Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br-].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Zn+].[NH4+].[Cl-]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)Oc1cccc2ccc(I)nc12
Reactant: [Zn+]c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)Oc1cccc2ccc(-c3ccccn3)nc12
Reaction time: 2 h

Procedure:
Reaction of 2-iodo-quinolin-8-ol 8 with 2-bromopropane following the method described in Example 8 gave 2-iodo-8-isopropoxyquinoline 9 in 84% yield. 9: 1H NMR (CDCl3): δ 7.75-7.67 (m, 2 H), 7.45 (dd, J=7.0 and 8.0, 1 H), 7.33 (dd, J=1.2 and 8.0, 1 H), 7.12 (dd, J=1.2 and 7.0, 1 H), 4.80 (m, 1 H), 1.49 (d, J=5.9, 6 H). To a stirred solution of 9 (29 mg, 0.093 mmol) and PdCl2(PPh3)2 (5 mg) in THF (2.5 mL) under an argon atmosphere at RT was added dropwise over 5 min 2-pyridylzinc bromide (0.370 mL of a 0.5 M solution in THF, 0.185 mmol). After 2 h, saturated NH4Cl (5 mL) was added and the mixture extracted with dichloromethane (10 mL×3). The combined extracts were washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. Subsequent column chromatography on silica (dichloromethane/MeOH, 19:1) gave 2-(pyrid-2-yl)-8-isopropyloxyquinoline as a yellow solid. The isopropyl ether was cleaved according to the procedure of Example 8, to give 2-(Pyrid-2-yl)-8-hydroxyquinoline P1 (22 mg, 89%) (data in Table 5).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][PH:17](=[O:21])[O:18][CH2:19][CH3:20]>C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]([P:17]([CH3:16])(=[O:21])[O:18][CH2:19][CH3:20])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO[PH](C)=O
Reactant: O=CCCNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)C(O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5.18 g of 3-(benzyloxycarbonylamino)propionaldehyde, 2.7 g of ethyl P-methylphosphinate and 2,53 g of triethylamine is heated to 100° under an inert gas atmosphere for 2 hours. After cooling to room temperature the volatile materials are removed under reduced pressure to afford a viscous oil. Chromatography thereof on silica gel gives ethyl P-(3-benzyloxycarbonylamino-1-hydroxy-propyl)-P-methyl-phosphinate as a colourless, viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cccc([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cccc(N)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To 10% palladium-carbon (100 mg), a solution of tert-butyl 3-((3-nitrophenyl)amino)piperidine-1-carboxylate (C21, 229 mg) in tetrahydrofuran (10 mL) and methanol (4 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl 3-((3-aminophenyl)amino)piperidine-1-carboxylate (C22, 211 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27]O)=[NH:26])=[CH:23][N:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]4[O:19][N:27]=[C:25]([C:24]5[CH:29]=[CH:30][C:21]([NH2:20])=[N:22][CH:23]=5)[N:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(Cl)cc3)cn12
Product: Nc1ccc(-c2noc(-c3cnc4ccc(-c5ccc(Cl)cc5)cn34)n2)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.36) (136 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate) and further purification by crystallization (MeOH/diethyl ether) as a white solid (34 mg, 17%). MS (ISP) 389.3 [(M+H)+]; mp 273° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH:28]([CH3:30])[CH3:29])[C:13]([N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[O:14]>>[CH2:21]([N:15]([CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])[C:13](=[O:14])[C@@H:12]([NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10])[CH:28]([CH3:29])[CH3:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)C(N)C(=O)N(CCN(C)C)Cc1ccccc1
Product: CC(C)[C@H](NC(=O)Nc1ccc(F)cc1)C(=O)N(CCN(C)C)Cc1ccccc1

Procedure:
Compound 14b was prepared from 4-fluorophenyl isocyanate and compound 13, using the method described in Example 22. MS (EI)=414 (M+).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=2[C:4](=O)[NH:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:4]1[C:6]2[C:7](=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[CH2:1][CH2:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Product: O=[N+]([O-])c1ccc2c(c1)C(Cl)=NCC2

Procedure:
Tricyclic heterocycles can be prepared by the process outlined in Scheme 8. 7-Nitro-2,3,4-trihydroisoquinolin-1-one 21 is heated in POCl3 at a temperature above RT, preferably at a temperature sufficient for reflux, to form the 1-chloro-7-nitro-3,4-dihydroisoquinoline 22. The 1-chloro-7-nitro-3,4-dihydroisoquinoline 22 is dissolved in a solvent, such as THF, and H2NNH2 is added. The reaction is heated with HC(OEt)3 at a temperature above RT, preferably at a temperature above about 75° C., and more preferably at a temperature at about 115° C. to give the nitro-substituted tricyclic. Hydrogenation, such as with an H2 atmosphere in the presence of a catalyst, such as Pd/C, gives 2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline 23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=O.O=S(Cl)Cl.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=1[C:7]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[Cl:19])=[O:9]
Reactant: Nc1ccccc1Cl
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(N)c(C(=O)Nc2ccccc2Cl)cc1OC
Yield: 55.2 %

Procedure:
Prepared according to Procedure A using 4,5-dimethoxyanthranilic acid (5.0 g, 25.4 mmol) and SOCl2 (5.5 mL, 76.1 mmol) in benzene (100 mL), followed by 2-chloroaniline (6.7 mL, 63.5 mmol) and CHCl3 (75 mL). The product was washed with aqueous NaHCO3 (2×25 mL) and HCl (0.5 M, 75 mL) and purified by chromatography in CH2Cl2 to provide 4.3 g of a brown foam (55%). 1H NMR (CDCl3) δ: 8.42 (dd, J=1.5, 8.3 Hz, 1H); 8.32 (br s, 1H); 7.40 (dd, J=1.4, 8.0 Hz, 1H); 7.31 (dt, J=1.4, 7.9 Hz, 1H); 7.05 (dt, J=1.5, 7.7 Hz, 1H); 7.03 (s, 1H); 6.24 (s, 1H); 3.88 (s, 3H); 3.87 (s, 3H). MS (ES): m/z 307.0 (M+).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]2[C:16]([NH2:17])=[N:15][CH:14]=[C:13]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][CH:22]=[N:23]4)[N:12]=2)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1N=C(N[C@H](C2C=CC=CC=2)CC)C(N)=NC=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.[C:59](=O)([O-])[O-:60].[K+].[K+]>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.CN(C)C=O.O>[C:1]1([C@@H:7]([N:10]2[C:11]3=[N:12][C:13]([C:18]4[CH:27]=[CH:26][CH:25]=[C:24]5[C:19]=4[CH:20]=[CH:21][CH:22]=[N:23]5)=[CH:14][N:15]=[C:16]3[NH:17][C:59]2=[O:60])[CH2:8][CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](Nc1nc(-c2cccc3ncccc23)cnc1N)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[C@H](Nc1nc(Br)cnc1N)c1ccccc1
Agent: OB(O)c1cccc2ncccc12
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)nc21
Yield: 77 %

Procedure:
(S)—N2-(1-phenylpropyl)-6-(quinolin-5-yl)pyrazine-2,3-diamine. (S)-6-Bromo-N2-(1-phenylpropyl)pyrazine-2,3-diamine (0.560 g, 1.83 mmol), quinoline-5-boronic acid (0.348 g, 2.01 mmol), tetrakis(triphenylphosphine)palladium (0.211 g, 0.183 mmol), potassium carbonate (1.01 g, 7.32 mmol), water (8 mL) and dimethylformamide (30 mL) were reacted according to General Procedure B. The crude was purified via Biotage silica gel chromatography (0-10% methanol/dichloromethane, 40S column) to afford the title compound (0.500 g, 77% yield). MS (ESI) m/z 356.3 [M+1]+.
Reaction SMILES: [N:1](C1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1)=[N+:2]=[N-].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:56])=[C:36]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=3[Cl:54])=[CH:42][C:41]=2[Cl:55])=[O:39])[CH:37]=1>>[N:31]([C:32]1[CH:33]=[CH:34][C:35]([CH3:56])=[C:36]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=3[Cl:54])=[CH:42][C:41]=2[Cl:55])=[O:39])[CH:37]=1)=[N+:1]=[N-:2]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl
Product: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 421 (0.21 mmol). The crude product was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C1C(/C=N/O)=CC=[N+:15](C[N+]2C=CC(/C=N/O)=CC=2)C=1.[Br-].[Br-].B>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH2:15]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: B
Agent: [Br-]
Solvent: C1CCOC1
Product: NCc1cc(Cl)cc(Cl)c1
Yield: 69.6 %

Procedure:
The reaction of 3,5-dichlorobenzaldehyde methoxime, (17.4 g, 85.7 mmole) and 0.98M borane in tetrahydrofuran (86 ml) substantially as described in 1B above produced 10.5 g (70%) of the title compound as a light yellow oil.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.B(F)(F)[F:14].CCOCC.N(OC(C)(C)C)=O>C(Cl)Cl.CCCCC>[F:14][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2
Reactant: Nc1cccc2c1C(=O)CCC2
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Solvent: CCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCCc2cccc(F)c21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The amine (Intermediate J3, 1.83 g, 11.3 mmol) in CH2Cl2 (17 mL) was added to BF3.OEt2 (2.80 mL, 22.1 mmol) at −15° C. More CH2Cl2 (20 mL) was added to the precipitate. Next, t-butyl nitrite (1.8 mL, 12.9 mmol) in CH2Cl2 (20 mL) was added at −15° C. and stirred for 10 min. and at 0° C. for 20 m. The mixture was diluted with pentane (40 mL), filtered and the solids were collected, washed with ether, and dried under vacuum. The solids were placed in a flask and heated to 115° C. for 10-15 min. followed by addition of 2N NaOH and CHCl3. The suspension was filtered and the aqueous phase was extracted with CHCl3. The organic layers were combined, dried over MgSO4, filtered and purified by chromatography on SiO2 with 15% EtOAc:Hx. The product, 8-fluoro-3,4-dihydro-2H-naphthalen-1-one (Intermediate J4) was isolated; 750 mg (40%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10].[Se](=O)=[O:13]>O1CCOCC1.O>[NH2:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=[CH:6][N:5]=1)[CH:1]=[O:13]
Reactant: O=[Se]=O
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccc(C=O)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 25.1 %

Procedure:
To a solution of 4-methyl-3-nitropyridin-2-amine (10.0 g, 65.0 mmol) in a mixture of dioxane (400 mL) and water (50 mL) was added selenium dioxide (29.0 g, 260 mmol) and the reaction mixture was heated to 100° C. for 16 hr and then cooled to RT and filtered through a pad of celite. The pad was washed with a mixture of EtOAc/THF (3:1 v/v, 100 mL) and the combined filtrate and washings were evaporated in vacuo. The residue was partitioned between EtOAc/THF (3:1 v/v, 100 mL) and sat aq. NaHCO3 (150 mL) diluted with water (150 mL). The aq layer was separated and was extracted with EtOAc/THF (3:1 v/v, 4×100 mL) and the combined organic extracts were dried and evaporated in vacuo to afford 2-amino-3-nitroisonicotinaldehyde as a brown solid (2.73 g, 25%); Rt 0.75 min (Method 2); m/z 168 (M+H)+, (ES+).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Cl:11][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[CH2:27]([Sn:31](CCCC)([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30].[Cl-].[Cl-].[NH4+]>O1CCCC1.C([Li])CCC.C(OCC)(=O)C>[Cl:11][C:12]1[N:20]=[C:19]([Sn:31]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:27][CH2:28][CH2:29][CH3:30])[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: CCCC[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
2,2,6,6-Tetramethylpiperidine (26.5 ml, 157 mmol) was dissolved in tetrahydrofuran (200 ml) in an argon atmosphere and n-butyl lithium (2.6 M hexane solution, 54 ml) was added dropwise at room temperature. After the completion of dropwise addition, the resulting mixture was stirred for 15 minutes. The reaction mixture was cooled to −78° C. followed by the dropwise addition of a tetrahydrofuran (30 ml) solution of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (7.5 g, 31.4 mmol) and the resulting mixture was stirred at the same temperature for 40 minutes. Tetrabutyltin chloride (26 ml, 94.3 mmol) was added dropwise to this solution and the resulting mixture was stirred for 30 minutes. An aqueous ammonium chloride solution was added, the resulting mixture was heated to room temperature followed by the addition of ethyl acetate, and the organic layer was fractionated. The organic layer was washed with water and saturated brine and dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1 to 8:2 to 7:3 to 6:4 to 5:5) to give the title compound (13.3 g, 80%) as a pale yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.I[CH2:12][CH:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>C1COCC1>[CH2:22]([CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: c1ccsc1
Reactant: CCCCCCCCC(CI)CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCC(CCCCCC)Cc1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A solution of thiophene (46.4 g, 551 mmol., 2.50 equiv.) and THF (300 mL) was cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 212 mL, 528 mmol., 2.40 equiv.) was added over 1 hour. The mixture was stirred for an additional 30 minutes at −78° C. before a solution of 1-iodo-2-hexyldecane (90.0 g, 220 mmol., 1.00 equiv) in THF (200 mL) was added slowly over 1 hour. After stirring for 1 hour at −78° C., the reaction mixture was warmed to ambient temperature and stirred for 18 hours. Water (200 mL) was added and the organic material was extracted with Et2O (3×250 mL), washed with additional water, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting brown residue was purified by silica gel column chromatography (hexanes) to give a pale yellow oil (52.03 g, 77% yield). 1H NMR (500 MHz, CDCl3) δ 7.12 (dd, J=5.2, 1.2 Hz, 1H), 6.92 (m, 1H), 6.76 (dd, J=3.4, 0.9 Hz, 1H), 2.76 (d, J=6.7, 2H), 1.62 (b, 1H), 1.33-1.21 (m, 24H), 0.91-0.87 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][NH:17]2)=[O:15])=[CH:5][CH:4]=1)#[N:2].[CH:29](=O)[C:30]([CH3:33])([CH3:32])[CH3:31].C1C=CC=CC=1>CCCCC>[CH2:22]([O:21][C@H:19]1[CH2:18][N:17]2[C@@H:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:13]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:14](=[O:15])[C@@H:16]2[CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(NC(=O)[C@@H]2C[C@@H](OCc3ccccc3)CN2)c2ccccc12
Reactant: CC(C)(C)C=O
Solvent: c1ccccc1
Solvent: CCCCC
Product: CC(C)(C)[C@H]1N(c2ccc(C#N)c3ccccc23)C(=O)[C@@H]2C[C@@H](OCc3ccccc3)CN21
Yield: 86.3 %

Procedure:
A suspension of 33B (151 mg, 0.38 mmol) and pivalaldehyde (100 μl, 0.90 mmol) in a mixture of dry benzene (0.5 ml) and dry pentane (5.0 ml) was refluxed for 25 hr with a Dean-Starke receiver (Ref: Org. Lett., 2 (18) 2781-2783, (2000)). The reaction mixture was evaporated to dryness and dried in vacuo. Purification using automated flash chromatography (35 g silica gel column, EtOAc/hexane gradient) gave the title compound as a light pink-colored solid (144.1 mg, 86.3%). m.p. 155-157° C. MS (ES): m/z 440 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[OH:45][C:46]([CH3:50])([CH3:49])[CH2:47][NH2:48].[Cl-].[Na+]>CN(C=O)C>[OH:45][C:46]([CH3:50])([CH3:49])[CH2:47][NH:48][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23]
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: CC(C)(O)CN
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NCC(C)(C)O)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
To a solution of 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (0.212 mmol) in DMF (5 mL) was added 1-hydroxybenzotriazole hydrate (0.318 mmol), N-ethyldiisopropylamine (0.848 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (0.318 mmol) and 2-hydroxy-2-methylpropylamine (0.318 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by preparative HPLC afforded the title compound (13 mg, 14%) as an off white solid. MS: m/e=402.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:40][N:41]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1
Yield: 95.1 %

Procedure:
Tert-butyl 4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6 yl)methyl)piperazine-1-carboxylate (4.08 gm) was reacted with 2.79 g 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to yield 4.38 g tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate. 150 mg of this crude intermediate was subjected to General Procedure D and subsequently reacted with 84 mg D-lactic Acid via General Procedure B to give 28 mg of 398 after reverse phase HPLC purification. MS (Q1) 485.3 (M)+.
Reaction SMILES: Cl.O1CCOCC1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:20]=3[N:19]=2)[N:9]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][CH:55]([CH:65]1[CH2:67][CH2:66]1)[CH2:56][C:57]([NH:59][C:60]1[NH:61][CH:62]=[CH:63][N:64]=1)=[O:58]>C(Cl)Cl>[CH:65]1([CH:55]([NH:54][C:27]([C:25]2[CH:24]=[CH:23][C:21]3[NH:22][C:18]([C:10]4[N:9]=[CH:8][C:17]5[C:12]([CH:11]=4)=[CH:13][CH:14]=[CH:15][CH:16]=5)=[N:19][C:20]=3[CH:26]=2)=[O:28])[CH2:56][C:57](=[O:58])[NH:59][C:60]2[NH:61][CH:62]=[CH:63][N:64]=2)[CH2:67][CH2:66]1
Reactant: O=C(O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1
Reactant: NC(CC(=O)Nc1ncc[nH]1)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(CC(NC(=O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1)C1CC1)Nc1ncc[nH]1
Yield: 4.3 %

Procedure:
203 mg (1.0 mmol) of 3-tert-butoxycarbonylamino-3-cyclopropyl-propionic acid (0.23 g, 1 mmol) was reacted with 380 mg (1.0 mmol) of HBTU and 130 mg (1.0 mmol) of 2-aminoimidazole sulfate as described in general procedure A. The desired amide product was isolated by column chromatography (EtOAc/silica) and carried on directly to the next step. The BOC compound in DCM (3 mL) was treated with 4.0 M HCl/dioxane (15 mL) for approximately 1 h. The solid 3-Amino-3-cyclopropyl-N-(1H-imidazol-2-yl)-propionamide (180 mg, 100%) was collected by filtration and used directly in the next step 289 mg (1 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid (289 mg, 1 mmol) was reacted with 380 mg (1 mmol) of HBTU and 3-amino-3-cyclopropyl-N-(1H-imidazol-2-yl)-propionamide (230 mg, 1 mmol) as described in general procedure A. A solid precipitated from the solution and was collected by filtration, washed with 1H2O and Et2O, to give 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-cyclopropyl-2-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide (20 mg, 4%). LCMS: 466 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 9.20 (s, 1H), 8.56 (s, 1H), 8.09-7.34 (m, 9H), 6.39 (s, 2H), 3.71 (t, 1H), 2.44 (m, 2H), 0.81 (m, 1H), 0.10 (m, 4H) ppm.