Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:23])[C:19]([NH2:22])([CH3:21])[CH3:20])[CH3:16].C(N(CC)CC)C.O>CN(C)C=O>[CH2:15]([O:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[NH:22][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(C)(C)N
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
1.28 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 12 ml of N,N-dimethylformamide; 1.16 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 1.20 g of 2-aminoisobutyric acid ethyl ester hydrochloride and 1.00 ml of triethylamine were added, followed by stirring at room temperature for 16 hours. Water was added, the crystal precipitated was collected by filtration; the filtrate was extracted with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was combined with the above crystal collected by filtration and subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:1). The desired fraction was collected and concentrated under reduced pressure to yield 1.20 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH:10]([C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)[OH:11])=[C:4]([CH3:24])[CH:3]=1.CN(C)C=O.[CH2:30](Br)[CH3:31].[H-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH:10]([C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)[O:11][CH2:30][CH3:31])=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1OCc1ccccc1C(O)c1nccn1C
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(c1ccccc1COc1ccc(Cl)cc1C)c1nccn1C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a mixture of 0.34 g (0.9 mmol) of 2-[2-(4-chloro-2-methylphenoxymethyl)-α-hydroxybenzyl]-1-methylimidazole, 3 ml of N,N-dimethylformamide and 0.13 ml (1.8 mmol) of ethyl bromide was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-[2-(4-chloro-2-methylphenoxymethyl)-α-ethoxybenzyl]-1-methylimidazole (0.30 g, 89.9%) as colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[O:47]1[C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=[N:48]1.C(N(CC)CC)C>O1CCCC1>[O:47]1[C:51]([C:52]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:53])=[CH:50][CH:49]=[N:48]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)c1ccno1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccno1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added isoxazole-5-carbonyl chloride (0.066 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 698 [M+H]+.
Reaction SMILES: [C:1](Br)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=[O:25])C.CCCCC[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH2:39]>O1CCOCC1>[C:1]([NH:39][C:38](=[O:25])[C:37]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCN
Reactant: CC(=O)O
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
R-(+)-prolinamide, 11, was converted to R-(+)-N-trilyl prolinamine, 12, using the procedure published in the literature (Hogberg, T., et al., Acta. Chem. Scand. 43, 660-664 (1989)), but using trityl bromide instead of trityl chloride. Compound 12 was reduced to R-(-)-B-trityl prolinamide,13, using sodium borohydride, acetic acid and dioxane. (Florvall, L., et al., J. Med. Chem. 25, 1280-86 (1982). The amine 12 was condensed with theacid 5 on the same basis as the synthesis of compound 6, to afford N-tritylbenzamide (14). Compound 14 was treated with hydrogen chloride in ethanol to give 15 in 65% yield. [α]D =-8.4° C. (C=1.4, MeOH), m.p. 200°-202° C. (hydrochloride salt), FT-IR (KBr) λ3390 (br, NH), 3300 (sharp, NH (amide)), 1660 (strong, C=O). 1H NMR (CDCI3) δ8.29 (br, NH), 7.95 (d, 1 H, J=1.95 Hz), 7.25 (d, 1H, J=1.99 Hz), 3.90 (s, 3H), 3.84 (s, 3H), 3.57 (m, 1H), 3.47 (m, 1H), 3.39 (m, 1H), 3.00 (m, 2H), 1.93 (m, 1H), 1.83 (m, 1H), 1.78 (m, 1H), 1.50 (m, 1H). Anal. calcd, for C14H20CIIO3N: C, H, N. Optical purity=100% retention time 8.75 mL (chiralcel OD, 10% ethanol/hexane, 1 mL/min).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C@H](O)C[C@H](C)[CH2:14][CH:15]=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18]CN(CC)CC.CS(Cl)(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:40]1[CH2:44][O:43][CH2:42][CH2:41]1>CC(O)C.C1C=CC=CC=1>[CH3:18][C@H:40]1[CH:41]=[CH:42][C:10]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH2:14][C@H:44]1[OH:43]
Reactant: CCN(CC)CC
Reactant: C[C@@H]1CC=C(S(=O)(=O)c2ccccc2)[C@H](O)C1
Reactant: C1CCOC1
Agent: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: c1ccccc1
Solvent: CC(C)O
Product: C[C@H]1C=CC(Sc2ccccc2)=CC[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
(4S)-4-Methyl-cyclohexa-1,5-dienesulfonyl)-benzene (29z). To a solution of 24z (355 mg, 1.40 mmol) and Et3N (0.19 mL, 1.40 mmol) in THF (10 mL) at 0° C. was added 0.11 mL (1.40 m-mol) of MsCl dropwise. After stirring at 0° C. for 1 h, the reaction mixture was cooled to −78° C., and freshly prepared LiHMDS (2.8 mL, 1.0 M in THF, 2.8 mmol) was added dropwise over 20 min. After stirring at −78° C. for 15 min, the reaction was quenched with saturated aqueous NH4Cl, diluted with ether, separated, further extracted with ether. The organic layers were washed with brine, dried over Na2SO4, and concentrated via rotary evaporation. The crude residue was purified with flash column chromatography (ethyl acetate/hexanes; 1:3) to provide 303 mg (92% yield) of 29 as a white solid with 99% ee by HPLC (Chiralpak AD 1.0 ml/min; 95:5 Hex:2-propanol, 19.57 min for minor enantiomer, 20.51 min for major enantiomer). Mp 54.0-56.0° C.; 1H NMR (CDCl3, 300 MHz): δ 7.85 (m, 2H), 7.48-7.61 (m, 3H), 6.91 (t, J=4.2 Hz, 1H), 6.01 (d, J=10.3 Hz, 1H), 5.81 (dd, J=10.3, 3.9 Hz, 1H), 2.38-2.57 (m, 2H), 2.15 (ddd, J=17.1, 11.1, 4.5 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ139.9, 138.2, 136.4, 134.5, 133.2, 129.1, 127.6, 117.4, 30.6, 26.9, 19.4. MS(EI) m/z 233 [M−H]+; HRMS (EI) calcd for C13H13O2S, 233.0636; found, 233.0632.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].F[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>CN(C=O)C.O>[N:1]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of (2.3 g, 19.46 mmol) 1H-benzimidazole in DMF (80 mL) at 0° C. was added sodium hydride (0.78 g, 19.46 mol, 60 wt. %) and the reaction mixture was stirred at 0° C. for 30 minutes, then at room temperature for 1 hour. Methyl 4-fluorobenzoate (3.0 g, 19.46 mmol) was then added and the reaction mixture was heated at 85° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with water (300 mL) and extracted with dichloromethane (4×250 mL). The combined organic layers were washed with water (2×250 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:10) provided 3.7 g (76%) of methyl 4-(1H-benzimidazol-1-yl)benzoate as a white solid. To a solution of methyl 4-(1H-benzimidazol-1-yl)benzoate (3.7 g, 14.7 mmol) dissolved in THF/MeOH (1:1, 90 mL) was added 1.0 M aqueous NaOH (0.587 g, 14.67 mmol) and the reaction mixture was allowed to stir for 12 h at room temperature and the solvent removed in vacuo. The residue was diluted with water (100 mL), cooled to 0° C., and the pH was adjusted to 6.0 with 1.0 N aqueous HCl. The resulting precipitate was filtered and dried to afford 3.4 g (96%) of 4-(1H-benzimidazol-1-yl)benzoic acid as a white solid. MS [239.0 m/e (M+H)].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1>CN(C=O)C.O>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:13][CH2:12][CH2:11][N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1
Reactant: Oc1ccncc1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(CCCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
Sodium hydride (946 mg of a 50% suspension in mineral oil, 19.7 mmol) was added to a solution of 4-hydroxypyridine (1.88 g, 1 9.7 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(3 -Bromopropoxy)tetrahydropyran (4.0 g, 17.9 mmol), (J. Chem. Soc. 1963, 3440), was added and the mixture heated at 100° C. for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 1-[3-(tetrahydropyran-2-yloxy)propyl]-1,4-dihydro-4-pyridone (1.5 g, 35%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(N)c(Nc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A mixture of 4-methyl-N2-phenylbenzene-1,2-diamine (600 mg, 3.03 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (861 mg, 4.55 mmol), HOAt (453 mg, 3.33 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (874 mg, 4.55 mmol) and 4-methylmorpholine (0.74 mL, 6.67 mmol) in anhydrous DCM (20 mL) was stirred at RT for 1.5 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in AcOH (10 mL) and heated to 70° C. for 20 h. After cooling to RT, volatiles were removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with a saturated solution of NaHCO3 (2×100 mL). The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was absorbed onto HM-N and the solvent was removed in vacuo. The product was purified by column chromatography (Si—PCC, gradient 10-60% EtOAc in cyclohexane) affording [(S)-1-(6-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (969 mg, 92%). LCMS: RT 3.10 min [M+H-tBu]+ 352.1.
Reaction SMILES: [NH:1]([CH2:5][CH2:6]O)CCO.II.[C:10]1(=[O:16])O[C:13](=O)[CH:12]=[CH:11]1.P(=O)(O)(O)O.[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N-:1]=[C:10]=[O:16].[N-:1]=[C:10]=[O:16].[C:22]1([CH2:28][C:6]2[CH:5]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccccc1
Reactant: OCCNCCO
Reactant: O=C1C=CC(=O)O1
Agent: II
Agent: O=P(O)(O)O
Product: [N-]=C=O
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
The above amounts of diethanolamine and iodine were added to the above amount of soybean oil with stirring. The mixture was stirred for 23 hours at a temperature between about 180° F. and about 227° F. Then, the above amounts of maleic anhydride, toluene and phosphoric acid were added with stirring. The mixture was refluxed for 8 hours using a Dean-Stark distilling trap, then distilled out of solvent to give a liquid soybean oil based polyol with a hydroxyl number of 52. A reaction mixture of about 10.00 grams of the polyol and the above indicated amount of diphenylmethane diisocyanate yielded a solid soybean oil based polyurethane material.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[CH:25][N:24]=1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:28]3[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1ncccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1ncccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 63.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2-Methoxy-pyridine-3-carbaldehyde (22.3 mg, 0.163 mmol) were reacted to produce 43 mg (64%) of the title compound. mp: 201° C., 1H NMR (300 MHz, DMSO-d6): 12.64 (s, 1H), 8.45 (d, J=8 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.75 (s, 1H), 7.22 (m, 2H), 7.17 (d, J=8 Hz, 1H), 6.39 (s, 1H), 6.36 (s, 1H), 5.23 (t, J=8 Hz, 1H), 4.05 (s, 3H), 2.89 (s, 1H), 2.78 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS: 455, 457 (M+H), HPLC: 2.39 min (G method).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH2:29])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Si]([N:43]=[C:44]=[O:45])(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:29][C:44]([NH2:43])=[O:45])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)N=C=O
Reactant: NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
A solution of (S)-(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methanamine (Compound 77, 0.16 mmol), DIPEA (207 mg, 1.6 mmol) and TMSNCO (184 mg, 1.6 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at room temperature for 70 hours. The reaction mixture was poured into saturated NaHCO3 aqueous and extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to afford the title compound. MS (m/z): 434 (M+H)+.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][CH:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.O>ClCCl>[CH3:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CC1CCCN1
Solvent: ClCCl
Solvent: O
Product: CC1CCCN1c1ccc([N+](=O)[O-])cc1N
Temperature: 100 °C

Procedure:
5 g (32.03 mmol) of 2-fluoro-5-nitroaniline and 4.9 ml (48.04 mmol) of 2-methylpyrrolidine (racemic) are placed in a screw reactor. The reactor is closed and the mixture is heated at 100° C. for 5 h. After cooling, the mixture is taken up with 100 ml of water and 100 ml of dichloromethane. The organic phase is separated, washed with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The resulting product is used as it is in the subsequent reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[N:13]([CH3:23])[C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][C:17]([F:22])=[CH:16][CH:15]=3)(=[O:11])=[O:10])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[N:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[N:13]([CH3:23])[C:14]4[C:19]([C:20]=3[CH3:21])=[CH:18][C:17]([F:22])=[CH:16][CH:15]=4)(=[O:11])=[O:10])=[C:4]([C:24]([F:25])([F:27])[F:26])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C)c2ccc(F)cc12
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)n(C)c2ccc(F)cc12
Yield: 58.2 %

Procedure:
This product was prepared in analogy to Example 2 starting from 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.100 g), 4-pyridineboronic acid (0.040 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (1.0 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.025 g) to obtain the title compound (0.058 g) as a brownish foam. MS (ISN): 462.4 (M−H)−
Reaction SMILES: [C:1]([CH:3]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]([CH3:18])([CH3:17])[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)#[N:2].[O-]CC.[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][C:3]1([C:1]#[N:2])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]([CH3:18])([CH3:17])[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: CC1(C)c2ccccc2C(C#N)c2ccccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1(C#N)c2ccccc2C(C)(C)c2ccccc21
Yield: 89.5 %

Procedure:
9-cyano-10,10-Dimethyl-9,10-dihydroanthracene [9] (0.8 g, 3.42 mmol) was added to sodium ethoxide prepared from Na metal (0.110 g, 4.80 mmol) and ethanol (10 mL) and heated under reflux for one hour leading to the development of a greenish brown solution. The solution was then cooled in an ice bath and ethyl bromoacetate (0.80 g, 4.80 mmol) was added dropwise via a syringe. The resulting mixture was then heated at reflux (4 h) and filtered. The solid residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by medium pressure liquid chromatography using pet. ether: EtOAc (9:1) as eluent to give 0.978 g (74%) of the product as a colorless oil. 1H NMR (CDCl3)d: 0.98-1.06 (t, 3H, CH3), 1.64-1.67 (d, J=9Hz, 3H, CH3), 1.71-1.74 (d, J=9 Hz, 3H, CH3), 3.04-3.07 (d, J=9Hz, 2H, CH2), 3.86-3.94 (q, 2H, CH2), 7.29-7.77 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 14.39, 33.85, 35.21, 38.37, 52.29, 61.38, 123.17, 127.53, 127.84, 128.17, 129.48, 130.97, 143.23, 167.97.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH3:18])=[C:10]([CH:14]=1)[C:11]([NH2:13])=[NH:12].[CH2:19]([CH:21]([C:26](=O)[CH2:27][CH3:28])[C:22](OC)=[O:23])[CH3:20]>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH3:18])=[C:10]([C:11]2[NH:13][C:22](=[O:23])[C:21]([CH2:19][CH3:20])=[C:26]([CH2:27][CH3:28])[N:12]=2)[CH:14]=1
Reactant: CCC(=O)C(CC)C(=O)OC
Reactant: CCCOc1ccc(-c2nnco2)cc1C(=N)N
Product: CCCOc1ccc(-c2nnco2)cc1-c1nc(CC)c(CC)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 8 with methyl 2-ethyl-3-oxovalerate in the same manner as that of example 1. 1H NMR (CDCl3) δ: 8.69 (1H, d), 8.51 (1H, dd), 7.05 (1H, d), 4.14 (2H, t), 2.69 (4H, m), 1.92 (2H, m), 1.31 (3H, t), 1.21 (3H, t), 1.12 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:14][C:15]([CH:17]=[CH2:18])=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[CH:14][CH:15]=[C:17]2[CH3:18]
Reactant: C=CC(C)=O
Reactant: Nc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccnc2ccc(Br)cc12

Procedure:
Stir a solution of 4-bromo-phenylamine (1 eq), in 1,4-dioxane and cool to approximately 12° C. Slowly-add sulfuric acid (2 eq) and heat at reflux. Add methylvinyl ketone (1.5 eq) dropwise into the refluxing solution. Heat the solution for 1 hour after addition is complete. Evaporate the reaction solution to dryness and dissolve in methylene chloride. Adjust the solution to pH 8 with 1 M sodium carbonate and extract three times with water. Chromatograph the residue on SiO2 (70/30 hexane/ethyl acetate) to obtain the desired subtitled intermediate. MS ES+ m/e =158.2 (M+1).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](S)=[N:10][C:9]=2[CH:14]=1.O>C(Cl)(Cl)Cl.CCOCC>[Br:1][C:11]1[S:12][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:14][C:9]=2[N:10]=1
Reactant: COc1ccc2sc(S)nc2c1
Reactant: BrBr
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2sc(Br)nc2c1
Reaction time: 0.5 h

Procedure:
A solution of bromine (3.6 eq) in chloroform (0.75M) was added dropwise over a period of 1 hr to a stirred suspension of 5-methoxy-2-mercaptobenzothiazole (1 eq) in chloroform at 0° C. The mixture was stirred for 30 min before it was added slowly to water and stirred for further 20 min. The mixture was filtered to remove a cream solid. The organic phase was dried and evaporated to leave a brown solid. The brown solid was dissolved in ether and filtered. The residue was washed with ether and the filtrate and washings were combined and evaporated, chromatographed (4:1 hexanes and ethyl acetate) to give the title compound as a pale yellow solid. MS: MH+=244