Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:58]=[CH:57][C:49]2[C:50]([CH2:53][C:54](O)=[O:55])=[CH:51][O:52][C:48]=2[CH:47]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:54](=[O:55])[CH2:53][C:50]3[C:49]4[CH:57]=[CH:58][C:46]([O:45][CH3:44])=[CH:47][C:48]=4[O:52][CH:51]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccc2c(CC(=O)NCc3cccc4c3C(=O)N(C3CCC(=O)NC3=O)C4=O)coc2c1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-(6-methoxy-1-benzofuran-3-yl)-acetic acid were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). After stirring at room temperature overnight, the mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]2-(6-methoxy-benzofuran-3-yl)-acetamide (0.76 g, 73%) as a white solid: mp 143-145° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.41 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.60 (s, 2H), 3.79 (s, 3H), 4.74 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.8 Hz, 1H), 6.85-6.89 (dd, J=2.2 and 8.6 Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.64-7.81 (m, 4H), 8.69 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.51, 30.90, 37.91, 48.83, 55.53, 95.93, 111.42, 114.55, 120.21, 120.91, 121.90, 127.12, 131.49, 133.29, 134.63, 139.06, 142.19, 155.57, 157.68, 166.90, 167.43, 169.78, 172.63, 172.73; Anal. Calcd. for C25H21N3O7: C, 63.16; H, 4.45; N, 8.84. Found: C, 62.90; H, 4.44; N, 8.74.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(O)C.C(OCC)(OCC)OCC.S(=O)(=O)(O)O>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(OCC)OCC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1CO
Yield: 97 %

Procedure:
A sample of 4-chloro-2-methylbenzoic acid was converted to the ethyl ester using ethanol/triethyl orthoformate/sulfuric acid in >95% yield. Reduction of the ester with LiAiH4/tetrahydrofuran gave 4-chloro-2-methylbenzyl alcohol in 97% yield as a colorless oil. Subsequent treatment with thionyl chloride/pyridine/CH2Cl2 gave the substituted benzyl chloride. The latter, on treatment with 40% excess sodium cyanide in DMF at 90° C. for 20 min. and normal work-up and crystallization from hexane/butyl chloride (2 crops) gave 4-chloro-2-methylbenzyl cyanide in 80% overall yield.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:29])[C:19]([C:27]#[N:28])=[C:20]4[C:26]=3[O:25][CH2:24][CH2:23][NH:22][CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12.O=[C:31]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[C:26]4[O:25][CH2:24][CH2:23][N:22]([CH:31]5[CH2:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34]5)[CH2:21][C:20]=4[C:19]([C:27]#[N:28])=[C:18]([Cl:29])[CH:17]=3)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCNC3)c2ncnc(N)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CN(C(=O)OC(C)(C)C)C2)C3)c2ncnc(N)c12
Temperature: 60 °C
Yield: 35.7 %

Procedure:
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (0.030 g, 0.078 mmol) was dissolved in methanol (3.0 mL), and the tert-butyl 3-oxoazetidine-1-carboxylate (0.027 g, 0.16 mmol) and then sodium cyanoborohydride (0.0098 g, 0.16 mmol) were added. The reaction was heated to 60° C. for 3 hrs and then allowed to cool to room temperature. The reaction was diluted with ethyl acetate and washed with brine. The organic layer dried over magnesium sulfate and concentrated to give the crude product as an amber oil. The oil was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient at pH 10 to give tert-butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate (0.015 g, 35%). LCMS calculated for C26H32ClN8O3 (M+H)+: m/z=539.2; found: 539.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:16]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Br[Mg]C1CCCC1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(CNS(C)(=O)=O)c1ccc(C2CCCC2)cc1
Yield: 13 %

Procedure:
Condition 1: The product of Example 1, 0.50 g (1.71 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) under an atmosphere of nitrogen. To this was added tetrakis-(triphenylphosphine)palladium(0) (0.099 g, 0.086 mmol) followed by cyclopentyl magnesium bromide (2 M in diethyl ether, 2.14 ml, 4.28 mmol). The solution was heated to reflux for 16 hours. Upon cooling the reaction was partitioned between water and diethyl ether. The aqueous layer was back extracted with diethyl ether twice and the organic fractions combined. The organic layers were washed with brine, dried (MgSO4) and concentrated in vacua. Chromatography (SiO2, 30% ethyl acetate/hexanes) gave the title compound 0.06 g (13%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])O)[CH2:15][CH2:14]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[CH:16]([CH:13]1[CH2:14][CH2:15]1)[C:9]1[C:8]2[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=2)[NH:11][CH:10]=1
Reactant: OC(c1ccc(F)cc1Cl)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3Cl)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 500 mg (2.82 mmol) of the compound from Example 8A and 566 mg (2.82 mmol) of the compound from Example 155A in analogy to the synthesis of the compound from Example 227. 394 mg (39% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N+:21]([O-])=O)[CH:15]=2)=[O:12])[N:7]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:21][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:8]2[N:7]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[CH3:20]
Reactant: [H][H]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c(N)c2)cc1
Yield: 85.9 %

Procedure:
1-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-3-(4-methyl-3-nitrophenyl)urea (93 mg) was hydrogenated over 10% Pd/C (50% wet, 10 mg) at atmospheric pressure of hydrogen in MeOH (2 mL) for 4 hr. The catalyst was removed by filtration through Celite® pad and the filtrate was evaporated in vacuo. The residue was triturated with IPE and the precipitates produced were collected by filtration to give 1-(3-amino-4-methylphenyl)-3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea (74 mg).
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:19][C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.Cl.Cl.[NH2:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[N:37]=1>>[NH2:42][C:38]1[N:37]=[C:36]([NH:35][CH2:34][CH2:33][NH:32][C:14]2[C:13]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:19][C:12]=3[N:17]=[C:16]([NH2:18])[N:15]=2)[CH:41]=[CH:40][N:39]=1
Reactant: NCCNc1ccnc(N)n1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC(c2ccccc2)C3)cc1
Agent: Cl
Product: Nc1nccc(NCCNc2nc(N)nc3c2CCCC(c2ccccc2)C3)n1

Procedure:
The product from Example 11C (102 mg, 0.248 mmol) and the product from Example 1E (73 mg, 0.323 mmol) were treated under the conditions of Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09-1.29 (m, 2H) 1.70-2.02 (m, 3H) 2.22-2.63 (m, 2H) 2.71 (dd, J=15.47, 5.16 Hz, 1H) 3.06-3.27 (m, 2H) 3.34-3.50 (m, 3H) 5.56-5.65 (m, 2H) 5.70-5.78 (m, 1H) 5.87 (s, 2H) 6.52 (s, 1H) 6.90 (s, 1H) 7.10-7.34 (m, 5H) 7.61 (d, J=5.55 Hz, 1H); MS (ESI+) m/z 391.1 (M+H)+.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][C:16]([F:15])([F:26])[F:27])=[CH:19][CH:20]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.54 g, 4.5 mmol), 4-trifluoromethoxy-benzylamine (0.916 mL, 6.0 mmol), and K2CO3 (1.24 g, 9.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.781 g, 41%). GC-MS: m/z 421 (M)+, 336 (M−85)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:14]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:44]1(B(O)O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.O>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]3)[CH:14]=[C:13]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1(Cc2cc(OS(=O)(=O)C(F)(F)F)cc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2cc(-c3ccccc3)cc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 300 mg of 1-tert-butyl 4-ethyl 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)methyl)piperidine-1,4-dicarboxylate, 87 mg of phenylboronic acid, 69.3 mg of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), 201 mg of potassium phosphate, 3 ml of 1,4-dioxane and 0.3 ml of water was stirred at 100° C. overnight, followed by cooling to room temperature. The reaction mixture was diluted with ethyl acetate. An insoluble matter was filtered off using Celite, and washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=9/1) to give the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][S@:2]([CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:3].[S:15](N)([C:18]1[CH:26]=[CH:25][C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16].CCCCCC>C(Cl)Cl>[S:15]([C:18]1[CH:26]=[CH:25][C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)([OH:3])(=[O:17])=[O:16].[CH3:1][S@@:2]([CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:22])=[O:3]
Reactant: C[S@@](=O)CCCOCc1ccccc1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: C[S@@](=N)(=O)CCCOCc1ccccc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.1 %

Procedure:
To a mixture of (R)-((3-(methylsulfinyl)propoxy)methyl)benzene (0.50 g, 2.36 mmol, 1 eq.) was dissolved in DCM (15 mL) followed by addition of NsNH2 (0.71 g, 3.53 mmol, 1.5 eq.) and PhIO (0.77 g, 03.53 mol, 1.5 eq.). The reaction mixture was stirred at room temperature for 10 min followed by addition of Rh2(OAc)4 (30 mg, 0.07 mmol, 0.03 eq.), stirred for 1.5 hours, and filtered. The filtered cake was slurried with DCM (30 mL). The combined DCM was concentrated to give an oil product that was reslurried with hexane to give a crude product (0.26 g) that was recrystallized from MeOH/DCM to furnish the title compound (0.148 g, 15%, 98% ee).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[CH:30]=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([Br:41])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nccn4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Yield: 127.2 %

Procedure:
To a solution of compound 4-1 (100 mg, 0.227 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.227 mmol.) and the mixture was heated to reflux for 2 hrs. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HCl(aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 150 mg of 4-3.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH:5]1[C:10]2[S:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([NH2:18])=[O:17])=[CH:7][CH:6]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([C:6]1[CH:5]=[C:10]([S:11][CH2:12][CH2:13][CH2:14][Cl:1])[C:9]([OH:15])=[C:8]([CH:7]=1)[C:16]([NH2:18])=[O:17])(=[O:21])[CH3:20]
Reactant: [Cl-]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cccc2c1OCCCS2
Agent: [Al+3]
Solvent: ClCCl
Product: CC(=O)c1cc(SCCCCl)c(O)c(C(N)=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.8 %

Procedure:
Solid aluminum chloride (9.0 g, 67.7 mmol) was suspended in 20 mL of dry dichloromethane at 0° C. The 7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene-4-carboxylic acid amide (2.7 g, 12.7 mmol) was added as a solution in 20 mL dichloromethane. The deep green solution was stirred at 0° C. for 10 min, then neat acetyl chloride (10 mL, 140.6 mmol) was added dropwise with stirring. The suspension was stirred at 0° C. for 20 min, then at rt for 30 h. The reaction was quenched with 4 N HCl and extracted repeatedly with ethyl acetate. Drying over Na2SO4 and concentration yeilded the crude product. Sgc (ethyl acetate) yielded the product as a tan solid (1.6 g, 44%). MS [M−H]− 286.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([N:23]=[C:24]([NH2:27])[NH:25][CH3:26])=[O:22])[NH:6]2.O.O.[Sn](Cl)Cl.O.N>C(O)C>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[C:7]2[C:3]([CH:4]=[C:5]([C:21]([N:23]=[C:24]([NH2:27])[NH:25][CH3:26])=[O:22])[NH:6]2)=[C:2]([Cl:1])[CH:10]=1
Reactant: CNC(N)=NC(=O)c1cc2c(Cl)cc(Oc3ccccc3[N+](=O)[O-])cc2[nH]1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CNC(N)=NC(=O)c1cc2c(Cl)cc(Oc3ccccc3N)cc2[nH]1
Yield: 51.2 %

Procedure:
A mixture of 0.23 g (0.60 mmol) of 4-chloro-1-methyl-6-(2-nitrophenoxy)-2-indoloylguanidine, 0.72 g (3.20 mmol) of tin (II) chloride dihydrate and 15 ml of ethanol was heated to reflux for 3 hours. After cooling, 28% ammonia water was added to the reaction mixture and ethanol was then distilled off under reduced pressure. The residue was extracted three times with ethyl acetate. The combined extracts were then washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography to give 0.11 g (51.6%) of 6-(2-aminophenoxy)-4-chloro-1-methyl-2-indoloylguanidine. The product was converted into the hydrochloride with hydrogen chloride/methanol to give 0.097 g of 6-(2-aminophenoxy)-4-chloro-1-methyl-2-indoloylguanidine hydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[N:10]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O>CN1CCCC1=O>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: Nn1ccc2ccccc21
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1c(Cl)ncnc1Nn1ccc2ccccc21
Yield: 78.9 %

Procedure:
A solution of 8 g of 4,6-dichloro-5-pyrimidinamine, and 7 g of 1H-indol-1-amine, in 100 ml N-methyl-2-pyrrolidone was stirred at 130°-135° for seven hours, then cooled, stirred with water and extracted with ether. The organic extract was washed with water and saturated sodium chloride, dried (anhy. MgSO4), filtered and evaporated to 16 g of a residue. This was purified by flash chromatography (silica, 5% ethyl acetate/DCM) to give 10 g solid. This was combined with product obtained from other condensations and purified by HPLC (silica 5% ethyl acetate/DCM) to give 7 g oil. This oil was crystallized from ether-petroleum ether to give 2.2 g solid, 6-Chloro-N4 -(1H-indol-1-yl)-4,5-pyrimidinediamine, m.p. 175°-176°.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Cl)[N:31]=1>CN(C)C=O>[Cl:29][C:30]1[N:31]=[C:32]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: ClCc1cccc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cccc(Cl)n4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloro-6-chloromethyl-pyridine (34.3 mg, 0.21 mmol) described in Manufacturing Example 52-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (15.9 mg, 37%) as a trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: Cc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nccnc2c1
Yield: 77.5 %

Procedure:
To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCl4 (80 mL) was added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling, the mixture was evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (50 mL×5). The extracts were concentrated under vacuum. The organics were combined and concentrated to give crude 6-bromomethylquinoxaline (12.0 g), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.85-8.87 (m, 2 H), 8.10-8.13 (m, 2H), 7.82 (dd, J=2.1, 8.7 Hz, 1 H), 4.70 (s, 2 H).
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].C(N(CC)CC)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[CH3:17][Si:18]([CH3:20])([CH3:19])[O:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4]
Reactant: C=CCOC(=O)C(C)O
Reactant: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(C)O[Si](C)(C)C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
7.69 g (60 mmol) of 2-propenyl 2-hydroxypropionate and 7.29 g (72 mmol) of triethylamine were dissolved in 130 ml of toluene, and 7.17 g (66 mmol) of trimethylsilyl chloride was dropwise added thereto at 5 to 10° C., taking 10 minutes. This was reacted at room temperature for 4 hours, the reaction liquid was washed twice with water, and the organic layer was separated and concentrated. The concentrate was purified through reduced pressure distillation to give 6.24 g (yield 52%) of 2-propenyl 2-(trimethylsilyloxy)propionate.