Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([OH:11])=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>C(#N)C>[Cl:27][CH2:26][CH2:25][CH2:24][O:11][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])[CH:5]=1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCl
Yield: 90.7 %

Procedure:
A mixture of N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (21.9 g, 66 mmol), caesium carbonate (998 g, 300 mmol) and 1-bromo-3-chloropropane (11 ml, 110 mmol) in acetonitrile (300 ml) was heated at reflux for 1 hour. The reaction mixture was cooled and the solvent evaporated in vacuo. Water (200 ml) was added and this was extracted with dichloromethane (2×150 ml). The organic solution was washed with brine (50 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue triturated with diethyl ether. The solid was collected by suction filtration and dried in vacuo to yield N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (17.7 g, 91% yield) as a white solid:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[F:20][C:21]1[CH:22]=[C:23]([C@H:28]([NH2:30])[CH3:29])[CH:24]=[CH:25][C:26]=1[F:27].C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:30][C@@H:28]([C:23]2[CH:24]=[CH:25][C:26]([F:27])=[C:21]([F:20])[CH:22]=2)[CH3:29])=[CH:13][CH:14]=1
Reactant: C[C@@H](N)c1ccc(F)c(F)c1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Product: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Yield: 92.2 %

Procedure:
Following a similar procedure to that described in Example (1a), 1.0 g of 4-chlorophenyl 3-nitrophenyl ketone, 1.11 g of (R)-1-(3,4-difluorophenyl)ethylamine hydrochloride, 2.93 ml of trietlaylamine, 0.50 ml of titanium tetrachloride, 1.01 g of sodium cyanoborohydride and 0.33 ml of acetic acid were reacted, to obtain 1.42 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NS(C)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine methyl 2-methoxy-5-methylsulfonamidobenzoate (1.0 g, 3.86 mmol) and lithium hydroxide (93 mg, 3.86 mmol) in tetrahydrofuran/water (50 mL/10 mL). After 18 hours, add lithium hydroxide (100 mg) and heat to reflux. After 1 hour, cool to ambient temperature and evaporate to remove most of the tetrahydrofuran. Dilute the evaporated reaction mixture with water (about 70 mL) and acidify to pH of about 1 using a 1 M aqueous hydrochloric acid solution. Evaporate to dryness and triturate with dichloromethane (200 mL). Filter and evaporate the filtrate to give the title compound: mp; 160-163° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:41])C(=O)C1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:41][C:22]1[CH:23]=[CH:24][C:19]2[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15][N:14]([S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[C:20]=2[C:21]=1[Cl:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3cccc(Cl)c32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)c(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-7-chloro-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 25, 60 mg, 0.121 mmol) in DCM (1 mL) was added NBS (23.7 mg, 0.133 mmol) and a few drops of TFA. After stirring at rt for 3 h, the reaction mixture was concentrated to dryness, and the residue was dissolved in ether, washed with sodium thiosulfate, water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC to provide the title compound. LC/MS: m/e 574 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13]([NH:15][C:16](=[O:20])OCC)=[S:14])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>[OH-].[Na+]>[C:1]1([C:7]2[CH:11]=[C:10]3[NH:12][C:13](=[S:14])[NH:15][C:16](=[O:20])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(-c2ccccc2)n[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(=S)[nH]c2cc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
Ethyl [(3-phenyl-1H-pyrazol-5-yl)amino]carbothioylcarbamate (8.4 g, 29 mmol) was dissolved in aqueous sodium hydroxide (100 mL, 2N solution) and the resulting solution was stirred at room temperature overnight. This solution was acidified to pH=1 with concentrated sulfuric acid, resulting in heavy precipitation. This precipitate was collected by filtration and dried to give 7-phenyl-2-thioxo-2,3-dihydropyrazolo-[1,5-a][1,3,5]triazin-4(1H)-one (5.7 g, 80%) as a white solid. 1H-NMR (DMSO-d6): δ 7.97 (m, 2H), 7.48 (m, 3H), 6.41 (s, 1H); MS m/z 245 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[C:29]4=[N:30][C:31]([CH3:35])=[CH:32][C:33]([CH3:34])=[C:28]4[N:27]=[C:26]3[CH2:36][CH3:37])[CH:19]=2)[OH:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:36]([C:26]1[N:25]([CH2:24][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])=[CH:15][CH:14]=2)=[O:17])[C:29]2=[N:30][C:31]([CH3:35])=[CH:32][C:33]([CH3:34])=[C:28]2[N:27]=1)[CH3:37]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1
Reaction time: 8 h
Yield: 98.2 %

Procedure:
[4-(tert-Butyldimethylsilyloxymethyl)phenyl][3-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)phenyl]methanol (0.923 g, 1.78 mmol) obtained in Step 3 was dissolved in chloroform (20 mL), and Manganese(IV) oxide (3.11 g, 35.8 mmol) was added to the solution, followed by stirring overnight. The unsoluble material was filtered out through Celite, and the filtrate was combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain {4-[3-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)benzoyl]benzyloxy}-tert-butyldimethylsilane (0.898 g, yield 98%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:23][CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:2][C:3]2[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=2)[CH2:17][CH2:18]1
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(CN2CCC(CO)CC2)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
tert-Butyl 4-(bromomethyl)benzoate (1 g, 3.13 mmol) and piperidin-4-ylmethanol (0.361 g, 3.13 mmol) were dissolved in acetonitrile (25 mL). K2CO3 (1.300 g, 9.40 mmol) was added and the reaction mixture was heated to reflux for 20 min. The reaction mixture was cooled down to room temperature, filtered and evaporated. The resulting solid was partitioned between ethyl acetate (50 mL) and 1 M HCl (50 mL). The layers were separated and the aqueous layer was washed with ethyl acetate and the organic layers were discarded. The aqueous layer was basified with 8 M NaOH to pH˜10 and extracted 2 times with 50 mL of ethyl acetate. The organic layers were combined, washed with brine and dried over MgSO4, filtered and evaporated. tert-Butyl 4-((4-(hydroxymethyl)piperidin-1-yl)methyl)benzoate (0.95 g, 2.99 mmol, 95% yield) was isolated as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.34 Hz, 2H), 7.39 (d, J=8.08 Hz, 2H), 3.56 (s, 2H), 3.51 (d, J=6.57 Hz, 2H), 2.90 (d, J=11.37 Hz, 2H), 1.94-2.04 (m, 2H), 1.73 (d, J=14.15 Hz, 2H), 1.61 (s, 9H), 1.40-1.56 (m, 2H), 1.30-1.37 (m, 2H); LC-MS Rt=0.67 min; MS (ESI): 306.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH:34]1(C=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH:34]1([CH2:27][N:24]2[CH2:23][CH2:22][CH:21]([N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:10](=[O:20])[CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=CC1CCCCC1
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(CC3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). Cyclohexanecarboxaldehyde (0.138 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 17 mg; HRMS (FAB+, NBA) (M+H)+ 449.3163, C29H41N2O2 requires 449.3168; LC-MS: (M+H)+ 449.2, tr 7.92 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36](Br)[N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2.[CH3:41][N:42](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:41]#[N:42])[N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2
Reactant: Cc1cc(CC(OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2cccc(Br)n2)cc2cn[nH]c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2cccc(C#N)n2)cc2cn[nH]c12
Temperature: 200 °C
Yield: 97 %

Procedure:
A microwave tube was charged with (±)-1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (18 mg, 0.0296 mmol, 1.0 equiv) and Pd(PPh3)4 (ca. 4 mg) and Zn(CN)2 (14 mg, 0.12 mmol, 4 equiv). DMF (0.5 mL) was added via syringe. The vial was sealed and heated by microwave at 200° C. for 20 min. Tetrahydrofuran was removed in vacuo and the residue was partitioned between ethyl acetate and ammonium hydroxide solution. The organic layer was separated and washed with water, brine, dried and concentrated. Flash column chromatography (10% methanol/methylene chloride) afforded the desired product (15.9 mg, 97%) as a white solid. MS (ESI) [M+H]+=554. 1H-NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.72 (br., 1H), 7.62-7.54 (m, 1H), 7.37 (br., 1H), 7.18-6.70 (m, 6H), 6.08-5.83 (m, 1H), 4.65-3.80 (m, 6H), 3.55-3.10 (m, 2H), 3.10-2.64 (m, 2H), 2.53 (s, 3H), 1.90-1.40 (m, 4H). HPLC tR=1.90 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([CH:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]#[N:22])=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[N:4]=[CH:3]1>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([CH:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][NH2:22])=[CH:15][CH:16]=3)[CH2:11]2)(=[O:8])=[O:9])[N:4]=[CH:3]1
Reactant: Cn1cnc(S(=O)(=O)N2CCc3ccc(C(C#N)Cc4ccccc4)cc3C2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N2CCc3ccc(C(CN)Cc4ccccc4)cc3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
The synthesis was performed starting from 0.123 mmol of 2-(2-(1-methyl-1H-imidazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-phenylpropanenitrile, which was dissolved in THF (1 ml), after which 0.37 mmol of BH3 THF complex (1 M in THF) was added at 0° C. The mixture was warmed to room temperature and stirred for 2 h. The mixture was diluted with CH2Cl2 and washed with 1 N HCl, saturated NaHCO3 and H2O. The aqueous phase was extracted with CH2Cl2. Combined organic phase was dried over MgSO4 and filtered. Evaporation of the solvent gave 50 mg of the crude material. The material was purified by flash chromatography to yield 11 mg of a white solid (22%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:10]=1
Reactant: Fc1ccc(S)cc1
Reactant: C#CC(=O)OCC
Product: CCOC(=O)C=CSc1ccc(F)cc1

Procedure:
Using Example 15 procedures, ethyl propiolate and 4-fluorobenzenethiol are reacted, yielding ethyl 3-(4-fluorophenylthio)-2-propenoate. Three equiv. of this is then combined with 1 equiv. of phenyl(trifluoromethyl)mercury and 3 equiv. of dry powdered sodium iodide. This mixture is refluxed in benzene for 15-20 hr, then filtered and solvent is removed to give ethyl 3-(4-fluorophenylthio)-2,2-difluorocyclopropanecarboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:32].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:32].[ClH:32].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(NCCN(CCO)CCO)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(NCCN(CCO)CCO)cc1

Procedure:
The 2-[[2-(4-nitrophenylamino)ethyl]-(2-hydroxyethyl)amino]ethanol (19) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[C:25]3[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=2)[NH:28][CH:27]=[C:26]3[CH:35]2[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]2)[CH:20]=[CH:21][CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.N1C=CC=CC=1.CN(C=O)C>[CH2:44]([S:41]([N:38]1[CH2:39][CH2:40][CH:35]([C:26]2[C:25]3[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=[C:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][NH:15][C:6]([CH:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:8])[CH:18]=4)[CH:24]=3)[NH:28][CH:27]=2)[CH2:36][CH2:37]1)(=[O:43])=[O:42])[CH3:45]
Reactant: O=C(O)C1CCOC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN)c4)cc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(=O)C5CCOC5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
To a solution of tetrahydro-3-furancarboxylic acid (17 mg, 0.144 mmol) in DCM (2.0 mL) was added pyridine (3 drops) and oxalyl chloride (18 mg, 0.144 mmol). Reaction mixture was stirred overnight at room temperature. To the mixture was then added 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (40 mg, 0.096 mmol) in DMF (1.0 mL) and DIEA (33 μL, 0.192 mmol). Reaction mixture was stirred at room temperature overnight. Reaction mixture was concentrated under nitrogen and purified by Gilson Preparatory HPLC to give 5.3 mg the title compound (10%).
Reaction SMILES: [BH4-].[Na+].Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[C:13](=[O:22])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CO>[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH:13]([OH:22])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC1CCN(Cc2ccccc2)CC1O
Reaction time: 0.25 h

Procedure:
Sodium borohydride (40 g) was added in portions to a stirred solution of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (23.6 g, 90 mmol) in methanol (500 mL), over 2 h. Water (300 mL) was added slowly, the mixture stirred for 15 min and then the organics were evaporated. The residue was partitioned between DCM and water (×3), the combined organic layers dried over anhydrous sodium sulfate, and the solvent evaporated to give 1-benzyl-4-hydroxymethyl-piperidin-3-ol product as a cis/trans mixture, which was used in the next step without further purification. M.S (M+1): 222.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH:19]=O)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])[CH2:28][O:29][C:25]=2[C:24]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.N1CCCCC1>CO>[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])/[C:28](=[CH:19]/[C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([O:9][CH2:8][CH2:7][N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:11]=4)[NH:15][N:14]=3)/[O:29][C:25]=2[C:24]=1[CH2:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccc(OCCN3CCOCC3)cc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(OCCN4CCOCC4)cc13)C2=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A solution of 5-(2-morpholinoethoxy)-1H-indazole-3-carboxaldehyde (0.0163 g, 0.0592 mmol) in methanol (0.5 mL) was added with tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0172 g, 0.0493 mmol) and piperidine (0.00335 g, 0.0394 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-[(6-methoxy-2-{[5-(2-morpholinoethoxy)-1H-indazol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0303 g, 99%).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([C:18]#[C:19][Si](C)(C)C)[CH:9]=1)(=[O:5])=[O:4].[OH-].[K+].Cl.CCCCCCC>C(O)C.O>[C:18]([C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:13]=[CH:12][C:11]=1[NH:14][C:15](=[O:17])[CH3:16])#[CH:19]
Reactant: CNS(=O)(=O)CCc1ccc(NC(C)=O)c(C#C[Si](C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCCCCCC
Product: C#Cc1cc(CCS(=O)(=O)NC)ccc1NC(C)=O
Temperature: 17.5 °C
Reaction time: 2.5 h

Procedure:
N-[4-(2-methylsulfamoyl-ethyl)-2-trimethylsilanylethynyl-phenyl]-acetamide (100 g) was dissolved in ethanol (1000 ml) at 25° C. and cooled to 15-20° C. Potassium hydroxide (20 gm) was added slowly maintaining temperature below 25° C., stirred for 2-3 hours and cooled to 10-15° C. pH of the reaction mixture was adjusted to 5 with 10% dilute HCl and concentrated under vacuum below 40° C. to obtain a residue. The residue was dissolved in water (250 ml) and extracted with dichloromethane (2000 ml). The organic layer was washed with water and concentrated under vacuum to obtain a residue. The residue was treated with heptane (200 ml) to obtain a solid which was filtered and dried under vacuum at 50-55° C. for 12 hours. (Yield: 70 g, HPLC Purity: 99%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=[O:9])=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CCOCC.O.C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([O:10][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[N:19]2)(=[O:9])=[O:8])[CH:2]=1
Reactant: On1nnc2ccccc21
Reactant: O=S(=O)(O)c1cccnc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(On1nnc2ccccc21)c1cccnc1
Temperature: 150 °C
Yield: 69.1 %

Procedure:
To pyridine-3-sulfonic acid (6 g) is added powdery phosphorus pentachloride (15.8 g) and the mixture is heated at 150° C. for 3 hours. The reaction mixture is concentrated under a reduced pressure at 60° to 70° C. and thereto is added anhydrous xylene. The mixture is concentrated under a reduced pressure and thereto is further added anhydrous xylene, and the mixture is again concentrated. To the resulting residue is gradually added water (20 ml) under cooling with dry ice-acetone to give a solution. The solution is added dropwise to a mixture of 1-hydroxy-1,2,3-benzotriazole (8.3 g), potassium carbonate (8.3 g), water (24 ml), benzene (40 ml) and ether (15 ml) at -2° to 0° C. with stirring. After the addition, to the mixture are added water (18 ml) and ether (15 ml) and the mixture is stirred at room temperature. The mixture is regulated at pH 7 to 8 with 1 N aqueous potassium hydroxide and then stirred for 2 hours. The reaction mixture is extracted with benzene-ether (240 ml). The extract is washed with a saturated aqueous sodium hydrogen carbonate and dried over potassium carbonate. After drying, the solvent is distilled off to give 1-(3-pyridylsulfonyloxy)-1,2,3-benzotriazole (7.2 g; 70%), melting point: 98° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[C:23]([CH3:29])[CH:22]=3)[N:18]=[N:17][C:16]=1[O:30][CH3:31])=[CH:9]2)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[OH:28][C:24]1[C:25]([CH3:27])=[CH:26][C:21]([C:19]2[N:18]=[N:17][C:16]([O:30][CH3:31])=[C:15]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14][CH:13]=4)[CH:20]=2)=[CH:22][C:23]=1[CH3:29]
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(-c4cc(C)c(O)c(C)c4)nnc3OC)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2cc(C(=O)O)ccc2[nH]1

Procedure:
480 mg of 2-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-1H-indole-5-carboxylic acid ethyl ester is dissolved in 4 ml ethanol and 4 ml aqueous 2N NaOH and heated by microwave irradiation for 10 min at 150° C. The solution is neutralized with aqueous HCl and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid).