Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]=[C:10]([NH:40]C(OC(C)(C)C)=O)[NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29]([C:31]2[C:36]([NH2:37])=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=2)=[O:30])=[NH:27])=[CH:17][CH:16]=1)=O)(C)(C)C>CO>[ClH:39].[ClH:1].[NH2:37][C:36]1[C:31]([C:29]([NH:28][C:26]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:11][C:10]([NH2:40])=[NH:9])=[CH:16][CH:17]=2)=[NH:27])=[O:30])=[N:32][C:33]([Cl:39])=[C:34]([NH2:38])[N:35]=1
Reactant: CC(C)(C)OC(=O)N=C(NCCOc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: N=C(N)NCCOc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
12N HCl (15 mL) was added dropwise to an ice cooled solution of N-(4-{4-[2-(N′,N″-di-tert-butoxycarbonylguanidino)ethoxy]phenyl}butyl)-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidine 5 (370 mg, 0.56 mmole) in methanol (15 mL) over 1 min. After the addition, the cooling bath was removed, and the reaction was allowed to stir for 30 min. TLC (silica gel, methylene chloride/methanol/concentrated ammonium hydroxide, 3:3:1) indicated slow reaction progression. An additional 15 mL of 12N HCl was added dropwise at room temperature, and after 2 h, TLC indicated reaction completion. The solvent was evaporated and methanol (100 mL) was added and then evaporated below 30° C., this process was repeated a further three times and then the residue was placed under vacuum at 40° C. for 2 days to afford 300 mg (96%) of the pure product as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.57 (m, 4H), 2.56 (m, 2H), 3.52 (m, 2H), 4.02 (t, 2H), 4.60 (br s, 2H), 6.88 (d, 2H), 7.14 (d, 2H), 7.41 (m, 8H), 7.91 (t, 1H), 8.93 (m, 2H), 9.33 (t, 1H), 10.55 (s, 1H). mp 223-230. m/z (ESI)=463 [C19H27ClN10O2+H]+.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][OH:18])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:22][C@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]1[N:33]2[CH:34]=[C:35]([O:38][C@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C@@H:42]([NH2:49])[CH2:41][CH2:40]3)[CH:36]=[CH:37][C:32]2=[N:31][N:30]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:49][C@@H:42]2[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:39]([O:38][C:35]3[CH:36]=[CH:37][C:32]4[N:33]([C:29]([N:24]5[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]5[CH3:22])=[N:30][N:31]=4)[CH:34]=3)[CH2:40][CH2:41]2)=[O:19])[N:8]([CH2:16][CH2:17][OH:18])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
A mixture of Intermediate 110b (143 mg, 0.40 mmol), Intermediate 81d (1151 mg, 0.40 mmol) and DIPEA (82 μL, 0.50 mmol) in dioxane (5 mL) was stirred at 100° C. for 4 h. After cooling, the reaction mixture was concentrated in vacuo and then partitioned between water and DCM. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried through a phase separator and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 3-15% MeOH in DCM followed by MDAP (Method 7) purification, to afford the title compound (36 mg, 15%) as a glassy white solid. LCMS (Method 5): Rt 4.02 min, m/z 587 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.92 (3H, d, J=6.3 Hz), 1.21 (9H, s), 1.44-1.57 (2H, m), 1.60-1.74 (2H, m), 1.74-1.87 (2H, m), 1.88-2.22 (4H, m), 2.86-2.96 (1H, m), 3.12-3.20 (2H, m), 3.63-3.71 (2H, m), 3.95 (2H, t, J=6.0 Hz), 4.82-4.91 (1H, m), 5.00 (1H, br s), 5.54 (1H, t, J=4.3 Hz), 6.07 (1H, s), 7.10 (1H, d, J=8.6 Hz), 7.22 (1H, dd, J=9.8, 2.2 Hz), 7.26-7.32 (1H, m), 7.35-7.42 (3H, m), 7.65 (1H, d, J=10.8 Hz), 7.71 (1H, d, J=2.1 Hz), 8.19-8.23 (1H, m).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[CH3:53][N:54]1[CH:58]=[C:57]([C:59](Cl)=[O:60])[CH:56]=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:59]([C:57]2[CH:56]=[N:55][N:54]([CH3:53])[CH:58]=2)=[O:60])[CH2:25]1
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)N2CC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)cn1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1-methyl-1H-pyrazole-4-carbonyl chloride as the starting materials in 50% yield. LCMS for C27H27ClN9O2 (M+H)+: m/z=544.0.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:43]I>C1(C)C=CC=CC=1>[I:43][CH2:2][CH2:3][CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: OCCCOC/C=C/c1ccc2c(c1)OCCO2
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: ICCCOC/C=C/c1ccc2c(c1)OCCO2
Yield: 193.6 %

Procedure:
Following the procedure described in example 7§C, but starting from trans-2,3-dihydro-6-[3-(3-hydroxypropoxy)prop-1-en-1-yl]benzo[1,4]dioxine (280 mg), triphenylphosphine (455 mg), imidazole (114 mg) and diiodine (355 mg) in toluene (2.6 mL) affords 780 mg of trans-2,3-dihydro-6-[3-(3-iodopropoxy)prop-1-en-1-yl]benzo[1,4]dioxine as a clear oil used without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][CH2:28][O:29]C5CCCCO5)[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:36])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:36])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: OCCn1cc(-c2ccc3ncc(Cc4c(F)cc5ncccc5c4F)n3n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,7-Difluoro-6-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Stage 170.1, 82.2 mg, 0.168 mmol) was dissolved in DCM (2 mL) and a solution of 4 N HCl in dioxane (0.126 mL) was added. The RM was stirred at rt for 1 h and the solvent was removed. It was then taken up with EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The solvent was removed and the residue was diluted in MeOH. The solution was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound (tR 0.8 min (conditions 2), MH+=407, 1H-NMR in DMSO-d6: 8.92 (dd, 1H); 8.51 (d, 1H); 8.38 (s, 1H); 8.06 (t, 2H); 7.72 (d, 1H); 7.59 (dd, 1H); 7.57 (s, 1H); 7.51 (d, 1H); 4.55 (s, 2H); 4.20 (t, 2H); 3.78-3.73 (m, 2H), 3.13 (s, 1H)).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([O:23][CH3:22])[CH:28]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(CN)on1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)on1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (120 mg, 0.4 mmol) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) (60.16 mg, 0.47 mmol) as starting materials; off white solid (32 mg, 19.6%). MS (ESI): 414 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].Cl[CH2:34][CH2:35][OH:36]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:34][CH2:35][OH:36])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: OCCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NC1CCN(CCO)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol (0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.09 g, 34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12](O)[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C.S([Cl:29])(C)(=O)=O>C(Cl)Cl>[Cl:29][CH:12]([C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(O)c1cc(OC)c(OC)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cl)c1cc(OC)c(OC)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To 139A (280 mg, 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.42 mL, 3.0 mmol) followed by mesyl chloride (0.12 mL, 1.5 mmol). After stirring at rt overnight, the reaction was filtered, concentrated and purified via silica gel chromatography (0-30% ethyl acetate/hexanes) to provide 139B (268 mg, 89%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17](=[O:53])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[N:24]([CH2:44][CH2:45][O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:25]2[C:34]3[CH:33]=[CH:32][C:31]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:30][C:29]=3[N:28]=[CH:27][C:26]=2[N:43]=1)([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([O:16][C:17](=[O:53])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[N:24]([CH2:44][CH2:45][O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:25]2[C:34]3[CH:33]=[CH:32][C:31]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:30][C:29]=3[N+:28]([O-:9])=[CH:27][C:26]=2[N:43]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
mCPBA (77% pure, 0.36 g, 1.6 mmol) was added to a solution of tert-butyl{4-[7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate (0.89 g, 1.6 mmol) in dichloromethane (50 mL), and the reaction was stirred for 2.5 hours under a nitrogen atmosphere. Additional mCPBA (150 mg) was added, and the reaction was stirred over two nights. The solution was washed with water, saturated aqueous sodium bicarbonate, water, and brine, dried over sodium sulfate, and concentrated under reduced pressure to provide 0.90 g of tert-butyl{4-[7-benzyloxy-5-oxido-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate as a tan foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.[C:13]([Si:17]([CH3:24])([CH3:23])[O:18][CH2:19]CC#C)([CH3:16])([CH3:15])[CH3:14].CO>N>[Si:17]([O:18][CH2:19][CH2:11][C:10]#[C:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:24])[CH3:23]
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: OCCCc1cccc(CO)c1
Agent: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCC#Cc1cccc(CO)c1

Procedure:
Prepared by the method of Aromatic Intermediate 18, step a using tert-butyldimethyl(but-3-ynyloxy)silane (0.92 g) in place of tert-butyldimethyl(prop-2-ynyloxy)silane. The preparative HPLC conditions were changed to XBridge™, Gradient: 75-99% methanol in 0.2% aqueous ammonia to avoid cleavage of the silyl protecting group. Yield 0.79 g.
Reaction SMILES: CO.Cl.CO.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:15][CH2:16][CH2:17][O:18]C2CCCCO2)[CH:7]=1>C(N(CC)CC)C>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:15][CH2:16][CH2:17][OH:18])[CH:7]=1
Reactant: c1cncc(CCN(CCCOC2CCCCO2)Cc2ccncc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: OCCCN(CCc1cccnc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A 2N-hydrogen chloride methanol solution (1.2 ml) was added to a methanol solution (4 ml) of (2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(tetrahydropyran-2-yloxy)propyl]amine (236 mg, 0.66 mmol), and stirred at room temperature overnight. A 2N-hydrogen chloride methanol solution (0.5 ml) was added to the mixture, and stirred at 50° C. for 3 hours. Triethylamine (0.64 ml) was then added to the reaction mixture, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane). The purified product was concentrated under reduced pressure to thereby obtain 186.3 mg (yield: quantitative) of 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol as an orange oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1([CH3:28])[N:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:18]2[C:17](=[O:24])[N:16]1[CH:25]([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:22]1[CH2:21][CH2:20][N:19]2[C:15]([CH3:14])([CH3:28])[N:16]([CH:25]([CH3:26])[CH3:27])[C:17](=[O:24])[CH:18]2[CH2:23]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CC(C)N1C(=O)C2CNCCN2C1(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)CN1CCN2C(C1)C(=O)N(C(C)C)C2(C)C
Temperature: 75 °C
Yield: 72.7 %

Procedure:
A mixture of 8.2 parts of 2-chloro-N-(2,6-dimethylphenyl)acetamide, 7.2 parts of hexahydro-3,3-dimethyl-2-(1-methylethyl)imidazo[1,5-a]pyrazin-1(5H)-one, 7 parts of N,N-diethylethanamine and 54 parts of N,N-dimethylformamide was stirred and heated for 3 hours at 75° C. After cooling to 0° C., the precipitate was filtered off and the filtrate was evaporated. The residue was dissolved in 300 parts of trichloromethane. This solution was washed with 50 parts of water, dried, filtered and evaporated. The residue was triturated in 2,2'-oxybispropane. After cooling to 0° C., the product was filtered off and dried, yielding 9.2 parts (72.7%) of N-(2,6-dimethylphenyl)hexahydro-3,3-dimethyl-2-(1-methylethyl)-1-oxoimidazo[1,5-a]pyrazine-7(8H)-acetamide; mp. 155° C. (intermediate 101).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: O=C(O)Cn1c(=O)ccc2ncccc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccc2ncccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (42 mg, 0.204 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.101 mmol) according to protocol A. Retention time (min)=2.295, method [7], MS(ESI) 431.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.57 (dd, J=4.6, 1.7 Hz, 1H), 8.16 (d, J=9.9 Hz, 1H), 8.11 (s, 1H), 7.98 (d, J=9.1 Hz, 1H), 7.62 (dd, J=8.8, 5.1 Hz, 1H), 7.01 (d, J=4.3 Hz, 1H), 7.05 (s, 1H), 5.33 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:34][C:8]2[N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:19][CH:18]=3)[C:10]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:11][C:7]=2[CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[CH2:12]([C:10]1[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:30][N:31]=[N:32][N:33]=3)=[CH:21][CH:22]=2)[C:8]2[S:34][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc2cc(C(=O)OC)sc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc2cc(C(=O)O)sc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
2-butyl-3-[(2'-{1H-tetrazol-5-yl}{1,1'-biphenyl}-4-yl)methyl]-3H-thieno[2,3-d]-imidazole-5-carboxylic acid methyl ester (1, A-B-C are --CH=C(CO2CH3)--S--; R6 -E=butyl; R1 =tetrazol-5-yl) prepared as described in Example 5 can be saponified with lithium hydroxide hydrate in THF/H2O (5:1) at room temperature for 24 hours to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]=O>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([CH3:26])[CH:28]=4)[NH:32][CH:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1ccc2[nH]cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 571.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.070 g, 0.020 mmol) in methanol (2.0 mL) was added with 5-methyl-1H-indole-3-carboxaldehyde (0.034 g, 0.021 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (93:7)) to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(5-methyl-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.056 g, 55%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.C(Cl)Cl>[C:34]1([CH:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)=[O:32])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3)) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 512.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Li]CCCC.CCCCCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>CCOCC>[CH3:1][N:2]([CH3:12])[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[B:24]([OH:29])[OH:25])(=[O:4])=[O:5]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)c1ccccc1B(O)O
Temperature: -70 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
A solution of N,N-dimethylbenzenesulfonamide (9.25 g; 50 mmol) in dry Et2O (150 ml) under N2 was cooled to −70° C. and added a solution of 2.5 M n-BuLi in hexane (24 ml; 60 mmol) such that the reaction temperature was kept below −60° C. The cooling bath was removed and the reaction mixture allowed to slowly warm up to +20° C. The reaction mixture was re-cooled to −70° C. and B(Oi-Pr)3 (16.1 ml; 70 mmol) was added. The reaction mixture was left cold and allowed to warm up over night, 1 M HCl (100 ml) was added and stirring was continued at rt. for 1 h. The reaction mixture was then extracted with Et2O (2×50 ml) and the combined organic fractions extracted with 1 M NaOH (4×50 ml). The combined aqueous fractions were neutralized with 1 M HCl and extracted with Et2O (4×100 ml). The combined organic fractions were dried (Na2SO4) and evaporated to dryness, washed with Et2O/hexane to give 3.4 g (30%) product.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COc1ccc2ncnc(Cl)c2c1
Product: COc1ccc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (87 mg, 0.3 mmol) and 4-chloro-6-methoxyquinazoline (59 mg, 0.3 mmol) as described in Example 46 and its corresponding hydrochloride salt was prepared as described in Example 4B Step 2 to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-ylthio)phenyl)urea as the mono-hydrochloride (76 mg, 0.15 mmol, 50%). 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.49 (s, 1H), 8.80 (s, 1H), 7.95 (d, 1H), 7.87 (s, 1H), 7.71 (dd, 1H), 7.55 (d, 1H), 7.49-7.42 (m, 2H), 7.29 (d, 1H), 6.50 (s, 1H), 4.00 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.