Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=CC=1C1C=CC(C(O)=O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:16]1([C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:9]([NH2:8])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 251 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 1-(3-aminomethyl)-4-methylpiperazine (19 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 h. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with toluene/methanol (8:2, 7:3, 6:4), which after evaporation of the solvents under vacuum gave N-(6-methyl-4′-{[3-(4-methylpiperazin-1-yl)propylamino]carbonyl)}-1,1′-biphenyl-3-yl)-2-pyrrolidin-1-ylisonicotinamide (48 mg, 89%). NMR; δH [2H6]-DMSO 10.51,(1H, s), 8.68,(1H, t), 8.17,(1H, d), 7.93,(2H, d), 7.76,(1H, dd), 7.72,(1H, d), 7.42,(2H, d), 7.28,(1H, d), 7.00,(1H, d), 6.95,(1H, d), 3.43,(4H, m), 3.29,(2H, q), 2.49–2.32,(10H, m), 2.21–2.19,(6H, m), 1.94,(4H, m), 1.70,(2H, m). LCMS: retention time 2.13 min, MH+541.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13]C(=O)OC(C)(C)C)=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][C:10]1([CH3:22])[S:9](=[O:23])(=[O:24])[C@@H:8]2[CH2:25][CH2:26][O:27][C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:29][C:6]=3[C@@:7]2([CH3:28])[N:12]=[C:11]1[NH2:13]
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(N)=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S1(=O)=O
Yield: 76.6 %

Procedure:
A solution of tert-butyl ((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (intermediate 19) (308 mg, 0.727 mmol) in DCM (5.5 ml) was treated with trifluoroacetic acid (2.70 ml, 36.4 mmol) for 15 min. The mixture was concentrated, redissolved in DCM, diluted with water and free-based with a saturated solution of NaHCO3. The mixture was extracted with DCM, organic extract was washed with brine, filtered through pad of celite and concentrated to afford (4aR,11bR)-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazine-2,10-diamine (180 mg, 0.557 mmol, 77% yield) as an off-white solid. LC/MS (ESI+) m/z=324.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[C:19]([OH:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:43][CH2:44][O:45][C:46](/[C:48](/[NH2:51])=[N:49]/O)=[O:47]>C(Cl)Cl.CCOC(C)=O>[NH2:51][C:48](=[N:49][O:20][C:19](=[O:21])[C:18]([N:13]1[C:14]2[C:10](=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[N:12]1)([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:22][CH3:23])[C:46]([O:45][CH2:44][CH3:43])=[O:47]
Reactant: CCC(C(=O)O)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: CCOC(=O)/C(N)=N/O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(N)=NOC(=O)C(CC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To a suspension of 2-(4-((tert-butoxycarbonyl)amino)-1H-indazol-1-yl)-2-(4-chlorophenyl)butanoic acid from Step A above (0.16 g, 0.37 mmol) in DCM (1.5 mL) was added 1,1′-carbonyldiimdazole (0.13 g, 0.78 mmol) to give a clear solution. The mixture was stirred for 7.5 hours at RT followed by addition of ethyl 2-oximinooxamate (0.13 g, 0.93 mmol). After stirring at RT overnight, the resulting mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, water and brine. The organic layer was separated, and concentrated. The resulting crude product was re-dissolved in a mixture of acetonitrile and water and dried in a lyophilized to give the title compound as light yellow solid. LC/MS m/z=544.1[M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH:16]([NH2:18])[CH3:17].[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([NH:18][CH:16]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:17])[N:23]=[CH:22][N:21]=1
Reactant: CC(N)c1nc2cnccn2c1-c1ccccn1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cnccn2c1-c1ccccn1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-pyridin-2-yl-imidazo[1,2-a]pyrazin-2-yl)-ethylamine (250 mg, 1.04 mmol) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (160 mg 1.04 mmol) in n-butanol (3 mL) was added DIEA (1.7 mL, 10.04 mmol) at rt. The reaction mixture was stirred at 110° C. overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-40% acetone in hexane to provide 4-amino-6-[1-(3-pyridin-2-yl-imidazo[1,2-a]pyrazin-2-yl)-ethylamino]-pyrimidine-5-carbonitrile: 1H NMR: (400 MHz, DMSO-d6) δ 1.537 (d, J=6.8 Hz, 3H), 5.837-5.906 (m, 1H), 7.269 (br s, 2H), 7.471-7.502 (m, 1H), 7.572-7.594 (m, 1H), 7.887-7.907 (m, 1H), 7.983-8.043 (m, 3H), 8.814-8.826 (m, 1H), 8.928-8.944 (m, 1H), 9.180 (d, J=1.2 Hz, 1H); LC-MS (ESI) m/z 358.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:16][CH2:17][O:18][CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][O:20]1>CS(C)=O.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:4][CH:3]=1
Reactant: BrCCOC1C=CC=CO1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc(OCCOC2CCCCO2)cc1
Reaction time: 0.33 h
Yield: 84.4 %

Procedure:
To a solution of 4-bromophenol (1.71 g, 9.91 mmol) in DMSO (40 mL) was added potassium t-butoxide (1.17 g, 10.4 mmol) and the mixture was stirred for 20 mins. Tetrahydro-2-(2-bromoethoxy-2H-pyran (2.18 g, 10.4 mmol) in DMSO (10 mL) was added dropwise and the reaction was stirred for 1 hr. It was then diluted with brine (100 mL) and extracted with ethylacetate (3×100 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, hexanes:ether, 85:15) to afford tetrahydro-2-(2-(4-bromophenoxy)ethoxy)-2H-pyran (2.52 g, 85%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]([NH:10][NH:11]C(OC(C)(C)C)=O)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].CO[C:38]([CH2:40][C:41]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=O)=[O:39]>C(Cl)Cl.C(O)(=O)C.C(OCC)(=O)C>[O:39]=[C:38]1[N:10]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([CH3:9])[CH3:8])[N:11]=[C:41]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH2:40]1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(C)(C)OC(=O)NNC(C)(C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CC1=NN(C(C)(C)c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
tert-Butyl 2-(2-phenylpropan-2-yl)hydrazinecarboxylate (250 mg, 1.00 mmol) was dissolved in methylene chloride (2 mL), mixed with p-toluenesulfonic acid monohydrate (0.40 g, 2.1 mmol) and stirred at room temperature for 18 hours. The reaction solution was basified with saturated aqueous sodium hydrogen carbonate and separated. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene (2.0 mL) and acetic acid (70 μL), mixed with dimethyl 1,3-acetonedicarboxylate (174 mg, 1.00 mmol) and stirred at 90° C. for 3 hours and at 105° C. for 3 hours. After completion of the reaction, the reaction solution was allowed to cool to room temperature and diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel12 g, ethyl acetate:hexane=1:9 to 3:7) to give 96.3 mg of the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])[C:10](=[O:15])[CH2:11][C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1([CH3:38])[O:37][C:35](=[O:36])[CH2:34][C:32](=[O:33])[O:31]1.C1CCC(N=C=NC2CCCCC2)CC1.[BH4-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][N:9]([CH2:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])[C:10](=[O:15])[CH2:11][CH2:12][CH:34]1[C:35](=[O:36])[O:37][C:30]([CH3:38])([CH3:29])[O:31][C:32]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c(CN(OCc2ccccc2)C(=O)CC(=O)O)c(OC)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: [BH4-]
Solvent: ClCCl
Product: COc1cc(OC)c(CN(OCc2ccccc2)C(=O)CCC2C(=O)OC(C)(C)OC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of 3-[benzyloxy(2,4,6-trimethoxybenzyl)amino]-3-oxopropanoic acid (9.41 g, 24.16 mmol), Meldrum's acid (3.84 g, 26.58 mmol), and DMAP (3.54 g, 29.0 mmol) in dichloromethane (125 mL) was dropwise added a solution of DCC (5.5 g, 26.6 mmol) in dichloromethane (25 mL) via addition funnel over a period of 1 h at 0° C. The mixture was left in the refrigerator overnight. DCU was filtered off and the filtrate was washed with 5% KHSO4 (3 times) and brine and dried over MgSO4 for 4 h in the refrigerator. The drying agent was removed by filtration and acetic acid (16 mL) was added to the filtrate. The mixture was again cooled at 0° C. and sodium borohydride (2.3 g, 60.4 mmol) was added in small portions while stirring over 1 h. The reaction mixture was left overnight in the refrigerator. The next day, the solution was washed 3 times with brine and 2 times with water. The organic layer was concentrated in vacuo and the crude material was recrystallized from EtOAc-hexanes mixture to give 8.08 g of N-benzyloxy-3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-N-(2,4,6-trimethoxybenzyl)-propanamide as a white solid (67% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[CH:10]([OH:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[CH:10]([O:28][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: OC1CN(Cc2ccccc2)CCC1c1cccc(OCc2ccccc2)c1
Product: c1ccc(COc2cccc(C3CCN(Cc4ccccc4)CC3OCc3ccc4ccccc4c3)c2)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-piperidin-3-ol with 2-bromomethylnaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a colourless resin; MS: 514 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]#[N:9].[Al+3].[Cl-].[Cl-].[Cl-].[C:14](Cl)([CH3:16])=[O:15]>ClCCCl>[C:14]([C:6]1[C:2]([CH3:1])=[C:3]([C:8]#[N:9])[NH:4][C:5]=1[CH3:7])(=[O:15])[CH3:16]
Reactant: Cc1cc(C)c(C#N)[nH]1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1c(C)[nH]c(C#N)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2-carbonitrile (1.2 g, 10 mmol) was dissolved in anhydrous 1,2-dichloroethane (15 mL) and AlCl3 (2.93 g, 22 mmol) was added proportion-wise. The reaction vessel was purged with N2 and was cooled in an ice-water bath. AcCl (0.71 mL, 10 mmol) was added dropwise and the mixture was stirred for 1 h with cooling and for a further 3 h at room temperature. The reaction mixture was quenched by careful addition of 2 M aq HCl. The acidity of the mixture was adjusted to approximately pH 6 by addition of NaHCO3. After separation of the organic phase, the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were washed (H2O, then brine), dried (MgSO4), and filtered. The solvent was evaporated to afford of 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carbonitrile (1.42 g, 88%) as a pale tan solid. 1H-NMR (CDCl3) δ: 2.44 (s, 3H, CH3), 2.45 (s, 3H, CH3), 2.54 (s, 3H, CH3), 8.75 (br. s, 1H, NH).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[C:25](=[O:27])=[O:26].Cl>O1CCCC1.CCCCCC.O>[CH2:18]([N:15]([CH2:16][CH3:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][C:5]([C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[CH:6]=1)[CH3:19]
Reactant: O=C=O
Reactant: CCN(CC)CCOCCc1ccc2sccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCOCCc1ccc2sc(C(=O)O)cc2c1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
In 30 mL of tetrahydrofuran is dissolved 6.00 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N,N-diethylamine. The solution is cooled to −60° C., and 10.6 mL of 1.57 mol/L solution of n-butyllithium in hexane is dropwise added. The resulting mixture is stirred at the same temperature as above for one hour, an excessive amount of dry carbon dioxide gas is introduced, after which the temperature is elevated to ambient temperature and the mixture is stirred for 30 minutes. Water is added to the mixture, pH is adjusted to 7 with 2 mol/L hydrochloric acid, and the solvent is distilled off under reduced pressure. The residue is purified by reversed phase column chromatography (eluent:water:methanol=7:3) and filtered together with ethyl acetate. Thus, 3.66 g of 5-{2-[2-(diethylamino)ethoxy]ethyl}-benzo[b]thiophene-2-carboxylic acid is obtained as a crystalline product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][N:16]1[C:20]2([CH2:24][CH2:23][NH:22][CH2:21]2)[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:15][N:16]1[C:20]2([CH2:24][CH2:23][N:22]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=3)[CH2:21]2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCCC12CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc(N2CCC3(CCCN3C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A mixture of 1.42 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 1.0 g of 1-methyl-1,7-diazaspiro[4,4]nonane and 1.48 g of potassium carbonate in 10 ml of DMSO is stirred at ambient temperature overnight. The mixture is diluted with 160 ml of water and extracted three times with 100 ml of ethyl acetate. The organic phases are dried over magnesium sulfate and concentrated under vacuum. The yellow oily residue is purified on silica, with an elution gradient with dichloromethane/methanol (100/0 then 90/10), so as to obtain 160 mg of 1-methyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in the form of an orangey-coloured oil.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]1=[NH2+:22].[Cl:23][CH2:24][C:25](Cl)=O.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]2[N:15]([N:14]=[C:25]([CH2:24][Cl:23])[N:22]=2)[CH:20]=1
Reactant: O=C(Cl)CCl
Reactant: Nn1cc(Cl)ccc1=[NH2+]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: ClCc1nc2ccc(Cl)cn2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
A mixture of 1-amino-5-chloropyridin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (500 mg, 1.45 mmol, Eq: 1.00), 2-chloroacetyl chloride (172 mg, 122 μl, 1.53 mmol, Eq: 1.05) and pyridine (242 mg, 247 μl, 3.05 mmol, Eq: 2.1) in DMF (5.00 ml) was stirred at 90° C. for 2 h. The mixture was poured on 20 ml half saturated aq. NaHCO3 and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated to an oil. Purification by column chromatography (SiO2, 0 to 80% EtOAc in n-heptane) gave the desired product (68 mg, 23%) as a white solid. MS m/z=202.1 (M+H+)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)(C)(C)C.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C(OCC)(=O)C>C1COCC1>[NH2:7][CH2:8][CH2:9][S:10]([C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)=[O:39]
Reactant: CC(C)(C)OC(=O)NCCSc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCS(=O)c1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C

Procedure:
A solution of [2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester (from Example 39 above) (150 mg, 0.35 mmol) in THF (approximately 15 mL) was treated with mCPBA (Acros, 97 mg, 0.42 mmol, 75%) at 0° C. The reaction mixture was allowed to stir and warm up to room temperature overnight. The mixture was poured into ethyl acetate and washed successively with aqueous saturated Na2S2O3 and aqueous saturated K2CO3. The organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by HPLC (silica gel, 40% ethyl acetate in hexanes). The resulting intermediate was precipitated out of THF with excess of pentane. This material was then dissolved at 0° C. in 50% TFA in CH2Cl2 solution (10 mL) that contained H2O (0.5 mL) and stirred for 2 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and extracted with aqueous ammonium hydroxide. The organic layer was dried over Na2SO4, filtered and concentrated to an orange solid. This solid was dissolved in THF and precipitated with excess of pentane to give 5-(2-amino-ethanesulfinyl)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as an orange solid. (Yield 75 mg, 62%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:12]([I:13])=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:12]([I:13])=[N:11][N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]nc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
NaH (1.31 g, 32.7 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0° C.) solution of 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (5.3 g, 16.4 mmol) in dry DMF (40 mL) The reaction mixture was stirred at 0° C. for 10 minutes before 2-(trimethylsilyl)ethoxymethyl chloride (4.91 mL, 27.8 mmol) was added dropwise via a syringe. The cold bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was placed in an ice bath, diluted with ethyl acetate (400 mL) and carefully quenched with water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (20:1) to give 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (6.59 g, 89%) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[N:13]=2)=[C:9]([CH3:11])[N:10]=1)=[O:4].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][C:3](=[O:4])[NH:5][C:6]2[S:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=4)[N:13]=3)=[C:9]([CH3:11])[N:10]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
A solution of 2-chloro-N-{4-methyl-5-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-thiazol-2-yl}-acetamide (40 mg, 0.1mmol) in DMF (2 mL) was cooled on an ice bath. Piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.21 mmol) was added. After stirring at room temperature for 16 h, the reaction mixture was purified by preparative RP-HPLC (0-60% MeCN in 0.1% aq CF3COOH over 40 min, 9 mL/min) to afford the title compound (20 mg) as a light yellow solid. Anal. RP-HPLC: tR=16.9 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>97%). 1H-NMR (CD3OD) δ: 2.65 (s, 3H, CH3), 2.87 (m, 4H, CH2), 3.36 (m, 4H, CH2), 4.66 (s, 2H, CH2), 7.71 (m, 1H, pyrimidinyl-H), 7.89 (t, 1H, J=8.1 Hz, Ph-H), 8.15 (m, 1H, Ph-H), 7.42 (m, 1H, Ph-H), 7.67 (m, 2H, pyrimidinyl-H & Ph-H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:14][C:13]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl.O>[C:30]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:24]=[CH:25][C:26]([CH2:28][CH3:29])=[CH:27][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:23])[CH:14]=1)[CH2:19][CH2:20][CH2:21][NH2:22])(=[O:32])[CH3:31]
Reactant: CCc1ccc(Oc2ccc(NCCCN)cc2F)c(OCc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (60 mg, 0.15 mmol) in 10 ml of dry dichloromethane, cooled to 0° C., was added acetic anhydride (20 mg, 0.19 mmol) taken in 0.5 ml of dichloromethane dropwise. The reaction mixture was warmed to rt and stirred for 1 h until reaction was complete on TLC. The reaction mixture was diluted with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined dichloromethane fraction was dried over anhydrous Na2SO4 and concentrated. The crude residue obtained was column purified over silica gel using 2% methanol in dichloromethane as eluant to get 50 mg, 75.4% of title compound.