=O)OC)S(C)(=O)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)C(C)(CCc1ccc(C#CBr)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 4.7 %

Procedure:
To a stirring solution of methyl 4-(4-ethynylphenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.5, 2.49 g, 8.46 mmol) and silver nitrate (144 mg, 0.85 mmol) in acetone (24 mL) was added NBS (2.5 g, 14.33 mmol) and the reaction was stirred at room temperature for 1.5 hr. Solvent was removed under reduced pressure to give a residue, which was purified by flash chromatography (silica gel/30-50% EtOAc/hexanes) to yield methyl 4-(4-(bromoethynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.6, 150 mg, 0.40 mmol, 4.75%). MS: m/z calcd for C15H17BrO4S 372.0/374.0. found [M+H]+ 373.0/375.0.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([NH:20][C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ncnc2ccncc12
Reactant: NCc1ccccc1
Solvent: CCO
Product: c1ccc(CNc2ncnc3ccncc23)cc1
Yield: 16.9 %

Procedure:
4-Methylthiopyrido[4,3-d]pyrimidine (160.4 mg, 0.902 mmol), and benzylamine (106.3 mg, 0.992 mmol) in EtOH (2 mL) are heated at 80° C. for 12 h, and then the solvent is removed under reduced pressure. The resulting solid is suspended in CH2Cl21 filtered, and the resulting solid is purified by preparative tlc on silica, eluting with 5% MeOH in CHCl3. Removal of the solvent under reduced pressure yields 4-benzylaminopyrido[4,3-d]pyrimidine (36 mg, 17%). 1H NMR (DMSO) δ 9.60 (1H, s), 9.37 (1H, t, J=5.8 Hz), 8.72 (1H, d, J=5.8 Hz), 8.57 (1H, s), 7.54 (1H, d, J=5.8 Hz), 7.37 (2H, d, J=7.0 Hz), 7.33 (2H, t, J=7.3 Hz), 7.25 (1H, t, J=7.2 Hz), 4.81 (2H, d, J=5.8 Hz).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[CH:19]=[CH:18][O:17][CH:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[O:17]1[CH:18]=[CH:19][C:15]([CH2:14][N:11]2[CH:4]=[C:3]([CH2:2][C:5]3[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=3)[N:13]=[N:12]2)=[CH:16]1
Reactant: [N-]=[N+]=NCc1ccoc1
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccoc3)nn2)c[nH]1
Yield: 42.9 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.101 g, 0.639 mmol) was reacted with 3-azidomethyl-furan (0.094 g, 0.767 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol-2-ylamine hydrochloride (0.077 g, 43%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), δ 7.60 (s, 1H), δ 7.38 (s, 1H), δ 6.53 (s, 1H), δ 6.37 (s, 1H), δ 5.46 (s, 2H), δ 3.95 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.1, 145.3, 144.1, 141.0, 123.3, 123.1, 110.3, 110.2, 109.9, 51.3, 19.9 ppm; HRMS (ESI) calcd for C11H12N6O (M+) 244.1145. found 244.1145.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([O:24]C)=[O:23])[C:15]=4[N:14]=3)=[C:9]([C:26]([F:29])([F:28])[F:27])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=4[N:14]=3)=[C:9]([C:26]([F:28])([F:27])[F:29])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
Methyl 2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylate (544 mg) and LiOH (95 mg, 4 mmol) were dissolved in THF/H2O (1:1, 24 mL). The reaction was stirred overnight at room temperature, then heated at 50° C. overnight. The solvents were removed in vacuo. The residue was taken up in water and the pH was adjusted to 7-8 with 1N HCl. After allowing the mixture to stirred for 1 hour, the solids were collected by filtration to afford 2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 159 as a pale solid (170 mg, 2-step yield: 40%). MS (ESI) calcd for C20H18F3N3O2: 389.14; found: 390 [M+H].
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[NH:8][CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([F:22])[CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:11]=[N:10][C:9]3[NH:8][CH2:7][CH2:6][O:5][C:4]=3[CH:3]=2)=[C:15]([F:22])[CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: Brc1cnc2c(c1)OCCN2
Product: Fc1cc(Cl)ccc1-c1cnc2c(c1)OCCN2

Procedure:
Prepared in a manner similar to that found in Example 1 using of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine with (4-chloro-2-fluorophenyl)boronic acid. 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 1H), 7.35-7.28 (m, 1H), 7.20-7.14 (m, 3H), 4.29-4.25 (m, 2H), 3.64-3.58 (m, 2H).