Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH:31]3[CH:29]([CH2:30]3)[CH2:28]2)[CH:24]=[N:25][CH:26]=1)=[O:14])(C)(C)C.ClC(O[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=O.[OH-].[Na+]>C(Cl)Cl.O>[CH2:37]([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:28][CH:29]3[CH:31]([CH2:30]3)[CH2:32]2)[CH:24]=[N:25][CH:26]=1)=[O:14])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(N2CC3CC3C2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CC[C@H]1COc1cncc(N2CC3CC3C2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.7 %

Procedure:
A mixture of CF3COOH, H2O, and CH2Cl2 (10:1:40, 153 mL) was added to a 250 mL round-bottom flask containing 3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-azabicyclo[3.1.0]hexane (6.00 g, 15.8 mmol). The flask was capped with a glass stopper, and the reactants were stirred at room temperature for 14 h. The reaction mixture was concentrated with a rotary evaporator (bath up to 35° C.) and was further dried with an oil pump (35° C.). The residue was dissolved in water (30 mL) and THF (100 mL). The mixture was stirred in an ice bath. Aqueous NaOH solution (5 N, approximately 20 mL) was added dropwise to adjust the pH of the solution to 10 (as monitored by spotting a few μL of the solution on pH paper). Benzyl chloroformate (4.9 mL, 31.6 mmol, 2.0 equiv.) was added dropwise over 30 min. During the addition, the pH of the solution was kept between 9 and 10 by gradually adding 5 N NaOH solution (approximately 20 mL). The pH of the solution was adjusted to 10 at the end of the addition. The ice bath was removed, and the mixture was stirred at room temperature for 18 h. The product was extracted into EtOAc (150+2×100 mL). The combined organic phases were concentrated, and the residue was purified by CC (SiO2, 25×3.8 cm, EtOAc/hexanes 3:1) to give the product as a colorless oil (4.00 g, 67%). 1H NMR (CDCl3, 500 MHz) δ 7.68 (br s, 1H), 7.63 (s, 1H), 7.38-7.26 (m, 5H), 6.40 (br s, 1H), 5.13 (s, 1H, J=12.2 Hz), 5.09 (s, 1H, J=8.8 Hz), 4.65-4.58 (m, 1H), 4.50-4.23 (m, 1H), 4.17-4.10 (m, 1H), 4.06-3.96 (m, 2H), 3.51 (d, 2H, J=8.8 Hz), 3.40 (d, 1H, J=8.3 Hz), 2.47-2.32 (m, 2H), 1.70 (t, 2H, J=3.4 Hz), 0.79 (td, 1H, J=7.6, 4.9 Hz), 0.33 (q, 1H, J=3.8 Hz). MS (EI) m/z 379 (M+, 10%), 288 (1.9%), 177 (4.8%), 176 (9.1%), 175 (11%), 148 (5.0%), 91 (100%). The product of a second run solidified on standing at room temperature; mp 80-81.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[CH2:19]CC#N)=[CH:4][CH:3]=1.[CH2:27]([OH:29])[CH3:28].[OH-:30].[Na+]>O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[CH2:19][CH2:28][C:27]([OH:30])=[O:29])=[CH:4][CH:3]=1
Reactant: CC(C)(CCC#N)Cc1nc2cc(F)ccc2n1Cc1ccc(Cl)cc1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)(CCC(=O)O)Cc1nc2cc(F)ccc2n1Cc1ccc(Cl)cc1

Procedure:
3 g of 5-[1-(4-chlorobenzyl)-5-fluorobenzimidazol-2-yl]-4,4-dimethylvaleronitrile, prepared in Example 157, are dissolved in a mixture composed of 30 ml of water and 30 ml of ethanol. 3 g of sodium hydroxide pellets are added and the mixture is refluxed for 15 hours. After cooling, 100 ml of water are added and the solution obtained is washed with ether. The aqueous phase is acidified by having sulfur dioxide bubbled through it and the crystals obtained are filtered off, washed with water and then with isopropyl ether and dried to give 2.3 g of 5-[1-(4-chlorobenzyl)-5-fluorobenzimidazol-2-yl]-4,4-dimethylpentanoic acid in the form of crystals melting at 184°-6° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[OH:10])[CH3:2].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20]>CN(C1C=CN=CC=1)C.ClCCl>[C:19](=[O:20])([O:21][CH3:22])[O:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(F)ccc1O
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(F)ccc1OC(=O)OC
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2-Ethyl-4-fluorophenol (2 g, 14.27 mmol) and DMAP (87 mg, 0.71 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (4 mL, 28.5 mmol), cooled to 0° C., then treated with methyl chloroformate (2.02 g, 1.65 mL, 21.40 mmol) and allowed to warm to room temperature over 2 h. The reaction was quenched with water, the layers separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (20% ethyl acetate/hexane) provided 2-ethyl-4-fluorophenyl methyl carbonate (2.4 g, 85% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.26-7.17 (m, 2H), 7.12-7.07 (m, 1H), 5.76 (s, 1H), 3.83 (d, J=4.3 Hz, 2H), 2.54-2.48 (m, 2H), 1.12 (t, J=7.6 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-])=[O:2].[N:15]#[C:16][NH2:17].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:14]=[C:16]([NH2:17])[N:15]=1)[CH2:8][CH2:9][CH2:10][CH2:11]3
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CCCC2
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)CCCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
A mixture of nitroaniline 174 (0.77 g, 4.0 mmol) and cyanamide (0.68 g, 16.0 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (5 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (100 mL) and filtered. The precipitate was washed with water (3×20 mL), washed with ether (10 mL) and dried. The residue was purified by chromatography, eluting with 5% MeOH/DCM, to give amine 175 (0.30 g, 35%) as a yellow powder: mp (MeOH/DCM) 270-274° C.; 1H NMR [(CD3)2SO] δ 7.83 (s, 1H, H-10), 7.23 (s, 1H, H-5), 7.11 (br s, 2H, NH2), 2.82-2.89 (m, 4H, H-6, H-9), 1.72-1.77 (m, 4H, H-7, H-8); 13C NMR [(CD3)2SO] δ 159.8, 146.9, 146.8, 136.2, 128.0, 124.0, 118.1, 29.1, 28.5, 22.0, 21.8. Anal. calcd for C11H12N4O.¼H2O: C, 59.9; H, 5.7; N, 25.4. Found: C, 60.4; H, 5.5; N, 25.5%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)[CH3:2].[S:16]([Cl:20])(=O)(=[O:18])[OH:17]>>[Cl:20][S:16]([C:5]1[CH:6]=[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])(=[O:18])=[O:17]
Reactant: CCOC(=O)Cc1ccc(OCC)cc1
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)Cc1ccc(OCC)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
After addition of 208 mg(1.0 mmol) of ethyl 2-(4-ethoxyphenyl)acetate to 0.2 ml(3.0 mmol) of chlorosulfuric acid dropwise at 0° C., the mixture was warmed to room temperature and stirred for one hour, and then poured into ice water. After the resultant was extracted with ethyl acetate, the extracted ethyl acetate solution was washed with water three times. The solvent was removed under reduced pressure to give 110 mg of the title compound in a yield of 34%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([N:26]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:37]([O-:39])=[O:38].NN>C(O)C>[NH2:26][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[N:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[CH:5]=[CH:4][C:3]([N+:37]([O-:39])=[O:38])=[C:2]([NH2:1])[N:7]=2)=[N:13][CH:14]=1
Reactant: Nc1nc(NCCNc2ncc(N3C(=O)c4ccccc4C3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Product: Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]isoindoline-1,3-dione and 20 mmol of hydrazine were stirred in ethanol at 75° C. for two hours and then purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([O:14][CH2:15][CH2:16]OC1C=CC=C(C)C=1C)=[O:13].Br[CH:27]1C2C1CNC1C=CC=CC=12.CC1C(C)=CC=CC=1O.[Cl:47][C:48]1[C:49]([CH3:55])=[C:50]([OH:54])[CH:51]=[CH:52][CH:53]=1>>[Br:1][C:2]1[C:3]2[CH:4]3[CH2:27][CH:5]3[CH2:6][N:7]([C:12]([O:14][CH2:15][CH2:16][O:54][C:50]3[CH:51]=[CH:52][CH:53]=[C:48]([Cl:47])[C:49]=3[CH3:55])=[O:13])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1c(O)cccc1Cl
Reactant: Cc1cccc(OCCOC(=O)N2CCCc3c(Br)cccc32)c1C
Reactant: BrC1C2CNc3ccccc3C12
Agent: Cc1cccc(O)c1C
Product: Cc1c(Cl)cccc1OCCOC(=O)N1CC2CC2c2c(Br)cccc21

Procedure:
The title compound was prepared using a procedure analogous to 2-(2,3-dimethylphenoxy)ethyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate except that 5-bromo-1,2,3,4-tetrahydroquinoline, HCl salt was replaced with bromo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinoline, and 2,3-dimethylphenol was replaced with 3-chloro-2-methylphenol. LCMS, [M+Na]+=460.0.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@H:15]3[C@H:17]([NH2:20])[CH2:18][CH2:19][C@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH:23](=O)[C:24]([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C.C([BH3-])#N>ClCCl>[CH2:23]([NH:20][C@H:17]1[C@H:15]2[C@H:14]([CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)CN[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3aS,4R,6aR)-2-(3-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (100 mg, 0.299 mmol) from Step A of Example 254 and pivalaldehyde (0.043 mL, 0.389 mmol) were combined in dichloromethane (1 mL). Acetic acid (0.3 mL) was added. The reaction was stirred at room temperature for 20 minutes, then PS-cyanoborohydride (147 mg, 0.359 mmol) was added. The reaction was stirred at room temperature for 72 hours, then filtered. The reaction mixture was washed with 1 N NaHCO3 and concentrate in vacuo. The crude material was purified using a 12 g silica gel cartridge with a gradient of 0-4% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.40-8.41 (bs, 1H), 8.22-8.25 (m, 1H), 7.92-7.95 (m, 1H), 7.75 (t, J=7.8 Hz, 1H), 3.42 (dd, J=9.8, 3.1 Hz, 1H), 3.17 (dd, J=9.6, 3.1 Hz, 1H), 3.06-3.10 (m, 1H), 2.96 (dd, J=9.6, 7.7 Hz, 1H), 2.74-2.77 (m, 1H), 2.48-2.53 (m, 1H), 2.30 (d, J=11.3 Hz, 1H), 2.22-2.27 (m, 1H), 2.22 (d, J=7.9 Hz, 1H), 1.78-1.92 (m, 2H), 1.18-1.31 (m, 3H), 0.90 (s, 9H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([CH2:10][NH:11][CH3:12])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[O:15]=[C:16]1[CH2:21][O:20][C:19]2[CH:22]=[C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)[CH:24]=[N:25][C:18]=2[NH:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([CH2:10][N:11]([CH3:12])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:23]3[CH:24]=[N:25][C:18]4[NH:17][C:16](=[O:15])[CH2:21][O:20][C:19]=4[CH:22]=3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CNCc1sc2ccc(F)cc2c1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
To a solution of (5-fluoro-3-methylbenzo[b]thiophen-2-yl)-N-methyl methanamine (200 mg, 0.96 mmol) in DMF (5 mL) were added in sequential order (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (185 mg, 0.87 mmol), 1-hydroxybenzotriazole (133 mg, 0.96 mmol), diisopropylethylamine (454 uL, 2.61 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (192 mg, 0.96 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product was extracted with ethyl acetate (3×10 mL), dried with sodium sulfate, filtered and concentrated. The crude product was purified using preparative HPLC to give the title compound (45 mg, 13%): 1H NMR (400 MHz, DMSO-d6) δ 11.42 (bs, 1H), 8.19 (s, 1H), 7.89-7.87 (m, 2H), 7.55-7.51 (m, 2H), 7.22-7.18 (m, 2H), 5.12-4.87 (2s, 2H, rotamers), 4.68 (s, 2H), 3.54 (s, 3H), 2.39 (s, 3H). MS (ESI) m/e 412 (C21H18FN3O3S+H)+.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:8][C:6](=[O:7])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].C([N:15](CC)CC)C.[OH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[OH:30])[CH2:24][CH2:25][NH2:26]>CO>[O:7]=[C:6]([NH2:15])[C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:8])[OH:11])[OH:10])[OH:9].[NH2:26][CH2:25][CH2:24][C:23]1[CH:27]=[CH:28][C:29]([OH:30])=[C:21]([OH:20])[CH:22]=1
Reactant: CCN(CC)CC
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: NCCc1ccc(O)c(O)c1
Solvent: CO
Product: NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 48.6 %

Procedure:
Gluconolactone (1.9 gm, 10.5 mmol) and triethylamine (TEA; 1.1 gm, 10.5 mmol) were added to methanol (25 mL) in a 100 mL round bottom flask with stirring. The gluconolactone was allowed to dissolve. When the solid was dissolved, the solution was stirred for an additional 10 minutes and then 3-hydroxytyramine (2.0 gm, 10.5 mmol) was added slowly, i.e., allowing it to dissolve. The reaction mixture was stirred in the dark for about 2 hrs. during which time a white solid precipitant appeared. The white solid precipitant was collected by filtration, washed with methanol (5 mL) and dried in vacuo for 6 hrs. to give dopamine gluconamide (1.69 gm, 5.10 mmol, 48.6% yield). Melting point of the synthesis product was 154-155° C. Predicted: C14H21N1 (331.32): C—50.75%, H— 6.39%, N— 4.23%; analysis results of synthetic product: C, 50.65; H, 6.63; N, 4.44.
Reaction SMILES: [C:1]([CH2:11][C:12]#[N:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[OH:15][N:14]=[C:11]([C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:12]#[N:13]
Reactant: O=N[O-]
Reactant: N#CCC(=O)C=Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(=NO)C(=O)C=Cc1ccccc1
Temperature: 3 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
Cinnamoyl acetonitrile (5.1 g; 0.03 mol) is dissolved in 50 ml of acetic acid. 10 ml of H2O are added and the mixture is cooled to 3° C. in an ice/salt bath. Partial precipitation occurs, but the mixture remains well stirrable. Sodium nitrite (4.14 g; 0.06 mol) is added by portions over 10 min, keeping the temperature between 3 and 5° C. Complete solution is observed during addition, but precipitation occurs again towards the end. The mixture is then stirred at 0° C. for 1.5 h. The mixture is diluted with 100 ml of iced water with stirring, the light ochre precipitate is filtered, and washed with ca 100 ml of water. The humid cake is redissolved in ether (100 ml), washed with water, brine and dried over magnesium sulfate. Rotary evaporation and drying affords 2-hydroxyimino-3-oxo-5-phenyl-pent-4-enenitrile (4.7 g; 78%) as a dark yellow solid (mp 144-145° C. dec) which is used without further purification in the next reaction step.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[NH:24]1[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][CH:2]([CH3:23])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][N:24]4[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]4)=[CH:19][CH:20]=3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3)no2)cc1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A solution of 3.06 g (10.0 mmol) of Aldehyde 1, 1.06 g (10.5 mmol) of 3-azetidine carboxylic acid and 5 mL of acetic acid in 150 mL of methanol was stirred for 20 min at rt. A solution of sodium cyanoborohydride (380 mg, 5.0 mmol) in 20 mL of methanol was added. The reaction mixture was stirred for 1 h then was filtered. The solids were washed with 30 ml of methanol and dried to afford 2.88 g (74%) of the title compound: 1H NMR (400 Mhz, CD3OD) δ 0.95 (d, J=6.6, 6H), 1.96 (m, 1H), 2.62 (d, J=7.3, 2H), 3.42 (m, 1H), 4.19 (m, 4H), 4.41 (s, 2H), 7.43 (d, J=8.0, 2H), 7.64 (d, J=8.2, 2H), 8.14 (d, J=8.0, 2H), 8.23 (d, J=8.2, 2H); ESI-MS 392 (M+H); LC-1: 3.0 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CCN(C(C)C)C(C)C.[CH3:45][C:46]([CH3:53])([C:48]1[S:49][CH:50]=[CH:51][N:52]=1)[NH2:47]>CN(C=O)C>[CH3:45][C:46]([NH:47][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]2([CH3:14])[CH2:11][O:12][CH2:13]2)[N:6]=1)=[O:17])([C:48]1[S:49][CH:50]=[CH:51][N:52]=1)[CH3:53]
Reactant: CC1(COc2nc(C(=O)O)ccc2Br)COC1
Reactant: CC(C)(N)c1nccs1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(COc2nc(C(=O)NC(C)(C)c3nccs3)ccc2Br)COC1
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (Example 280b) (30 mg, 100 μmol) in dry DMF (1 ml) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (29.1 mg, 105 μmol) and Hunig's base (52.4 uL, 300 umol). The reaction was stirred at r.t for 30 min, followed by addition of α,α-Dimethyl-2-thiazolemethanamine (Example 12c) (14.2 mg, 100 μmol). The reactions was stirred at room temperature overnight and monitored by LC-MS. When the reaction was complete, purification was directly done by preparative HPLC without any work-up procedure to give the title compound (9.8 mg, 23%). MS (EI): m/e=425.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[NH:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[NH:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][C:8]=1[O:9][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-c2nc3ncccc3[nH]2)ccc1O
Product: COc1cc(-c2nc3ncccc3[nH]2)ccc1OS(C)(=O)=O

Procedure:
Prepared analogously to Example 1 from 2-(3'-methoxy-4'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and methanesulfonic acid chloride.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C[C@H](C)N1
Yield: 59.7 %

Procedure:
2,6-cis-Dimethylpiperazine (40.3 mmol, 4.6 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (40.3 mmol, 13.58 g) and potassium carbonate (81 mmol, 11.13 g) were combined and stirred overnight at room temperature in acetonitrile (25 mL). The reaction mixture was diluted with ethyl acetate and filtered through dicalite. The filtrate was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 90/10/1 dichloromethane/methanol/ammonia) to afford the title compound (8.91 g).
Reaction SMILES: N(=[C:3]1[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[NH:5][C:4]1=[O:16])[N:12]=[CH:11][CH:10]=[CH:9]3)N.[O-]CC.[Na+].C(O)(=O)C>O>[CH2:3]1[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[NH:5][C:4]1=[O:16])[N:12]=[CH:11][CH:10]=[CH:9]3
Reactant: NN=C1C(=O)Nc2ccc3ncccc3c21
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2c(ccc3ncccc23)N1
Yield: 33.2 %

Procedure:
A solution of 2.3 g (12 mmol) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione and 2.0 ml (0.06 mol) of hydrazine in 50 ml of DMF and 50 ml of ethanol was stirred at reflux for 2 h. The resulting suspension was allowed to cool to ambient temperature and was then chilled in an ice bath and filtered. The solid was washed with a small volume of ethanol and allowed to air dry to give 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one as an orange solid (1.8 g, 73%): 1H NMR (DMSO-d6): δ 7.37 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.71 (dd, J=4.2, 1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 (br d, J=14.7 Hz, 1H), 10.89 (br d, J=14.7 Hz, 1H), 10.95 (br s, 1H); ESI−MS m/z 213 (M+H)+. A solution 1.8 g (8.5 mmol) of 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one in 50 ml of freshly prepared 0.5 M sodium ethoxide solution was stirred at reflux for 3 h. The solution was diluted with 50 ml of water, neutralized with acetic acid, and concentrated on a rotary evaporator until cloudy. The solution was stored in a refrigerator overnight. The solid was filtered off, and the filtrate was extracted with three 80-ml portions of EtOAc. A solution of the solid in MeOH/EtOAc was combined with the extracts. and passed through a short pad of silica gel, eluting with EtOAc. The solution was then concentrated to a small volume on a rotary evaporator, and the resulting suspension was diluted with an equal volume of ethanol, sonicated, and filtered to give 3-H-pyrrolo[3,2-f]quinoline-2-one as a light green solid (0.52 g, 33%); 1H NMR (DMSO-d6): δ 3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4, 4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70 (dd, J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H); APCI−MS m/z 183 (M−H)−.