Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:17].[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[N:17]1[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1F
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2F)C1

Procedure:
The title compound is prepared in analogy to Example 20c) from 2-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and itaconic acid. Yield: 67% of a purple solid. MS: m/e=346.1 (M+H)+.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1>>[S:11]1[CH:15]=[CH:14][C:13]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:12]1
Reactant: OB(O)c1ccsc1
Reactant: Ic1ccc2cn[nH]c2c1
Product: c1cc(-c2ccc3cn[nH]c3c2)cs1

Procedure:
(237 mg, 71%); from 6-iodo-1H-indazole (403.5 mg, 1.65 mmol) and 3-thiopheneboronic acid (236.5 mg, 1.8 mmol).
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=O)[C:7]([CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH2:5][CH2:4]1.C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21]>CN(C=O)C>[CH:10]([C:7]1[C:6]([O:13][CH3:14])=[CH:5][CH:4]=[C:3]2[C:8]=1[N:21]=[C:20]([NH2:22])[N:19]=[CH:2]2)([CH3:12])[CH3:11]
Reactant: N=C(N)N
Reactant: COC1=C(C(C)C)C(=O)C(=CO)CC1
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: COc1ccc2cnc(N)nc2c1C(C)C
Temperature: 150 °C

Procedure:
A mixture of 6-hydroxymethylene-2-isopropyl-3-methoxy-cyclohex-2-enone (3.5 g) and guanidine carbonate (7 g) in DMF (40 mL) was heated at 150° C. for 4 hours. The solvent was removed under reduced pressure, then ice-cold water was added to the residue. The product was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, then brine, and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to give a crude mixture of dihydroquinazolines (4 g). The dihydroquinazolines were aromatized to the title compound by heating in nitrobenzene (70 mL) at 150° C. in the presence of 10% Pd-C (400 mg) for 3 days. The catalyst was removed by filtration, then the filtrate was concentrated, and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as an off-white solid (2.1 g, 54.2%). mp 112–113° C.; 1H NMR (CDCl3): δ 1.38 (d, 6H, 2×CH3), 3.95 (s, 3H, OCH3), 4.24 (m, 1H, CH), 5.0 (br s, 2H, NH2), 7.02 (d, 1H, Ar-H, J=9 Hz), 7.55 (d, 1H, Ar-H, J=9 Hz), 8.87 (s, 1H, Ar-H); MS m/z 218.05, C12H15N3O (M++1).
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:30]([NH:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][C:39](=[O:44])[N:40]3[CH3:43])=[CH:35][CH:34]=2)=[O:31])=[C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[CH:14]=1>C(O)C>[ClH:8].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:30]([NH:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][C:39](=[O:44])[N:40]3[CH3:43])=[CH:35][CH:34]=2)=[O:31])=[C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[CH:14]=1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCC3CCCCN3C(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCC3CCCCN3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 198 %

Procedure:
4 M hydrogen chloride/ethyl acetate solution (5 mL) was added to an ethanol (5 mL) solution of tert-butyl 2-{[(5-chloro-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]carbonyl}phenyl)amino]methyl}piperidin-1-carboxylate (540 mg), followed by stirring at room temperature for 2 hours. By collecting the resulting precipitate by filtration, 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-[(piperidin-2-ylmethyl)amino]benzamide hydrochloride (470 mg) was obtained as a solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.C(N1CCC2(CC3C=CC=CC=3O2)CC1)C1C=CC=CC=1.[H][H].CCOCC>C(O)(C)C.[Pd]>[NH:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC3(CC2)Cc2ccccc2O3)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: c1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C

Procedure:
A solution of 5.3 g of 2,3-dihydro-1'-benzylspiro[benzofuran-2,4'-piperidine], free base of Example 1, in 250 ml of isopropyl alcohol is hydrogenated in a Paar shaker, 50 psig, 65°-70° C., with 1 g of a 10% palladium/carbon catalyst until the uptake of hydrogen is completed. Thereafter, the solution is successively permitted to cool to ambient temperature, filtered and concentrated to dryness, leaving a white solid. The solid is dissolved in a benzene-ether mixture, the solution is filtered through celite and then concentrated again, providing a white solid which, upon trituration with ether, provides the product, 2,3-dihydrospiro[benzofuran-2,4'-piperidine], mp 56°-58.5° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]1([C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A mixture of methyl 4-[5-phenyl-1,3,4-oxadiazol-2-yl]benzoate (0.180 g), 1 M aqueous sodium hydroxide solution (1.3 ml), tetrahydrofuran (2 ml) and methanol (1 ml) was stirred at room temperature for 1 hr. and acidified by adding 1 M hydrochloric acid. The crystals were collected by filtration to give 4-[5-phenyl-1,3,4-oxadiazol-2-yl]benzoic acid (0.150 g, yield 88%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: >300° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19])=[O:11].Cl.O.[N+]([O-])([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>>[OH:1][C:2]1[CH:7]=[C:6]([N:8]=[N+:27]=[N-:28])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19])=[O:11]
Reactant: Nc1ccc(NC(=O)Nc2ccccc2I)c(O)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(NC(=O)Nc2ccccc2I)c(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
The N-(2-hydroxy-4-aminophenyl)-N′-(2-iodophenyl)urea(77 mg, 0.21 mmol) was added to HCl/H2O (0.21 mL/0.42 mL), and cooled to 0° C. Sodium nitrate (14.5 mg, 0.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. Sodium azide (14 mg, 0.21 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 5:1) gave product (20 mg, 24%). EI-MS m/z 396 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:30][CH3:31])[C:3]=1[C:32](=[O:34])[NH2:33].[Cl:35][CH2:36][C:37](=O)[CH2:38]Cl>O(CCOC)C>[C:32]([C:3]1[C:2]2[N:7]([CH:38]=[C:37]([CH2:36][Cl:35])[N:1]=2)[C:6]([S:8][CH3:9])=[N:5][C:4]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[O:30][CH3:31])(=[O:34])[NH2:33]
Reactant: O=C(CCl)CCl
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(SC)nc(N)c1C(N)=O
Solvent: COCCOC
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(SC)n2cc(CCl)nc2c1C(N)=O
Temperature: 80 °C

Procedure:
A mixture of the product of Example 13D (629 mg, 1.28 mmol) and 1,3-dichloropropan-2-one (652 mg, 5.13 mmol) in 1,2-dimethoxylethane (20 mL) was heated at 80° C. for 18 hours. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 97/3 dichloromethane/methanol to give the title compound. MS: 562 (M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][C@H:35]1[CH2:39][NH:38][C@H:37]([C:40]([OH:42])=[O:41])[CH2:36]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:38]5[CH2:39][CH:35]([OH:34])[CH2:36][CH:37]5[C:40]([OH:42])=[O:41])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: O=C(O)C1CC(O)CN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with trans-4-hydroxy-L-proline. A yellow solid 131 was obtained (0.017 g, 33%). 1H-NMR (CDCl3, 400 MHz) δ 2.42-2.51 (m, 1H), 3.66-3.72 (m, 1H), 3.85-3.91 (m, 1H), 4.00-4.06 (m, 1H), 4.28-4.34 (m, 4H), 4.64-4.69 (m, 1H), 4.85-4.95 (m, 1H), 6.81 (s, 1H), 6.92-6.96 (m, 2H), 7.03 (dd, J=1.8 Hz, 8.4 Hz, 1H), 7.06-7.10 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.92-7.96 (m, 1H); MS (APCI) m/z 519 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC(Cl)C.[F:25][C:26]([F:35])([F:34])[C:27](=O)[C:28](OCC)=[O:29]>ClCCl.CN(C)C=O.ClCCl.CCCCCC>[F:8][C:5]1[CH:4]=[C:3]2[C:2]([N:1]=[C:27]([C:26]([F:35])([F:34])[F:25])[C:28]([OH:29])=[N:9]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: Nc1ccc(F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Oc1nc2cc(F)ccc2nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a pressure tube was added 1,2-diamino-4-fluorobenzene (5.0567 g, 40.1 mmol) and p-toluenesulfonic acid (7.63 g, 40.1 mmol) followed by dichloroethane (40.1 ml). The suspension was stirred for a few minutes and ethyl trifluoropyruvate (5.11 ml, 42.1 mmol) was added. The tube was capped and the suspension was stirred at 80° C. and the solid dissolved. The stiffing continued overnight and then the solution was cooled to rt, diluted with dichloromethane/dimethylformamide (4/1, 2×50 ml) and washed with NaHCO3 (1 N, 2×100 ml) and water (100 ml). The combined aq. layers was back-extracted with dichloromethane/dimethylformamide (4/1, 2×50 ml). The combined organic layer was dried (anh. Na2SO4), filtered, and concentrated to give a dark mixture of solid and oil. This residue was diluted with dichloromethane and hexane and concentrated to give a solid (7 g). The ratio of isomers (6-F/7-F) was 2/1 based on 1H NMR integration of the crude material. The solid was dissolved in acetone and silica gel (140 g) was added. The mixture was concentrated, and the solid mixture was loaded on a silica gel column. The column was eluted with ethyl acetate/hexane=1/6 to 1/3 and then the 6F-isomer was flushed out with ethyl acetate/hexane=2/1) to give the title compound 106a.
Reaction SMILES: C[S-].[Na+].C[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:25][N:22]1[CH2:21][CH2:20][N:19]([CH2:18][C:12]2([C:9]3[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=3)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:24][CH2:23]1
Reactant: COc1ccc(C2(CN3CCN(C)CC3)CCOCC2)cc1
Agent: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1CCN(CC2(c3ccc(O)cc3)CCOCC2)CC1
Temperature: 130 °C
Yield: 103.3 %

Procedure:
To a suspension of sodium thiomethoxide (660 mg, 9.4 mmol) in N,N-dimethylformamide (2 ml) was added 1-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methyl}4-methylpiperazine (410 mg, 1.3 mmol) in N,N-dimethylformamide (3 ml). The reaction mixture was heated to 130° C. under nitrogen for 18 hours. The mixture was then allowed to cool down to room temperature and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate (2×30 ml). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to provide a pale brown oil. This was azeotroped with toluene and dried under high vacuum to provide the title compound (390 mg, 100%) as an off-white solid. HRMS ESI+ m/z 291.2062 [MH]+.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18]CC)=[O:17])[CH3:10])=O)(C)(C)C.[Li+].[OH-].[ClH:39]>O1CCOCC1.O>[ClH:39].[NH2:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][C:33]([CH3:34])([CH3:36])[CH3:35])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])[CH3:10]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(C(C)N)[nH]3)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (326b) (6.30 g, 12.71 mmol) and LiOH hydrated (2.67 g, 63.6 mmol) in dioxane (24 mL) and water (24 mL) was heated in an oil bath at 100° C. for 10 h. The reaction mixture was concentrated to half of its volume. The remaining mixture was lyophilized for 24 h to give a yellow solid. The yellow solid suspended in 15 mL of dioxane at 0° C. was treated with 35 mL of 4 N HCl in dioxane. The resulting orange mixture was stirred at RT for 2 h. The mixture was concentrated to half of its volume. The insoluble solid was filtered, rinsed with 2×10 mL of ether. The filtrate was discarded. The orange solid was dried in a vacuum oven at 40° C. for 1 h to give 2-(1-aminoethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (326c), which was used as crude material and based on theoretical yield. m/z (ESI, +ve) 368.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:11]=[N:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[NH:5][C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:26][C:27]1[N:28]([CH3:32])[N:29]=[CH:30][N:31]=1>CN(C=O)C>[CH3:32][N:28]1[C:27]([CH2:26][O:8][C:6]2[N:5]=[C:4]3[N:9]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:10]=[CH:11][C:3]3=[C:2]([NH2:1])[CH:7]=2)=[N:31][CH:30]=[N:29]1
Reactant: Nc1cc(=O)[nH]c2c1cnn2-c1ccccc1
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1cc(N)c2cnn(-c3ccccc3)c2n1
Temperature: 60 °C
Yield: 95.9 %

Procedure:
To a solution of 4-amino-1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (0.30 g, 1.33 mmol) in DMF (8 ml) under nitrogen was added cesium carbonate (0.95 g, 2.92 mmol) followed by 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.27 g, 1.61 mmol). The resulting suspension was heated at 60° C. for 17 h. The mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous phase extracted a second time with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (0.41 g, 96%), m.p. 164-166° C. δH (400 MHz; CDCl3) 3.91 (3H, s), 4.70 (2H, br s), 5.58 (2H, s), 5.89 (1H, s), 7.28-7.31 (1H, m), 7.48-7.52 (2H, m), 7.88 (1H, s), 7.98 (1H, s), 8.15-8.18 (2H, m); m/z (ES+) 322 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2([NH:19][C:20]([NH:22]C(=O)C1C=CC=CC=1)=[S:21])[C:14]([F:18])([F:17])[CH2:15][OH:16].CN>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:7][CH2:8]1)[C:5]2([NH:19][C:20]([NH2:22])=[S:21])[C:14]([F:18])([F:17])[CH2:15][OH:16]
Reactant: O=C(NC(=S)NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2)c1ccccc1
Agent: CN
Solvent: CO
Product: NC(=S)NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of N-{[6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-4H-spiro[chromene-3,1′-cyclopropan]-4-yl]carbamothioyl}benzamide (340 mg, 0.684 mmol) in MeOH (1.7 mL) was added methylamine (9.8M MeOH solution, 698 μL, 6.84 mmol). The mixture was stirred for 3 hours at ambient temperature. The mixture was concentrated azeotropically with toluene 3 times to give crude 1-[6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-4H-spiro[chromene-3,1′-cyclopropan]-4-yl]thiourea (268 mg).
Reaction SMILES: Cl.Cl.[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.N([O-])=O.[Na+].[N-:24]=[N+:25]=[N-].[Na+]>Cl>[N:17]([C:16]1[CH:18]=[CH:19][C:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=2)=[CH:14][CH:15]=1)=[N+:24]=[N-:25]
Reactant: Nc1ccc(-c2ccc3ccccc3n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1ccc(-c2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
T446 To a solution of 4-(quinolin-2-yl)aniline dihydrochloride (29.0 mg, 0.1 mmol) in 1 N HCl (1 mL) was added NaNO2 solution (7.0 mg in 0.3 mL water, 0.1 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hrs before NaN3 (7.8 mg in 1.0 mL water, 0.12 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour and concentrated. The residue was purified by HPLC (acetonitrile/water) to give T446 as a light yellow solid (23.0 mg, 64%). 1H NMR (400 MHz, CD3OD): δ 8.31 (d, J=8.8 Hz, 1H), 8.10 (m, 2H), 8.00 (m, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.85 (dd, J=8.2, 1.4 Hz, 1H), 7.69 (m, 1H), 7.50 (m, 1H), 7.16 (m, 2H); MS (ESI): 247 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:31])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl.CCOC(C)=O>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-[2-(2,4-Dichloro-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (AMR01046, 1.0 g, 2.15 mmol) was dissolved in DCM (20 ml), and cooled to 0° C. and to this was added TFA (5 ml). This was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was poured onto solid potassium carbonate (12 g), and water (50 ml) added. Extracted with DCM and the organic layers dried over anhydrous magnesium sulphate, and evaporated in-vacuo, to afford a cream oil, 0.77 g, 98%. R.f. 0.2 (EtOAc) 1HNMR (CDCl3, 300 MHz) δ 1.72 (2H, m, CH2), 1.87 (2H, m, CH2), 2.39 (1H, m, CH), 2.68 (2H, td, J=2.7, 12.3 Hz, CH2), 3.16 (2H, dt, J=3.6, 7.2, 12.6 Hz, CH2), 6.66 (1H, dd, J=1.5, 8.1 Hz, ArH), 6.87 (1H, d, J=8.7 Hz, ArH), 6.94 (1H, td, J=1.8, 8.1 Hz, ArH), 7.07 (1H, td, J=1.2, 7.8 Hz, ArH), 7.15 (1H, dd, J=2.7, 9.0 Hz, ArH), 7.43 (1H, d, J=2.4 Hz, ArH), 8.34 (1H, dd, J=6.9 Hz, ArH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[NH:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1.[N+:28]([C:31]1[S:35][C:34]([CH:36]=O)=[CH:33][CH:32]=1)([O-:30])=[O:29].N1C=CC=CC=1>ClC(Cl)C.C(O)(=O)C>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:16]2[N:1]([CH2:36][C:34]3[S:35][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)[C:2]3=[N:7][CH:6]=[C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])[CH:4]=[C:3]3[N:15]=2)=[CH:19][CH:20]=1)[CH3:26]
Reactant: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)cnc2N)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)cnc3n2Cc2ccc([N+](=O)[O-])s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 6-amino-5-[[(4-ethoxyphenyl)acetyl]amino]-N,N-diethyl-3-pyridinecarboxamide (30 mg, 0.08 mmol) in dichloroethane (0.5 mL) and acetic acid (0.5 mL) at room temperature was added 5-nitro-2-thiophenecarboxaldehyde (19 mg, 0.12 mmol). The mixture was stirred for 4.5 hours. BH3. pyridine (8.2 μL, 0.08 mmol) was added and the reaction brought to 84° C. After stirring overnight, the mixture was cooled to room temperature and 5-nitro-2-thiophenecarboxaldehyde (19 mg, 0.12 mmol) was added. The mixture was stirred for 5 hours. BH3.pyridine (8.2 μL, 0.08 mmol) was added and the reaction brought to 84° C. After stirring overnight, the reaction was quenched with 1 M NaOH aqueous solution (20 mL) and extracted with EtOAc (20 mL). The aqueous phase was back-extracted with additional dichloromethane (2×20 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([3% MEOH+0.5% NH4OH aq] in CH2Cl2) to provide the title compound 2-[(4-ethoxyphenyl)methyl]-N,N-diethyl-3-[(5-nitro-2-thienyl)methyl]-3H-imidazo[4,5-b]pyridine-6-carboxamide (purity: >84% at 215 nm, >81% at 254 nm, >68% at 280 nm). 1H-NMR (400 MHz, CDCl3): δ 1.23 (m, 6H), 1.40 (t, J=6.8 Hz, 3H), 3.36 (br s, 2H), 3.60 (br s, 2H), 3.98 (q, J=6.8 Hz, 2H), 4.29 (s, 2H), 4.84 (s, 2H), 6.80 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H), 7.66 (d, J=4.1 Hz, 1H), 7.77 (d, J=4.1 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H). MS (ESI) (M+H)+: 494.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:14][C:15]([O:17]CC)=[O:16])=[N:9][N:10]2[CH3:13])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:14][C:15]([OH:17])=[O:16])=[N:9][N:10]2[CH3:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1nn(C)c2cc(Cl)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(CC(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Aqueous potassium hydroxide (5.93 mL, 10%) was added to ethyl (6-chloro-1-methyl-1H-indazol-3-yl)acetate (Preparation 169, 1.78 g, 0.704 mol) in MeOH (30 mL). The mixture was stirred for 1 hour at 25° C. then the methanol was evaporated in vacuo. The aqueous residue was washed with diethyl ether (30 mL) then acidified with aqueous HCl (6 M). The mixture was extracted with ethyl acetate (30 mL) and the organic phase was dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (DCM:MeOH 95:5) to afford the title compound as a white solid in 56% yield, 865 mg.