Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:39][CH2:40][CH3:41])[C:5]1[CH:6]=[C:7]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:35](OC)=[O:36])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)[CH:8]=[CH:9][CH:10]=1)[CH3:2].C(OC(OCC)C1C=C(C2C(C3C=CC=C(C(OCC)OCC)C=3)C(=O)C3C(C(OCC)=O)=CC=CC=3N2)C=CC=1)C.O.[NH2:85][NH2:86]>CO>[CH2:40]([O:39][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[C:7]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:85][NH:86][C:35](=[O:36])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])[CH:22]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:41]
Reactant: CCOC(OCC)c1cccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2cccc(C(OCC)OCC)c2)c1
Reactant: NN
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1cccc(C(OCC)OCC)c1)C(c1cccc(C(OCC)OCC)c1)N2
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(OCC)OCC)c2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of methyl 2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (370 mg, 0.59 mmol) in hydrazine monohydrate (5 mL) and methanol (5 mL) was stirred at 40° C. for 2 hr. The mixture was cooled to room temperature and filtered to give 8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (250 mg, yield 77%) as a light yellow solid. LC-MS (ESI) m/z: 544 (M+1)+.
Reaction SMILES: [N:1]1([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:21][O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH2:25]>>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:25][C@H:24]([C:23]([O:22][CH3:21])=[O:28])[CH2:26][OH:27])=[O:16])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Product: COC(=O)[C@H](CO)NC(=O)c1ccc(-n2cnc3ccccc32)cc1

Procedure:
Using essentially the same procedures described in Example 1, step 2, and Example 2, and employing methyl 4-(1H-benzimidazol-1-yl)benzoate and serine methyl ester HCl as reactants, the title compound was obtained and identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 8.12 (s, 1H), 8.05 (d, J=7.2 Hz, 2H), 7.88-7.90 (m, 1H), 7.69-7.71 (m, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.51-7.57 (m, 2H) 7.36-7.38 (m, 2H), 7.22-7.24 (m, 1H), 4.92-4.94 (m, 1H), 4.10-4.23 (m, 4H), 3.86 (s, 3H), 3.6 (s, 3H). LCMS (ESI+) 340 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C(OO)(=[O:18])C>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)COc1ncc(B(O)O)cc1Cl
Reactant: CC(=O)OO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)COc1ncc(O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 138.6 %

Procedure:
To a suspension of 5-chloro-6-isobutoxypyridin-3-ylboronic acid (3.02 g, 13.1 mmol) in acetic acid/water (1:1 20 mL) cooled to 0° C. was slowly added peracetic acid (3.9 mL, 20.0 mmol) and the reaction mixture was maintained at 0° C. for 1.5 hours and then at room temperature for 1 hour. Additional peracetic acid (3.9 mL, 20.0 mmol) was added and the reaction stirred at room temperature for 40 minutes after which time the suspension dissolved. The reaction mixture was quenched with sodium thiosulphate solution (15 mL) and stirred for 5 minutes. The mixture was extracted with ethyl acetate (2×30 mL) and the combined organic extracts washed with brine (30 mL), dried over magnesium sulphate and filtered. The solvent was removed under reduced pressure to give a yellow oil (3.66 g). Purification by flash column chromatography (Biotage™ 50 g silica cartridge) eluting with a gradient of dichloromethane/methanol (100% to 90% to 80%) gave the title compound (1.94 g, 73%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)[CH:2]=C.C[OH:13]>C(Cl)Cl>[O:13]=[CH:2][CH2:1][C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1
Reactant: CO
Reactant: C=CCc1ccc(C#N)cn1
Solvent: ClCCl
Product: N#Cc1ccc(CC=O)nc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
A mixture of 6-(Prop-2-en-1-yl)pyridine-3-carbonitrile (4.8 g, 33 mmol) in 80 mL of DCM and 20 mL of MeOH was cooled to −70° C. Ozone was bubbled through the mixture until the mixture turned blue (about 20 minutes). The excess of ozone was removed by flush with N2 flow until the mixture turned colorless. 5 mL of Me2S was added to the mixture which was then warmed slowly to room temperature and stirred for 2 hours. The solvent was removed under vacuum below 30° C. to afford the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([Br:10])=[CH:5][C:3]=1[OH:4].[OH-].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[C:6]([Br:10])=[CH:5][C:3]=1[OH:4]
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1cc(Br)c(O)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1cc(Br)c(O)cc1Br
Temperature: 55 °C
Reaction time: 10 h
Yield: 60 %

Procedure:
2,5-Dibromohydroquinone 3 (40.2 g, 0.15 mol) was dissolved in a solution of sodium hydroxide (9.2 g, 0.23 mol) in 1.5 L of absolute ethanol at room temperature under nitrogen atmosphere. The reaction mixture was warmed to 50-60° C. with constant stirring. The dodecylbromide (36 ml, 0.15 mol) was added drop wise to the above reaction mixture at 60° C. After 10 h of stirring under nitrogen atmosphere, the reaction mixture was cooled and the precipitate formed was filtered and washed with methanol. This precipitate was identified as dialleylated-2,5-dibromohydroquinone as a side product. The filtrate was evaporated to remove the solvent. 2 L of distilled water was added to the residue and the mixture was acidified with 36% HCl, boiled gently for 1 h and cooled. The resulting precipitate was collected by filtration, washed with water and dried in vacuo. The crude product was purified by column chromatography using a mixture of solvents (CH2Cl2: hexanes, 4:6) to get the pure product in 60% yield.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[N:4]=1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][S:25]([CH:22]3[CH2:24][CH2:23]3)(=[O:27])=[O:26])=[CH:14][CH:13]=2)[N:4]=1
Reactant: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)C1CC1

Procedure:
The title compound was prepared from ({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine and cyclopropanesulphonyl chloride using a similar procedure to that described for Example 88.
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][C@H:37]([OH:39])[C@@H:36]([OH:40])[C@H:35]([OH:41])[C@H:34]1[CH2:42][OH:43]>CN(C=O)C>[C:1]([O:22][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH:37]([OH:39])[CH:36]([OH:40])[C@H:35]([OH:41])[CH:34]1[CH2:42][OH:43])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1CCCCl
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OCCCN1CC(O)C(O)[C@H](O)C1CO
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic acid 6 (6.94 g, 22.95 mmol) in DMF (25 mL) was added K2CO3 (12.69 g, 91.78 mmol) at room temperature and the mixture was stirred for 30 min. Then a solution of hydrochloride salt of (2R,3R,4R,5S)-1-(3-chloropropyl)-2-(hydroxymethyl)piperidine-3,4,5-triol 5 (5.5 g, 22.95 mmol) in DMF (25 mL) was added to the reaction mixture and the mixture was heated at 60° C. for 36 h. The reaction mixture was then filtered through a celite pad, washed with DCM (100 mL). The filtrate was concentrate under reduced pressure to get crude which was purified by column chromatography using 100-200 mesh silica gel and eluting with 6% methanol in DCM to afford 3-[(3R)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]propyl (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoate, compound 7 (4.5 g, 39%) as brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Br[CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CCOC(=O)CCCCBr
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: CCOC(=O)CCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and ethyl 5-bromovalerate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (62%) as a gummy material: 1H NMR (300 MHz, CDCl3) δ 7.28 (t, 1H), 7.14 (d, 1H), 7.03 (t, 1H), 6.88 (d, 1H), 6.48 (s, 1H), 6.13 (s, 1H), 5.84 (d, 2H), 4.76 (ABq, 2H), 4.07 (q, 2H), 3.87-3.65 (m, 2H), 2.35 (t, 2H), 1.80-1.64 (m, 4H), 1.20 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.4, 173.1, 155.9, 148.8, 142.3, 142.2, 132.5, 128.9, 124.04, 123.3, 119.5, 108.6, 103.0, 101.5, 93.6, 80.5, 60.4, 58.2, 39.9, 33.7, 26.8, 22.2, 14.2; MS (ES+) m/z 432.09 (M+23).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[N:16]=[C:15]2[CH:27]=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[N:16]=[C:15]3[CH:27]=[O:28])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1nn(C2CCCCO2)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (258 mg, 1.83 mmol, 1.00 equiv), (R/S) 5-hydroxy-1-(oxan-2-yl)-1H-indazole-3-carbaldehyde (300 mg, 1.22 mmol, 0.67 equiv) and Cs2CO3 (1.2 g, 3.68 mmol, 2.01 equiv) in 1,4-dioxane (25 mL) was stirred at 100° C. for 4 h. The reaction mixture was cooled to room temperature and then diluted with 50 mL of H2O. The resulting mixture was extracted with 3×200 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-13% of ethyl acetate in petroleum ether to give 350 mg (52%) of (R/S) 5-(4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a light yellow solid. 1H-NMR (300 MHz, CDCl3): δ 10.3 (s, 1H), 8.23-8.18 (m, 2H), 8.01 (s, 1H), 7.78-7.75 (m, 1H), 7.27-7.23 (m, 1H), 7.04-7.00 (m, 1H), 5.89-5.85 (m, 1H), 4.06-4.01 (m, 1H), 3.85-3.77 (m, 1H), 2.60-2.52 (m, 1H), 2.21-2.17 (m, 2H), 1.86-1.74 (m, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:22](N)([NH2:25])(=[O:24])=[O:23]>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:22]([NH2:25])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Reactant: NS(N)(=O)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)S(N)(=O)=O)CC1

Procedure:
A solution of 2.05 g of 4-benzylamino-piperidine-1-carboxylic acid tert.-butyl ester and 3.39 g of sulfamide in 100 ml of 1,2-dimethoxy-ethane is refluxed for ca. 10 hours. From the mixture obtained solvent is evaporated, the evaporation residue obtained is treated with EtAc and unsoluble parts are filtered off. The filtrate obtained is subjected to chromatography on silica gel. 4-[N-(Aminosulfonyl)-benzylamino]-piperidine-1-carboxylic acid tert.butylester is obtained. mp 140-142°. 1H-NMR (DMSO) δ: 7.30-7.41 (s/m, 9+2H), 1.64 (m, 2H), 2.53-2.72 (broad, 2H), 3.71 (tt, 1H), 8.83-8.96 (broad, 2H), 4.26 (s, 2H, CH2), 6.86 (bs, 2H, NH), 7.19 (t, 1H), 7.28 (t, 1H), 7.36 (d, 1H). 13C-NMR (DMSO) δ:28.51, 30.13, 43.35, 47.11, 56.52, 79.12, 127.06, 127.48, 128.49, 140.59, 154.156.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.BrC1C2N(C=CN=2)N=C(Cl)C=1.[O:36]1[CH2:39]C(N2CCN(C3C=CC(N)=NC=3)CC2)[CH2:37]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([CH:24]4[CH2:39][O:36][CH2:37]4)[CH2:22][CH2:23]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Nc1ccc(N2CCN(C3COC3)CC2)cn1
Reactant: CN1CCN(c2ccc(Nc3cc(Cl)nn4ccnc34)nc2)CC1
Agent: Clc1cc(Br)c2nccn2n1
Product: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nccn2n1
Yield: 77 %

Procedure:
Following the procedures as described for compound 104b, 8-bromo-6-chloroimidazo[1,2-b]pyridazine 104a (233 mg, 1.0 mmol), and 5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-amine (234 mg, 1.0 mmol) were reacted to give 105a as a white solid (296 mg, 77%). LCMS: [M+H]+ 386
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24][CH3:25].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24][CH3:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(Cc2ccccc2)c1C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
A 24.1 ml (38.6 mmole) of n-butyllithium.hexane solution was added dropwise to 10.0 g (38.6 mmole) of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene dissolved in anhydrous tetrahydrofuran (100 ml), under an atmosphere of argon at -40° C. over the period of 10 minutes, followed by stirring for another 20 minutes. Then, 3.32 g (38.6×0.6 mmole) of cuprous bromide was added, followed by stirring at -40° to -20° C. for 1 hour. After addition of a solution of 6.60 g (38.6 mmole)of benzyl bromide in tetrahydrofuran (15 ml), the cooling bath was removed, the reaction solution was stirred at 70° C. for 1 hour and cooled with ice, followed by addition of 1N hydrochloric acid (50 ml) and stirring. The tetrahydrofuran was distilled off under reduced pressure, and isopropyl ether was added to the residue. The insoluble matter was filtered through a bed of Hyflo Supercell, and the isopropyl ether layer was separated out, washed with water and aqueous sodium chloride solution successively, dried (magnesium sulfate) and evaporated. The residual solution was distilled under reduced pressure to give 8.62 g (83%) of 1-benzyl-2,5-dimethoxy-3,4,6-trimethylbenzene, b.p.140°-142° C. (0.3 torr) and m.p. 70° to 71° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([CH2:9][C@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]([O:13][CH3:14])=[O:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:23]=O>CO.[Pd]>[C:19]([O:18][C:16]([NH:15][C@@H:10]([CH2:9][CH:4]([CH2:3][CH2:2][NH:1][CH3:23])[C:5]([O:7][CH3:8])=[O:6])[C:11]([O:13][CH3:14])=[O:12])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: C=O
Reactant: COC(=O)C(CCN)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CNCCC(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.4 %

Procedure:
The crude (4S)-dimethyl 2-(2-aminoethyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (5.00 g, 15.7 mmol) was dissolved in methanol (100 mL) and 40% formaldehyde (1.0 g, 14 mmol) and Pd/C (0.8 g) were added. The mixture was stirred under H2 atmosphere (20 psi) for 8 h at ambient temperature. The mixture was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure to afford (2S)-dimethyl 2-((tert-butoxycarbonyl)amino)-4-(2-(methylamino)ethyl)pentane dioate (5.0 g, crude) as a dark brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:18][CH2:17][N:16]3[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)[C:3]=1[F:19].O.[NH2:21][NH2:22]>O1CCOCC1>[F:19][C:3]1[C:4]([N:9]2[CH2:18][CH2:17][N:16]3[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)=[N:5][C:6]([CH3:8])=[N:7][C:2]=1[NH:21][NH2:22]
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NN)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (9aS)-8-(6-chloro-5-fluoro-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (assumed 31.03 g, 108.2 mmol) in dioxane (430 mL) was added hydrazine monohydrate (31 mL). The mixture was heated and stirred at 80° C. overnight, and then at 85° C. for 7 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (500 mL) and washed with saturated aq. NaHCO3 (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and this organic phase was washed with saturated aq. NaHCO3 (100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and dried under high vacuum overnight to provide (9aS)-8-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (27.98 g, 92% yield for 2 steps) as a light yellow solid. LCMS: (M+H)+: 283.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH:11]([C:13]1[CH:14]=[C:15]([C:30]([O:32][CH3:33])=[O:31])[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])[CH3:12]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([NH:5][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([O:32][CH3:33])=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(C(C)Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: Nc1cccc(Cl)c1F
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)Nc2cccc(Cl)c2F)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
3-chloro-2-fluoroaniline (0.239 mL, 2.17 mmol) was added to a stirred suspension of methyl 8-(1-bromoethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (215 mg, 0.54 mmol) dissolved in DCM (3 mL) at room temperature. The resulting suspension was stirred for 16 hrs then the temperature was increased to 50° C. for 16 hrs. The crude product was purified by flash chromatography on silica gel eluting with 5% methanol in DCM. The solvent was evaporated to dryness to afford methyl 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (206 mg, 82%) as a white solid. Mass Spectrum: M+H+ 461.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5].[CH:7]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16](=[O:19])[CH:17]=[CH2:18])([CH3:9])[CH3:8].[NH4+].[Cl-]>C1COCC1>[CH:7]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16](=[O:19])[CH2:17][CH2:18][CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5])([CH3:9])[CH3:8]
Reactant: C=C(C)CCBr
Reactant: C=CC(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)CCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
47 mg (1.9 mmol) of Mg chips is stirred at room temperature (or while being heated intermittently) in 1.5 ml of absolute THF with 283 mg (1.9 mmol) of 4-bromo-2-methyl-1-butene, until all Mg has gone into solution. This Grignard solution is mixed at -30° C. with a suspension of 197 mg (1.00 mmol) of CuBr--Me2S in 1.5 ml of absolute THF. It is stirred for 30 minutes at this temperature; 117 mg (0.64 mmol) of 20 on 2 ml of absolute THF is added; it is stirred for 16 hours at -10° C. and hydrolyzed with 10 ml of saturated NH4Cl solution. It is extracted three times with 20 ml of Et2O each. After drying on MgSO4, the solvent is removed. By flash-chromatographic purification with pentane/Et2O (15:1), 128 mg (0.51 mmol, 79%) of 21a is obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([C:27]([OH:29])=O)=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:22])([F:24])[F:23])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:29]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Reactant: NCCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCCCO)c(F)cc21
Yield: 75.4 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (4-hydroxy-butyl)-amide (44 mg) was prepared by General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (50 mg), 4-amino-1-butanol (12 mg), HBTU (53 mg), and DIEA (31 uL). LC/MS: m/z 497.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.34 (bs, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.89-7.59 (m, 2H), 7.58-7.40 (m, 1H), 7.36 (d, 1H), 4.44 (s, 1H), 3.62 (s, 3H), 3.49-3.39 (m, 2H), 3.32-3.20 (m, 2H), 1.67-1.36 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH2:15]([C:17]([O-:19])=[O:18])[CH3:16].C(O)(=O)C.[I:24]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:24][C:7]1[CH:6]=[CH:5][C:4]2[NH:3][C:2](=[O:1])[C:11]3[NH:12][CH:13]=[CH:14][C:10]=3[C:9]=2[CH:8]=1.[CH2:15]([C:17]([O-:19])=[O:18])[CH3:16]
Reactant: II
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Agent: [Ag+2]
Agent: CCC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.7 %

Procedure:
1.49 g (4.7 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with one equivalent of acetic acid is added to a suspension of 1.61 g (5.17 mmol) of diiodine and 1.31 g (5.17 mmol) of silver sulfate in anhydrous ethanol (100 mL). The reaction mixture is stirred at room temperature for 6 hours then the solvents are evaporated under vacuum. The residue is taken up in water and the product is extracted copiously with a mixture of ethyl acetate/methanol 95/5. The organic phases are dried over magnesium sulfate, filtered on celite and evaporated under vacuum to give 1.4 g (78%) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.