Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=CC(C2C=CC3N(C=C(NC(=O)C)N=3)N=2)=CC=1NS(C1C=CC(C(O)(C)C)=CC=1)(=O)=O.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[CH:45][C:46]3[N:47]([CH:49]=[C:50]([NH:52][C:53](=[O:55])[CH3:54])[N:51]=3)[N:48]=2)O1.Br[C:58]1[CH:59]=[C:60]([NH:65][S:66]([C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[Cl:76])(=[O:68])=[O:67])[C:61]([Cl:64])=[N:62][CH:63]=1>>[Cl:64][C:61]1[N:62]=[CH:63][C:58]([C:43]2[CH:44]=[CH:45][C:46]3[N:47]([CH:49]=[C:50]([NH:52][C:53](=[O:55])[CH3:54])[N:51]=3)[N:48]=2)=[CH:59][C:60]=1[NH:65][S:66]([C:69]1[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=1[Cl:76])(=[O:68])=[O:67]
Reactant: CC(=O)Nc1cn2nc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1Cl
Agent: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(C(C)(C)O)cc4)c3)ccc2n1
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4Cl)c3)ccc2n1
Yield: 15.2 %

Procedure:
Following the procedure described for compound N-(6-(6-chloro-5-(4-(2-hydroxypropan-2-yl)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 35), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (200 mg, 662 μmol) (Example 35, Step 3) was reacted with N-(5-bromo-2-chloropyridin-3-yl)-2-chloro-4-fluorobenzenesulfonamide (265 mg, 662 μmol) to afford the title compound as a grey solid (50 mg, 25% yield). MS (ESI positive ion) m/z: 495 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.12 (s, 3H), 7.33-7.43 (m, 1H), 7.77 (dd, J=8.61, 2.15 Hz, 1H), 7.83 (d, J=9.39 Hz, 1H), 7.99 (dd, J=8.80, 6.06 Hz, 1H), 7.99 (dd, J=8.80, 6.06 Hz, 1H), 8.12 (d, J=9.39 Hz, 1H), 8.33 (d, J=8.41 Hz, 2H), 8.91 (s, 1H), 10.82-10.92 (br s, 1H), 10.96 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1cccc2c1CCN=C2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1cccc2c1CCNC2C

Procedure:
In close analogy to the procedure described above, 1-Methyl-5-methoxy-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: C[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C=[O:13].S(=O)(=O)(O)O.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[OH:29]>C(O)(=O)C>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:7]=[CH:8][CH:9]=1.[CH2:20]=[O:29].[CH:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][C:24]=2[OH:13])[CH:19]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Cc1cccc2ccccc12
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1cccc2ccccc12
Product: c1ccc2ccccc2c1
Reaction time: 24 h

Procedure:
In a procedure analogous to that described in Example 1, 1-methylnaphthalene (142 g, 1 mol) was condensed with formaldehyde (170 mL, 2.25 mol) in acetic acid solvent (175 mL) using sulfuric acid (25 mL) catalysis. After reacting for 24 hours 2-naphthol (143 g, 1 mol) was added over 7 minutes. The reaction mass was heated under reflux an additional 5 hours and worked up as in Example 1. The results are shown in Table A.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[N:3]=1.CO[C:13](OC)(OC)[CH2:14][CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>COCCO>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([NH:9][C:13]([CH2:14][CH2:15][CH3:16])=[N:8]2)=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(Cl)nc(N)c1N
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Temperature: 140 °C
Yield: 47.1 %

Procedure:
A mixture of 2-Chloro-4,5-diamino-6-methylpyrimidine (0.80 g, 5.04 mmol), trimethylorthobutyrate (1.2 ml, 7.6 mmol) and p-TsOH (0.0 8 g) in 2-methoxyethanol (24 ml) was heated in an oil bath at 140° C. for 24 hours. The product was isolated as described in Step 2 of Example 12 and purified by flash chromatography using EtOAc-hexane (1:1) to give the crystalline titled compound (0.5 g, 47%). NMR(CDCl3): δ 1.03 (t, J=8 Hz,3H), 1.9 (q,2H), 2.82 (s, 3H), 3.0 (t, J=8 Hz, 2H), FAB-MS: m/e 211 and 213 (M+H). Analysis calculated for C9H11N4Cl: C, 51.31; H, 5.26; N,26.60. Found: C, 51.43; H, 5.50, N, 26.81.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[O:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCC1>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10](/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc2c1OCCO2
Solvent: c1ccncc1
Solvent: C1CCNC1
Product: O=C(O)/C=C/c1cccc2c1OCCO2
Temperature: 0 °C

Procedure:
A mixture of 2,3-dihydrobenzodioxin-5-carboxaldehyde (Morishima, et al., Eur. Pat. Appl. 309,766, 5 Apr. 89) (9.25 g, 56.4 mmol), malonic acid (11.73 g, 112.8 mmol), pyrrolidine (1 mL), and pyridine (25 mL) was heated to reflux for 2 hr, cooled, and then poured into ice water (300 mL). The white precipitate was filtered, washed with 1N HCl, and air dried (9.83 g, 84.6%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:9]=[N:8][N:7]=1.BrCC1C=CC(C(OCC)=O)=CC=1.[NH:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31]1.N1C2C=CN=CC=2N=C1>>[CH:11]1([N:10]2[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:32]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:38]4[N:30]=[CH:31]3)=[N:7][N:8]=[N:9]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: c1cnc2nc[nH]c2c1
Reactant: ClCCCCc1nnnn1C1CCCCC1
Agent: CCOC(=O)c1ccc(CBr)cc1
Agent: c1cc2[nH]cnc2cn1
Product: c1cnc2c(c1)ncn2CCCCc1nnnn1C1CCCCC1

Procedure:
Utilizing the procedure described in Example 1(a) employing 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in lieu of ethyl 4-bromomethylbenzoate and imidazo[4,5-b]pyridine in lieu of imidazo[4,5-c]pyridine yielded an impure mixture of isomers. The mixture was purified by column chromatography (silica gel, 5% ethanol in chloroform) to yield a less polar isomer which was recrystallized from diethyl ether-chloroform to yield 3-[4-(1-cylohexyl-1H-tetrazol-5-yl)butyl]-3H-imidazo[4,5-b]pyridine as a colorless crystalline solid, having a melting point of 94°-95° C. and the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:4]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[N:21][CH:22]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cn1

Procedure:
3-Chloro-4-phenyl-1H-pyrrole-2,5-dione (1.55 g, 7.47 mmol) was dissolved in DMF (25 mL) under nitrogen atmosphere and cooled in an ice-bath. tert-Butyl [5-(bromomethyl)pyridin-2-yl]carbamate (2.14 g, 7.46 mmol) was added followed by anhydrous potassium carbonate (1.03 g, 7.47 mmol)and the mixture was stirred for one and a half hours whereafter the cooling-bath was removed. The mixture was stirred for another two hours and then neutralized with 1% HCl. Water (100 mL) was added and the mixture was extracted with CH2Cl2 (50 mL×3). The extracts were combined, washed with water (100 mL×2), dried with magnesium sulphate, filtered and evaporated. The crude product (3.41 g) was used without further purification. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J=2 Hz, 1H), 7.92-7.89 (m, 3H), 7.83 (bs, 1H), 7.72 (dd, J=9, 2 Hz, 1H), 7.49-7.47 (m, 3H), 4.71 (s, 2H), 1.52 (s, 9H).
Reaction SMILES: ClC[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8](COC)[C:7]=2[CH:19]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[N:20]1([C:3]2[CH:4]=[CH:5][C:6]3[O:11][C:10]4[N:12]=[CH:13][CH:14]=[N:15][C:9]=4[NH:8][C:7]=3[CH:19]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: c1c[nH]cn1
Reactant: COCN1c2cc(CCl)ccc2Oc2nccnc21
Product: c1cn(-c2ccc3c(c2)Nc2nccnc2O3)cn1

Procedure:
The following compound was obtained by reacting 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzoxazine with imidazole and then treating by the same method as the one of Example 8.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C1(NC2CCC(F)(F)CC2)CCCCC1.NC1SC=NC=1.C(OC(=O)CS)C>>[CH:24]1([N:15]([CH:16]2[CH2:17][CH2:18][C:19]([F:22])([F:23])[CH2:20][CH2:21]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCC(F)(F)CC2)s1
Agent: CCOC(=O)CS
Agent: FC1(F)CCC(NC2CCCCC2)CC1
Agent: Nc1cncs1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCC(F)(F)CC2)s1

Procedure:
{2-[3-Cyclohexyl-3-(4,4-difluoro-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester prepared using general procedures (A) and (B) using cyclohexyl-(4,4-difluoro-cyclohexyl)amine and 5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:6]([N+:19]([O-])=O)=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H][H]>[Ni].CCO>[NH2:16][C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[CH:3][NH:19]2)=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc2cc[nH]c2cc1N
Yield: 29.4 %

Procedure:
A mixture of (E)-ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate (15 g, 0.050 mol) and Raney Nickel (5 g) in EtOH (500 mL) was hydrogenated at room temperature under 50 psi of hydrogen for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-5-carboxylate (3.0 g, 30%). 1H NMR (DMSO-d6) δ 10.68 (s, 1 H), 7.99 (s, 1 H), 7.01-7.06 (m, 1 H), 6.62 (s, 1H), 6.27-6.28 (m, 1 H), 6.16 (s, 2 H), 4.22 (q, J=7.2 Hz, 2 H), 1.32-1.27 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[NH:18])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:2].C([Li])CCC.Cl[P:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[N:18][P:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCc1ccccc1NC(=N)c1ccc(C)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: CCc1ccccc1NC(=NP(c1ccccc1)c1ccccc1)c1ccc(C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.19 g of N1-(2-ethylphenyl)-4-methylbenzamidine (Amidine VIII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the residue was treated with 20 mL of pentane. The light yellow solid was collected and dried (1.45 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1/[CH:22]=[CH:23]/[O:24]C.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C@H:7]([CH2:22][CH:23]=[O:24])[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]1=[O:10]
Reactant: CO/C=C/[C@@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CC=O)c(OC)c1
Temperature: 50 °C
Yield: 58.3 %

Procedure:
To a solution of benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((E)-2-methoxyvinyl)-4-oxoazetidin-3-yl)carbamate (1.58 g, 3.70 mmol) in dioxane (37 ml) was added HCl (7.4 ml, 7.4 mmol) and heated to 50° C. for 4 h. After cooling to rt, the reaction mixture was quenched with saturated NaHCO3 (aq) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried with Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc-Heptane, 0-80%) to afford the title compound (0.89 g, 58%). LCMS: Rt=0.86 min, m/z=413.0 (M+1). Method 2m_acidic.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.[Br:21][C:22]1[CH:23]=[CH:24][C:25](F)=[C:26]([CH:29]=1)[C:27]#[N:28].C(N(CC)C(C)C)(C)C.C(#N)C>CCOC(C)=O>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: COc1ccc(CNc2ncnc3c2CNCC3)cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2CN(c2ccc(Br)cc2C#N)CC3)cn1

Procedure:
A mixture of N-((6-methoxypyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (350 mg, 1.3 mmol), 5-bromo-2-fluorobenzonitrile (640 mg, 3.2 mmol), N,N-diisopropylethylamine (0.67 mL, 3.9 mmol), and acetonitrile (4 mL) was subjected to microwave irradiation at 180° C. for 3 h. After that additional 5-bromo-2-fluorobenzonitrile (450 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. After cooling, the mixture was diluted with EtOAc (100 mL) and washed with aq. Na2CO3 solution and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column (EtOAc: 100%) to yield a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.O.[NH2:10][NH2:11]>>[CH3:8][C:4]1[N:3]=[C:2]([NH:10][NH2:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)n1
Reactant: NN
Solvent: O
Product: Cc1cccc(NN)n1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of 2-bromo-6-methyl-pyridine (602.10 g) and hydrazine hydrate (1570 ml) was refluxed at 120° C. for 6 hours, and then stirred at room temperature for about 48 hours. The solid separated was extracted with diethylether (3×1.5 L) and the combined ether extracts were washed with brine, dried over Na2SO4, filtered and concentrated (˜430 g). The residue was stirred in a mixture of ether (200 ml) and hexane (1.5 L), filtered and washed with 5% diethylether in hexane to give a pale yellow solid (sticky). The solid was vacuum distilled at 106-113° C./2 mm, which solidified instantly. The solid was then dissolved in 2 L of diethylether and precipitated by adding 2 L of hexane, filtered and vacuum dried to give 1-(6-methylpyridin-2-yl)hydrazine as white solid (240 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:15])[CH:11]=[CH:12][CH:13]=1.[CH:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>C1(C)C=CC=CC=1.C(O)C.O>[CH:24]([C:26]1[CH:31]=[C:30]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:15])[CH:9]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: O=Cc1cccc(OB(O)O)c1
Reactant: O=C(NCCN1CCCC1)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2cccc(C(=O)NCCN3CCCC3)c2)c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Palladium tetrakistriphenyl phosphine (735 mg) and 2 M aqueous sodium carbonate (21.2 ml) were added to a solution of 3-bromo-N-[2-(1-pyrrolidinyl)ethyl]phenylcarboxamide (6.31 g) in toluene (50 ml), and then a solution of 3-formylphenylboric acid (3.49 g) in ethanol (15 ml) was added thereto, and the mixture was stirred at 90° C. for 15 hours. The reaction solution was diluted with water and then extracted with diethyl ether. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, whereby the title compound (6.83 g) was obtained.
Reaction SMILES: C([C@@H]1CC[C@@H](C)C[C@H]1[O:11][C:12]([C@@H:14]1[CH2:27][C:26]2[CH:25]=[C:24]3[C:19]([O:20][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([O:36]CC5C=CC(Cl)=C(Cl)C=5)=[CH:32][CH:31]=4)[C:22](=[O:29])[N:23]3[CH3:28])=[CH:18][C:17]=2[CH2:16][N:15]1[C@@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:13])(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:21]2[O:20][C:19]3[C:24](=[CH:25][C:26]4[CH2:27][C@@H:14]([C:12]([OH:13])=[O:11])[N:15]([C@@H:46]([C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)[CH2:47][CH3:48])[CH2:16][C:17]=4[CH:18]=3)[N:23]([CH3:28])[C:22]2=[O:29])=[CH:31][CH:32]=1
Reactant: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Temperature: 0 °C
Reaction time: 3 h
Yield: 108.4 %

Procedure:
(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (230 mg) was dissolved in 10 mL of dry DCM and cooled to 0° C. Boron trichloride (3 mL, 1M solution in hexanes) was added and the mixture stirred at 0° C. for 3 hours. Mixture was concentrated and treated with water/saturated sodium bicarbonate until pH 7. Aqueous mixture was extracted three times with ethyl acetate-THF (9-1) and organic layer combined. The combined organic layer were dried over sodium sulfate and concentrated to provide (3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (153 mg, LC/MS: m/z 474).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](=[S:13])[NH2:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][CH:18](OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[S:13]1[CH:18]=[CH:17][N:12]=[C:11]1[C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:15][CH:14]=1
Reactant: COC(CBr)OC
Reactant: NC(=S)c1ccc(N2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: c1csc(-c2ccc(N3CCOCC3)cc2)n1
Temperature: 95 °C
Yield: 81.2 %

Procedure:
To a solution of 4-morpholinobenzothioamide (2.22 g, 10 mmol) in EtOH (50 mL) were added 2-bromo-1,1-dimethoxyethane (1.69 g, 10 mmol) and p-toluenesulfonic acid (1.90 g, 10 mmol). The reaction mixture was heated at 95° C. overnight, then cooled to rt and filtered. The filter cake was dried to give the title compound as a yellow solid (2.00 g, 81%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BrH:26]>>[Br:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(CO)cc2)cc1
Reactant: Br
Product: CCCCCCCCCCOc1ccc(-c2ccc(CBr)cc2)cc1
Temperature: 115 °C

Procedure:
To 0.81 g (2.51 mmol) of 4-hydroxymethyl-4'-decyloxybiphenyl was added 15 ml of an aqueous solution containing 47% HBr, and then heated at 115° C. for 3 hours. After completion of the reaction, the resultant mixture was extracted with ether and washed with water, which was further washed with an aqueous solution containing saturated NaHCO3 and washed again with water. The reaction product was concentrated and, then, separated by colomun chromatography, to thereby obtain 0.92 g of 4'-bromomethyl-4-decyloxybiphenyl.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:10]([N+:19]([O-:21])=O)=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=1)[C:13]#[N:14])([C:3](OCC)=[O:4])=[O:2].CN(C)C=O.N>O1CCCC1.[Pt]>[C:13]([C:12]1[C:11]([C:17]#[N:18])=[C:10]2[C:9]([NH:8][C:1](=[O:2])[C:3](=[O:4])[N:19]2[OH:21])=[CH:16][CH:15]=1)#[N:14]
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c(C#N)c1[N+](=O)[O-]
Agent: [Pt]
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(=O)c(=O)n(O)c2c1C#N
Yield: 58.4 %

Procedure:
2 g (0.9 mmol) 4-ethoxalylamino-3-nitrophthalonitrile in 15 ml tetrahydrofuran:dimethylformamide: 25% aqueous ammonia (30:10:0.7) was hydrogenated at atm. pressure by using 25 mg 5% Pt-C as a catalyst. The precipitate was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 1N aqueous potassium hydroxide. The filtrate was acidified with concentrated hydrochloric acid. The precipitate was filtered off and washed with water, ethanol and ether to give 0.120 g (76%) of 7,8-dicyano-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 7.7 (2H, dd). IR (KBr): 2240 (m). MS (m/e): 228 (M+, 3%), 184 (100%).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Br:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[CH:10]=[CH:9][C:8]([F:30])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)ccc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Br)c32)ccc1F
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-5-fluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 55 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 10 minutes. After adding 0.3 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 68 mg of the title compound as-a colorless powder.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:18]#[N:19])=[C:8]([C:10]([OH:17])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.[H-].[Na+]>CN(C)C(=O)C>[C:37]([O:36][C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:6]2[C:7]([C:18]#[N:19])=[C:8]([C:10]([OH:17])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:12])[CH3:13])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][CH:24]=1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C#N)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 90.4 %

Procedure:
Following a procedure similar to that described in Example 45(a), but using 282 mg of 2-butyl-4-[1-hydroxy-2-methyl-1-(1-methylethyl)propyl]imidazole-5-carbonitrile (prepared as described in Preparation 30), 409 mg of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and 47 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 5 ml of N,N-dimethylacetamide, 513 mg of the title compound were obtained as a viscous oil.