Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].[CH3:12][C:13](OC(C)=O)=[O:14].[NH2:19][C@H:20]([C:23]([OH:25])=[O:24])[CH2:21]O>CC(O)=O>[C:13]([NH:19][CH:20]([CH2:21][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([F:11])[CH:4]=2)[NH:8][CH:7]=1)[C:23]([OH:25])=[O:24])(=[O:14])[CH3:12]
Reactant: Fc1cc2cc[nH]c2cc1Cl
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](CO)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)NC(Cc1c[nH]c2cc(Cl)c(F)cc12)C(=O)O
Temperature: 80 °C
Yield: 37 %

Procedure:
To a solution of 6-chloro-5-fluoroindole (1.8 g, 10.8 mmol) and Ac2O (10 mL) in AcOH (30 mL) was added L-serine (2.2 g, 20.9 mmol), the mixture was heated to 80° C. After TLC indicated the reaction was complete, the mixture was cooled to 0° C., neutralized to pH 11, and washed with MTBE. The aqueous phase was acidified to pH 2 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried with Na2SO4, filtered, and concentrated. The residue was purified with chromatography (Petroleum ether/EtOAc 1:1) to give 2-acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionic acid as a light yellow solid (1.2 g, 37% yield).
Reaction SMILES: [CH:1]([C:3]1([C:12]([OH:14])=O)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2].S(Cl)([Cl:17])=O>>[CH:1]([C:3]1([C:12]([Cl:17])=[O:14])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2]
Reactant: C=CC1(C(=O)O)Cc2ccccc2C1
Reactant: O=S(Cl)Cl
Product: C=CC1(C(=O)Cl)Cc2ccccc2C1

Procedure:
A mixture 2,3-dihydro-2-vinyl-1H-indene-2-carboxylic acid (5.09 g) and thionyl chloride (25 ml) was refluxed for 10 hours. Excess thionyl chloride was distilled off under reduced pressure. The crude product was used as such for the following reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:23](#[N:26])[CH:24]=[CH2:25]>C(O)(=O)C>[C:23]([CH2:24][CH2:25][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[CH:6][CH:7]=1)#[N:26]
Reactant: Nc1ccc(CCCN2CCN(c3ccccc3)CC2)cc1
Reactant: C=CC#N
Solvent: CC(=O)O
Product: N#CCCNc1ccc(CCCN2CCN(c3ccccc3)CC2)cc1
Yield: 81.2 %

Procedure:
A mixture consisting of 29.5 gm (0.1 mol) of N-[γ-(p-amino-phenyl)-n-propyl]-N'-phenyl-piperazine (m.p. 102° C), 5.8 gm (0.11 mol) of acrylnitrile and 20 ml of glacial acetic acid was refluxed for 20 hours. Thereafter, the solvent was distilled off in vacuo, and the residue was recrystallized from dilute methanol, yielding 28.3 gm (81.3% of theory) of N-[γ-(p-[β-cyanoethyl-amino]phenyl)-n-propyl]-N'-phenyl-piperazine, M.P. 141°-143° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:36])=[N:22][N:23]3[CH:28]=[CH:27][C:26]([CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][C:24]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[Cl-].[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][Zn+])=[CH:41][CH:40]=1.O1CCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][C:2]2[N:3]=[C:4]([C:20]3[C:21]([CH3:36])=[N:22][N:23]4[CH:28]=[CH:27][C:26]([CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][C:24]=34)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[CH:41][CH:40]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: CCOC(OCC)c1ccn2nc(C)c(-c3nc(Br)c(-c4ncn(COCC[Si](C)(C)C)n4)s3)c2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccn2nc(C)c(-c3nc(Cc4ccc(Cl)cc4)c(-c4ncn(COCC[Si](C)(C)C)n4)s3)c2c1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A mixture of 3-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridine (0.907 g, 1.53 mmol) and bis(tri-t-butylphosphine)palladium(0) (39.0 mg, 0.0764 mmol) in a 40 mL vial was evacuated under low vacuum and backfilled with nitrogen four times. 4-Chlorobenzylzinc chloride in tetrahydrofuran (0.50 M, 7.0 mL, 3.5 mmol) was added and the solution was again evacuated under low vacuum and backfilled with nitrogen twice. The solution was heated to 60° C. for 4 hours. The reaction mixture was cooled to rt, quenched with water, adjusted to ˜pH 6 with acetic acid, and extracted with EtOAc (2×). The organic layers were combined, washed with water, brine, dried over Na2SO4, filtered and evaporated to give a crude residue which was purified by column chromatography on silica gel column using EtOAc/hexane (0/100 to 40/60) as an eluant to give a solid product (0.806 g, 85% pure by 1H-NMR, yield 70.5%). LCMS: (FA) ES+ 639, 641. 1H NMR of pure fraction (400 MHz, CDCl3) δ: 8.36-8.39 (m, 2H), 8.27 (s, 1H), 7.45-7.47 (m, 2H), 7.23-7.25 (m, 2H), 6.99-7.01 (m, 1H), 5.54 (s, 2H, 5.50 (s, 1H), 4.67 (s, 2H), 3.66-3.74 (m, 4H), 3.57-3.62 (m, 2H), 2.74 (s, 3H), 1.26-1.30 (m, 6H), 0.95-0.99 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO.Cl[CH2:7][C:8]([NH:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](=[O:39])[N:15]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][CH3:38])[CH:29]=1)[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]2=[O:21])=[O:9]>O1CCCC1>[CH3:1][N:2]([CH3:3])[CH2:7][C:8]([NH:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](=[O:39])[N:15]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][CH3:38])[CH:29]=1)[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]2=[O:21])=[O:9]
Reactant: CNC
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CNC(=O)CCl)c3C2=O)ccc1OC
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CNC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
Dimethylamine/methanol (2.0 M, 2.95 mL) was added to a stirred solution of 2-chloro-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide (1.0 g, 1.96 mmol) in tetrahydrofuran and the mixture was stirred at room temperature for 24 hours. The tetrahydrofuran was removed in vacuo and the residue was dissolved in methylene chloride (60 mL). The methylene chloride solution was washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride:methanol 97.5:2.5) to give 2-(dimethylamino)-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide (0.6 g, 59%). To as stirred solution of the amine in ethyl acetate (10 mL) was added 1N hydrogen chloride in ether (4 mL). The resulting suspension was filtered and washed with ether to give 2-(dimethylamino)-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]1,3-dioxoisoindolin-4-yl}methyl)acetamide hydrochloride (0.55 g) as a white solid: mp 103-105° C.; 1H NMR (DMSO-d6) δ 10.06 (s, 1H), 9.37 (m, 1H), 7.83-7.73 (m, 3H), 7.10 (s, 1H), 6.97-6.92 (m, 2H), 5.82-5.76 (dd, J=4.1, 10.2 Hz, 1H), 4.81 (d, J=5.6 Hz, 2H), 4.38-4.32 (dd, J=10.3, 14.1 Hz, 1H), 4.19-4.12 (dd, J=4.4, 14.4 Hz, 1H), 4.05-3.08 (m, 4H), 3.73 (s, 3H0, 3.02 (s, 3H), 2.82 (s, 6H0, 1.32 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ 167.60, 167.20, 164.79, 148.88, 147.85, 137.84, 134.69, 133.36, 131.51, 129.59, 127.09, 122.14, 119.79, 112.41, 111.76, 63.84, 57.17, 55.49, 52.98, 47.29, 43.13, 41.09, 37.82, 14.67; Anal. Calcd. for C26H32N3O7SCl+0.56H2O: C, 53.23; H, 5.92; N, 7.45, S, 5.68; Cl, 6.28. Found: C, 53.22; H, 5.87; N, 7.37; S, 5.64; Cl, 6.52.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20]C)[N:12]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([OH:20])=[C:13]([C:11]2[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])[O:9][CH:10]=2)[CH:18]=1
Reactant: COC(=O)CCCCc1nc(-c2cc(Cl)ccc2OC)co1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)CCCCc1nc(-c2cc(Cl)ccc2O)co1

Procedure:
Dissolve 5-[4-(5-Chloro-2-methoxy-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (0.32 g, 1.0 mmol) in CH2Cl2 (2 mL) under nitrogen at RT. Add boron tribromide (1M in CH2Cl2, 3 mL) and stir at RT until the reaction is complete. Quench the mixture into water and extract with EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) to allow for isolation of 5-[4-(5-chloro-2-hydroxy-phenyl)-oxazol-2-yl]-pentanoic acid (0.27 g, 91%). MS (ES): (M+1)+ 296.1, 298.1 m/z.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:21]1[CH:25]=[CH:24][N:23]=[N:22]1)=[CH:6][NH:7][NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[CH:11][N:10]=1)C.C[O-].[Na+].[ClH:30]>C(O)C.CO>[ClH:30].[N:15]1([C:13]2[N:12]=[CH:11][N:10]=[C:9]([N:8]3[C:4](=[O:3])[C:5]([N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)=[CH:6][NH:7]3)[CH:14]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=CNNc1cc(N2CCOCC2)ncn1)n1ccnn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Temperature: 10 °C

Procedure:
Batch 2: A further amount of the title compound is obtained as follows: The residue (2.4 g) obtained from the mother liquor during the synthesis of Example Compound 71, which contains the open-ring intermediate state of the cyclization, 3-[2-(6-morpholin-4-ylpyrimidin-4-yl)hydrazino]-2-(1H-1,2,3-triazol-1-yl)prop-2-enoic acid ethyl ester, is dissolved in 12 ml ethanol and 1.5 ml 30% strength sodium methylate solution in methanol are added at RT, while stirring. The mixture is subsequently stirred at RT for 45 min, then adjusted to pH 5 with 2 N hydrochloric acid and subsequently stirred at RT for a further 16 h. The mixture is cooled to 10° C. and the solid is filtered off and washed with 3.5 ml dioxane. The mixture is dried under a high vacuum for 16 h, 5 ml methanol are then added and the mixture is subsequently stirred at RT for 1 h. The solid is filtered off, washed with 2 ml methanol and dried under a high vacuum to give a further 997 mg of the title compound in this way.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11])[CH:2]1[O:4][CH2:3]1.[N-:13]=[N+:14]=[N-:15].[Na+]>O1CCOCC1>[N:13]([CH2:3][CH:2]([OH:4])[CH2:1][N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11])=[N+:14]=[N-:15]
Reactant: CC(C)C1OCCN1CC1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)C1OCCN1CC(O)CN=[N+]=[N-]
Temperature: 80 °C

Procedure:
Into a 500 ml., three-neck flask equipped with a mechanical stirrer, thermometer attached to a thermowatch, temperature controller and a condenser with a drying tube, is charged 171g. (1 mole) of 3-glycidyl-2-isopropyloxazolidine, 71.5g (1.1 mole) sodium azide and 250 cc of dioxane. The mixture is stirred and heated at 80°C for 6-8 hours and the solvent is then removed in vacuo to afford 3-(3-azido-2-hydroxypropyl)-2-isopropyl-1,3-oxazolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:8][C:10]2[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH:15]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(Oc2cncc(Br)c2)ccc1[N+](=O)[O-]
Yield: 99.9 %

Procedure:
The reaction and post-treatment were carried out according to Example (1a) using 5-bromo-3-hydroxypyridine (5.01 g, 28.8 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (US200216506 A1, 7.50 g, 26.2 mmol), sodium hydride (63%, 1.10 g, 28.8 mmol) and DMF (87 mL) to obtain the title compound (11.1 g, 99%) as a yellow brown solid.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)c1cc(N)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Yield: 33.9 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-isopropyl-1-phenyl-1H-pyrazol-5-amine (423 mg, 2.1 mmol) and potassium carbonate (378 mg, 2.7 mmol) in anhydrous DCM (8 ml) was added dropwise phenyl chloroformate (0.39 ml, 3.1 mmol) as a solution in DCM (2 ml) to afford phenyl 3-isopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (229 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 1.27 (d, J=6 Hz, 6H), 3.01 (m, 1H), 6.46 (s, 1H), 7.14-7.36 (m, 2H), 7.38-7.57 (m, 8H); LC-MS (ESI) m/z 322 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[C:15]4[CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([NH2:28])[CH:25]=5)[C:16]=4[NH:17][C:18]=3[C:19]=2[F:20])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:29](OCC)(OCC)OCC.[N-:39]=[N+:40]=[N-:41].[Na+]>CC(O)=O.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[C:15]4[CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([N:28]6[CH:29]=[N:41][N:40]=[N:39]6)[CH:25]=5)[C:16]=4[NH:17][C:18]=3[C:19]=2[F:20])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(N)cc2C4)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(-n3cnnn3)cc2C4)cc1
Temperature: 80 °C

Procedure:
7-(4-Butyl-phenyl)-6-fluoro-5,10-dihydro-indeno[1,2-b]indol-2-ylamine (example 98, step 1, 60 mg, 0.1620 mmol) is dissolved in AcOH (1.6 mL). Triethyl orthoformate (38 mg, 0.2591 mmol, 1.6 eq.) and sodium azide (15 mg, 0.2429 mmol, 1.5 eq.) are added to the starting material solution sequentially at room temperature. The resulting reaction mixture is heated to 80° C. for 3.5 h. After cooling to room temperature, the reaction is diluted with EtOAc and sequentially washed with H2O, 1 N HCl (aq), and saturated aqueous NaCl. The organic solution is dried over Na2SO4 and concentrated. The resulting residue is purified by reverse phase HPLC to afford the title compound as a tan solid: 1H NMR (400 MHz, Acetone-d6) δ 11.31 (bs, 1H), 9.77 (s, 1H), 8.15 (s, 1H), 7.97 (s, 2H), 7.62-7.52 (m, 3H), 7.38 (d, 2H), 7.21 (dd, 1H), 3.99 (s, 2H), 2.69 (t, 2H), 1.72-1.63 (m, 2H), 1.50-1.40 (m, 2H), 0.99 (t, 3H); ESMS m/z 424.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:14])[CH2:9][NH:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:22](Br)[CH:23]=[CH2:24]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([OH:14])[CH2:9][N:10]([CH2:11][CH2:12][OH:13])[CH2:24][CH:23]=[CH2:22])=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: OCCNC[C@H](O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: C=CCN(CCO)C[C@H](O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To (R)-1-(4-chlorophenyl)-2-[(2-hydroxyethyl)amino]-1-ethanol (755 mg, 3.5 mmol) produced in Example 12, dimethylacetamide (5 mL), triethylamine (532 mg, 1.5 equivalents) and allyl bromide (508 mg, 1.2 equivalents) were added. The mixture was stirred at 25° C. for 16 hours. Toluene (5 mL) and distilled water (5 mL) were added to the mixture, and the organic layer and aqueous layer were separated. The organic layer was washed twice with distilled water (5 mL), then concentrated and dried under vacuum, to obtain 817 mg of the title compound as colorless oil (yield: 79%, chemical purity: 92.2 area %). The retention time in the chemical purity analysis method was 2.0 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[N:22][N:23](CC5C=CC(OC)=CC=5)[C:16]=34)[C:11]([CH3:33])=[CH:10][N:9]=2)[CH:7]=1.ClC1C=CC(F)=C(C2C=C(NC3C4C(=CN(CC5C=CC(OC)=CC=5)N=4)N=CC=3)C(C)=CN=2)C=1.[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[N:22][NH:23][C:16]=34)[C:11]([CH3:33])=[CH:10][N:9]=2)[CH:7]=1.[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]
Reactant: COc1ccc(Cn2ncc3nccc(Nc4cc(-c5cc(Cl)ccc5F)ncc4C)c32)cc1
Agent: COc1ccc(Cn2cc3nccc(Nc4cc(-c5cc(Cl)ccc5F)ncc4C)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(-c2cc(Cl)ccc2F)cc1Nc1ccnc2cn[nH]c12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To the flask containing N-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine (0.561, 1.184) was added TFA (5.9 mL) and the mixture was stirred at 70° C. for 3 hours. The reaction was cooled to room temperature and concentrated under vacuum to a dark amber residue. To this residue was combined with dichloromethane (25 mL) and saturated sodium carbonate solution (25 mL) resulting in a precipitate which was filtered, rinsed with dichloromethane and water and dissolved in EtOAc, then extracted with water and saturated sodium bicarbonate The organic layer was separated, dried over sodium sulfate, and concentrated to give a yellow solid that was purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 18-25% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to give the title compound as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30-2.40 (m, 3H) 7.42 (dd, J=10.86, 8.84 Hz, 1H) 7.53-7.67 (m, 1H) 7.79 (br. s., 1H) 7.94-8.04 (m, 1H) 8.46 (d, J=5.81 Hz, 1H) 8.76 (s, 1H). MS [M+H] found 354.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:5]=1OCC(N)=O.C(=O)([O-])[O-].[K+].[K+].C[N:25]1CCCC1=O>>[CH3:1][O:2][CH2:3][C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:5]=1[NH2:25]
Reactant: COCc1cc([N+](=O)[O-])ccc1OCC(N)=O
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCc1cc([N+](=O)[O-])ccc1N
Temperature: 100 °C

Procedure:
20 g of the 2-(2-methoxymethyl-4-nitrophenoxy)acetamide made in step 1 are dissolved in 55 ml of N-methylpyrrolidone, mixed with 29 g of potassium carbonate and heated for 3 hours at 100° C. Subsequently the reaction mixture is cooled to room temperature and the solvent is removed in vacuum at 60 to 80° C. The remaining residue is crystallized by addition of 100 ml water. 8.8 g of a yellowish product are obtained with a melting point of 90 to 92° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[C:17](O)([CH3:20])([CH3:19])[CH3:18].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:9])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: CC(C)(C)O
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reaction time: 96 h

Procedure:
Commercially available 2-nitro-terephthalic acid 4-methyl ester (4.84 g, 21.49 mmol) in DCM (54 mL) was treated with tert-butanol (4.05 mL, 42.99 mmol), di-tert-butyl dicarbonate (12.19 g, 55.87 g) and DMAP (0.79 g, 6.45 mmol). After 4 days at room temperature, the reaction was diluted with DCM (100 mL), washed with 1N HCl (100 mL), aqueous NaHCO3 and finally with water. After drying over sodium sulphate and evaporation of the volatiles, the title compound was obtained as a brownish oil in more than quantitative yield (6.51 g). The crude was employed in the following step with no further purification.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][CH:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:7]1)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>C(Cl)Cl>[CH2:10]([CH:8]1[CH2:9][CH:6]([CH:4]=[O:5])[CH2:7]1)[CH:11]([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)C1CC(CC(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: ClCCl
Product: CC(C)CC1CC(C=O)C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxy-N-methyl-3-isobutylcyclobutanecarboxamide (77 g) in methylene chloride (235 mL) was added dropwise diisobutylaluminum hydride (1.0 M in methylene chloride) (473.2 mL) at −78° C. The mixture was stirred at −78° C. for 2 hr. After an addition of 1.5 M sulfuric acid (630 mL) at ice temperature, the mixture was extracted with methylene chloride. The combined organic layer was washed with 1.5 M sulfuric acid, water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate comprising the title compound was used in the next step.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].Br[CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.BrCC1CCCCO1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:12]4=[O:20]
Reactant: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)Nc2ccccc21
Reactant: BrCC1CCOCC1
Agent: BrCC1CCCCO1
Product: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)N(CC2CCOCC2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 4-(bromomethyl)tetrahydropyran to replace 2-(bromomethyl)tetrahydro-2H-pyran, 2-methyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one was obtained (44%) as a colorless solid: mp 186-187° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.66-7.60 (m, 1H), 7.34-7.27 (m, 1H), 7.13-7.07 (m, 1H), 7.06-6.91 (m, 3H), 5.04-4.97 (m, 1H), 4.78-4.72 (m, 1H), 4.07-3.93 (m, 3H), 3.52-3.35 (m, 3H), 2.52 (s, 3H), 2.32-2.15 (m, 1H), 2.07-1.95 (m, 1H), 1.91-1.80 (m, 1H), 1.57-1.42 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.4, 169.3, 160.6, 149.2, 143.1, 132.7, 129.1, 128.7, 123.7, 123.0, 122.3, 119.9, 108.7, 108.5, 81.5, 67.9, 62.4, 58.1, 46.6, 34.3, 30.9, 20.2, 14.6; MS (ES+) m/z 407.0 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=1.[NH2:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24].C(N(CC)CC)C>O1CCCC1>[CH:10]1[C:11]2[CH:12]=[CH:13][C:14]3[C:5](=[CH:4][C:3]([CH2:2][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:20]4[C:15]=3[CH:16]=[CH:17][CH:18]=[CH:19]4)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(N)(CO)CO
Reactant: BrCc1cc2c3ccccc3ccc2c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 6-bromomethylchrysene (4.82 g, 15 mmol), 2-amino-2-methylpropane-1,3diol (3.15 g, 30 mmol), and triethylamine (1.67 g, 16.5 mmol) was refluxed in tetrahydrofuran (75 mL) under nitrogen. After one hour all the solids had dissolved and NMR analysis indicated that the 6-bromomethylchrysene had been consumed. Water (150 mL) was added and the mixture was cooled to ambient temperature. The solids were collected by filtration, washed with water (3×30 mL), and dried in vacuo to give 3.67 g (71% yield) of 2-(6-chrysenylmethylamino)-2-methylpropane-1,3diol. 1H NMR (CDCl3) 1.19 (s, 3 H), 1.81 (br s, 1 H), 3.53 (d, J=5.0 Hz, 2 H), 4.39 (s, 2 H), 4.58 (t, J=5.0 Hz, 2 H), 7.78 (m, 4 H), 8.11 (m, 2 H), 8.45 (d, J=8.4 Hz, 1 H), 8.9 (m, 4 H).