Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C:14]([NH2:16])=[O:15])[C:3]([NH2:5])=[NH:4].Cl.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:33])[CH:30](O)[OH:31].C(O)(=O)CCCC(O)=O.Cl.Cl.Cl.N(CCCCCCC=CC(NC(O)C(N)=O)=O)C(N)=N>O>[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:33])[CH:30]([NH:16][C:14](=[O:15])[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[OH:31]
Reactant: N=C(N)NCCCCCCC=CC(N)=O
Reactant: NCCCNCCCCNC(=O)C(O)O
Agent: Cl
Agent: N=C(N)NCCCCCCC=CC(=O)NC(O)C(N)=O
Agent: O=C(O)CCCC(=O)O
Solvent: O
Product: N=C(N)NCCCCCCC=CC(=O)NC(O)C(=O)NCCCCNCCCN
Temperature: 60 °C
Yield: 38.9 %

Procedure:
A mixture of 206.2 mg (0.84 mmole) of 9-guanidino-2-nonenamide hydrochloride, 291.0 mg (1.00 mmole) of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride, 109.6 mg (0.84 mmole) of glutaric acid and 0.2 ml of water was heated at 60° C. for 24 hours. After completion of the reaction, the reaction mixture was purified in a manner similar to that in Example 1 using CM-Sephadex® C-25 (Na-type) and Sephadex® LH-20 to obtain 135.0 mg (31.1% yield) of a white powder of N-[4-(3-aminopropyl)aminobutyl]-2-(9-guanidino-2-nonenamido-2-hydroxyethanamide trihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl-].[C:25]([SiH:29]([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30])=[CH:9][CH:10]=1
Reactant: C[SiH](C)C(C)(C)C
Reactant: Oc1ccc(Cc2cc(I)ccc2Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
4-(2-chloro-5-iodobenzyl)phenol (8.5 g, 24.7 mmol) and triethylamine (5.0 g, 49.5 mmol) were dissolved in methylene chloride (200 mL). To the resulting mixture were added tert-butyldimethylsilane chloride (5.6 g, 37.1 mmol) and 4-(dimethylamino)pyridine (305 mg, 2.5 mmol) at 0° C. After the completion of addition, the mixture was warmed up to room temperature, and stirred for 18 hr. To the mixture was added water (100 mL). The resulting mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (100 mL×2). The organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:100) to produce 10.0 g of a product in a yield of 88%.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([CH2:24]O)[CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(OCC)(=O)C>[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][Cl:1])[CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Cl
Reactant: OCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(CCl)cc43)CC2)cc1
Yield: 94 %

Procedure:
Conc. hydrochloric acid (280 ml) was added to 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline (about 70 g) and the resultant mixture was stirred at 80° C. for a day. Under ice cooling, the reaction solution was neutralized with a conc. aqueous solution of sodium hydroxide followed by addition of ethyl acetate (200 ml). The resulting crystals were collected by filtration and dissolved in ethyl acetate (500 ml) and a 5 N aqueous solution (500 ml) of sodium hydroxide and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (70 g) as a pale yellow powder (yield: 94%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.COCCOC.C1COCC1.[OH-].[Na+]>O>[Br:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Br)cnc(OC)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: O
Product: COc1ncc(Br)c2c1c(-c1ccc(CC(=O)O)cc1)nn2-c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a mixture to methyl (4-(7-bromo-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetate (270 mg) in a mixed solvent of DME (1.0 mL), THF (1.0 mL) and water (0.5 mL) was added 8N aqueous sodium hydroxide solution (0.346 mL), and the mixture was stirred at 60° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The aqueous layer was neutralized with 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (235 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[NH2:13][CH:14]([C:16]([N:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1([CH3:25])[CH3:24])=[O:17])[CH3:15]>CC(O)C>[CH3:25][C:19]1([CH3:24])[NH:20][C:21](=[O:23])[CH2:22][N:18]1[C:16](=[O:17])[CH:14]([NH:13][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:15]
Reactant: CC(N)C(=O)N1CC(=O)NC1(C)C
Reactant: CCOC(=O)CN1CCCC1=O
Solvent: CC(C)O
Product: CC(NC(=O)CN1CCCC1=O)C(=O)N1CC(=O)NC1(C)C

Procedure:
The same procedure of Example 25, starting from ethyl 2-oxo-1-pyrrolidineacetate and 1-(D,L-alanyl)-2,2-dimethyl-4-imidazolidinone, afforded the title compound, m.p. 198°-200° C. (2-propanol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([O:9][Si](C)(C)C)[C:7]#N)=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].BrC[CH2:24][CH2:25][C:26]#[N:27]>O1CCCC1>[C:26]([CH2:25][CH2:24][CH2:7][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:9])#[N:27]
Reactant: C[Si](C)(C)OC(C#N)c1ccsc1
Reactant: N#CCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCCCC(=O)c1ccsc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of the 2-(3-thienyl)-2-trimethylsilyloxyacetonitrile thus obtained (14.0 g.) in tetrahydrofuran (12 ml.) was added to a stirred solution of lithium diisopropylamide [prepared at 0° C. in tetrahydrofuran solution (200 ml.) from diisopropylamine (6.7 g.) and n-butyl-lithium (43.4 ml. of 1.55 molar solution in hexane)] in tetrahydrofuran (200 ml.) which was cooled to -78° C. under an atmosphere of nitrogen, and the mixture was stirred at that temperature for 15 minutes. 4-Bromobutyronitrile (9.8 g.) was added and the mixture was stirred at -78° C. for 1 hour and then at laboratory temperature for 1 hour. Aqueous N-hydrochloric acid (75 ml.) was added, the mixture was stirred at laboratory temperature for 90 minutes and the phases were then separated. The aqueous phase was extracted twice with ethyl acetate (100 ml. each time) and the combined organic phase and extract were stirred with aqueous N-sodium hydroxide solution (50 ml.) for 18 hours. The organic phase was separated, dried and evaporated to dryness and the residue was flash chromatographed on a silica gel column using a 19:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 4-cyano-1-(3-thienyl)butan-1-one.
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:24][CH:25]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCCNC(=O)c2ccc(C(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(C(=O)NCCOc2ccc(C(=O)O)cc2)cc1
Yield: 82 %

Procedure:
Methyl 4-[2-(4-isopropylbenzamido)ethoxy]benzoate (102.42 g) was dissolved in 1 liter of ethanol with heating. A solution of 14.4 g of sodium hydroxide in 200 ml of water was added to the above ethanolic solution and the mixture was heated to reflux for 2 hours. The reaction solution was concentrated in vacuo, 1 liter of ice water was added to the residue, the mixture was neutralized with 10% hydrochloric acid, crystals separated out therefrom were collected by filtration, washed with water, dried and recrystallized from ethanol to give 80.5 g (yield: 82%) of crystalline product. M.p. 202°-203° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][N:15]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Reactant: CN
Solvent: C1CCOC1
Product: CN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with THF (350 mL), 124c (10.0 g, 32.2 mmol), 2M methylamine solution in THF (113 mL, 225 mmol) and stirred at room temperature for 72 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting solid was stirred with a mixture of ethyl acetate (75 mL) and 10% aqueous potassium carbonate (75 mL). The aqueous layer was separated and extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with 10% aqueous potassium carbonate (75 mL), followed by brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate concentrated under reduced pressure to afford 128a in 97% yield (5.70 g) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 6.62 (s, 1H), 4.28 (t, 2H, J=5.4 Hz), 3.67 (s, 2H), 2.95 (t, 2H, J=5.4 Hz), 2.52 (s, 3H); MS (ESI+) m/z 183.0 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:33][CH2:34][N:35]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[CH2:36][CH2:37]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCNCC2)N1
Reactant: COC(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 80 °C
Yield: 53 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.36 g, 0.54 mmol) prepared in example 5a in ethanol (2 mL) was added triethylamine (0.15 mL, 1.08 mmol) and methyl bromoacetate (0.124 g, 0.81 mmol) (Aldrich). The reaction mixture was heated at 80° C. for 2 h, then cooled to room temperature. The mixture was partitioned between dichloromethane and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc=7:93) to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(1-methoxycarbonylmethyl-4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a light yellow solid (Yield 0.21 g, 53%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=O)[C:7]=2[N:17]=1.C([O-])(=O)C.[NH4+].[N+:23]([CH3:26])([O-:25])=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=[CH:26][N+:23]([O-:25])=[O:24])[C:7]=2[N:17]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc2c(n1)c(C=O)c1n2CCCO1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2CCCO1

Procedure:
300 mg (1.29 mmol) of the compound obtained in Step G dissolved in 15 ml of nitromethane are heated at 120° C. for 4 hours in the presence of 250 mg (3.23 mmol) of ammonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation of the organic phase yields the title compound in the form of a yellow solid.
Reaction SMILES: Cl.[CH:2]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)([CH3:4])[CH3:3].[CH:37](I)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(#N)C.CN(C=O)C>[CH:2]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C@:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([CH3:37])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)I
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc([C@]3(O)CCCN(C)C3)n(C)c2n1
Temperature: 75 °C

Procedure:
The HCl salt of 3-(2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)piperidin-3-ol (80 mg) was reacted with isopropyl iodide (1.5 eq) and potassium carbonate (5 eq) in a 1:1 mixture of DMF and Acetonitrile (2 mL). The reaction was heated at 75° C. for 18 hours until complete. The reaction mixture was diluted with Ethyl acetate and extracted with a saturated ammonium chloride solution. The organic layer was dried, filtered and concentrated to give 581 [4.6 mg; MS (Q1) 491.3 (M)+] and 582 [4.7 mg; MS (Q1) 491.3 (M)+] following reverse phase purification and subsequent chiral separation.
Reaction SMILES: [CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:2].[CH3:44][N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CCN(c1cc(-c2ccc(N3CCNCC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(-c2ccc(N3CCN(C4CCN(C)CC4)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide (0.3 g, 0.51 mmol) and 1-methylpiperidin-4-one (0.086 g, 0.76 mmol) in dichloroethane (5 mL), acetic acid (0.18 g, 3.06 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.33 g, 1.55 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by prep. HPLC to afford the title compound (0.12 g, 34.38%).
Reaction SMILES: [Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH3:13]O>C1COCC1>[Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CO
Reactant: CC(Br)c1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Br)cc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
A solution of trimethylsillyldiazomethane in THF (2M, 49.1 mL, 98.3 mmol) was added dropwise to a solution of 4-(1-bromoethyl)benzoic acid (15 g, 66 mmol) in methanol (75 mL) and THF (75 mL) at 0° C. The resulting mixture was stirred at 23° C. for 3 h, then concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution (2×). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 2H, J=8.5 Hz), 7.51 (d, 2H, J=8.2 Hz), 5.21 (q, 1H, J=6.7 Hz), 3.92 (s, 3H), 2.06 (d, 3H, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].CO.[BH4-].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([F:12])=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)c(F)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CO)c(F)c1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 56.7 %

Procedure:
In a 100 mL round bottomed flask equipped with a stir bar was placed 3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30, 1.67 g, 7.17 mmol), methanol (12 mL), dichloromethane (12 mL) and sodium borohydride. The reaction mixture was allowed to stir at room temperature for 17 hours, quenched with water (10 mL) and 1M HCl (5 mL) and extracted with dichloromethane (2×30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The crude material was triturated with hexanes (15 mL) to produce 955 mg (57%) of (3-bromo-2-fluoro-4-methoxy-phenyl)-methanol (I-31) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCC1CCCCN1Cc1ccccc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCCCC2Cn2cnc(-c3ccccc3)c2)cc1
Reaction time: 16 h
Yield: 24.1 %

Procedure:
4-Phenylimidazole (1.3 g) was treated with sodium hydride (0.6 g 50% in oil) in dry tetrahydrofuran (80 ml). When gas evolution had ceased, 2-bromomethyl-N-benzylpiperidine (2.5 g) in tetrahydrofuran (30 ml) was added. The mixture was stirred for 16 h, solvent removed at reduced pressure and treated with ice/water (1:1, 100 ml). The mixture was extracted with dichloromethane (2×), the combined organic phase washed with water, solvent removed at reduced pressure and the residue column chromatographed (silica gel, 0.5→9.5% dichloromethane/methanol). Appropriate fractions were combined to give the title compound 0.72 g.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:28](O)=[O:29])[CH:6]=1)[CH2:2][CH2:3][CH3:4].P(C#N)(=O)(OCC)OCC.[Cl:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.Cl>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:28]([NH:46][C:45]2[CH:47]=[CH:48][C:42]([Cl:41])=[CH:43][CH:44]=2)=[O:29])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1cc(C(=O)Nc2ccc(Cl)cc2)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h
Yield: 37.9 %

Procedure:
A solution of 5-butyl-1-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]pyrazole-3-carboxylic acid (0.8 g) and diethyl phosphorocyanidate (90% purity, 0.76 g) in DMF (6 ml) was allowed to stir at 0°-5° C. for 1 hour. 4-Chloroaniline (0.25 g) and triethylamine (0.62 g) were added to the solution and the mixture was stirred at room temperature for 3 hours. The reaction solution was made acidic by addition of 1N-HCl and extracted with ethyl acetate. The organic layer was dried and evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give colorless powder (0.38 g, 38%),
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([O:17]C(C)(C)C)=[O:16])[CH:10]=[CH:11][CH:12]=1)([O:5][CH3:6])=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1)([O:5][CH3:6])=[O:4]
Reactant: COP(=O)(OC)c1cccc(/C=C/C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COP(=O)(OC)c1cccc(/C=C/C(=O)O)c1

Procedure:
tert-butyl (2E)-3-[3-(dimethoxyphosphoryl)phenyl]acrylate was dissolved in dichloromethane (6 ml). TFA (3 ml, 38.9 mmol) was added. The reaction was allowed to stir for approximately one and a half hours. The reaction was complete as indicated by LCMS. The reaction was diluted with DCM and washed with brine. The aqueous layer was extracted three times with DCM. The combined organic layer was dried over Na2SO42, filtered, and concentrated. MS: calc'd 257 (MH+), exp 257 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([O:21]C)=O)[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([NH:24][C:25]4[S:26][CH:27]=[C:28]([CH3:30])[N:29]=4)=[O:21])[N:14]([CH3:18])[S:15](=[O:16])(=[O:17])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(O)c2c(c3cc(Cl)ccc3n2C)S(=O)(=O)N1C
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)C2=C(O)c3c(c4cc(Cl)ccc4n3C)S(=O)(=O)N2C)n1
Yield: 81 %

Procedure:
8-Chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 18 from methyl 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 81% of theory.