Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]I.O>CCOCC>[CH3:23][C:22]([OH:24])([C@H:21]([NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH3:26])[CH3:27]
Reactant: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reactant: C[Mg]I
Solvent: O
Solvent: CCOCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)O

Procedure:
To a stirred solution of (3R)-3-(trityl-amino)-pentan-2-one (0.87 g, 1 eq, 2.54 mmol) in Et2O (100 mL) under an argon atmosphere at room temperature, was added methylmagnesium iodide (3 M in ether, 2.54 mL, 3 eq, 7.62 mmol) dropwise. The solution was placed in a preheated oil bath at 45° C. and refluxed at this temperature for 16 h. The mixture was recooled to 0° C., H2O (100 mL) added, the solution filtered through Celite, and the Celite washed with more Et2O (50 mL). The combined organic phase was separated, the aqueous phase was extracted with Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (NgSO4) and evaporated in vacuo. The residue was purified by silica gel colunm chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.21 g (23%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.26 (t, J=7.42 Hz, —NHCH (CH2CH3)CH(CH3)OH), 1.00 & 1.25 (2×s, 6H, —NHCH(CH2CH3) C(CH 3)2 OH), 0.72-1.43 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 1.84 (m, 1H, —NHCH (CH2CH3)C(CH3)2OH), 2.90 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.32 (s, 1H, —NHCH(CH2CH3) C(CH3)2OH), 7.17-7.46 (m, 15H, 3×Ph).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([C:24]2[CH:25]=[C:26]([C:30]([F:34])([F:33])[C:31]#[N:32])[CH:27]=[CH:28][CH:29]=2)[CH:17]=1>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:34])([F:33])[C:31]3[NH:32][N:3]=[N:2][N:1]=3)[CH:25]=2)[N:19]=[C:20]([O:22][CH3:23])[N:21]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(F)(F)C#N)c2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(F)(F)c3nnn[nH]3)c2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
Sodium azide (10 mg, 0.15 mmol) is added to a stirred solution of (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-difluoro-acetonitrile (50 mg, 0.11 mmol) in N,N′-dimethylformamide (4 mL) and the reaction is stirred for 4 hours at 80° C. The reaction is quenched with water, acidified to pH 2 (0.05 N HCl), extracted twice with ethyl acetate. The combined extracts is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is diluted in toluene and concentrated in vacuo to afford [2-(2,4-dichloro-phenyl)-ethyl]-(6-{3-[difluoro-(1H-tetrazol-5-yl)-methyl]-phenyl}-2-methoxy-pyrimidin-4-yl)-amine [45 mg, Example 82(c)]. LCMS: RT=2.29 minutes, LCMS: 492, 494 (M+H). IC50=0.1 nM
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br-:10].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1cnccn1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cnccn1
Reaction time: 8 h
Yield: 38.3 %

Procedure:
Acetylpyrazine (244 mg, 2.0 mmol) was suspended in glacial acetic acid (10 mL) and treated with pyridinium tribromide (640 mg, 2.0 mmol). The reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:1 hexane/ethyl acetate, to provide 2-(2-bromoacetyl)pyrazine as a brown solid (154 mg, 38%). 1H NMR (200 MHz, DMSO-d6) δ 9.16 (d, J=1.5 Hz, 1H), 8.94 (d, J=2.4 Hz, 1H), 8.82 (dd, J=1.5, 2.4 Hz, 1H), 4.99 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([F:19])[CH:13]=3)[CH:11]=1)[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2.[OH-].[Na+:28]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([F:19])[CH:13]=3)[CH:11]=1)[O:8][C@H:7]([C:20]([F:22])([F:23])[F:21])[C:6]([C:24]([O-:26])=[O:25])=[CH:5]2.[Na+:28]
Reactant: Cc1ccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)O)=C3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2cc(Cl)cc3c2O[C@H](C(F)(F)F)C(C(=O)[O-])=C3)cc1F

Procedure:
A solution of 95.1 mg (0.246 mmole) of 6-chloro-8-(3-fluoro-4-methylphenyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 2.0 mL of ethanol was treated with 2.439 mL of0.1008N NaOH. The resultant mixture was lyophilized to provide a quantitative yield of a yellow solid: 1H NMR (CD3OD/400 MHz) 2.29 (d, 3H, J=1.6 Hz), 5.84 (q, 1H, J=7.2 Hz), 7.17-7.20 (m, 2H), 7.24-7.29 (m, 3H), 7.40 (s, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[NH:39][C:40](=[O:47])[O:41][C@H:42]([CH2:44][CH2:45][CH3:46])[CH3:43]>>[CH3:20][N:19]([CH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:4]2[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]3=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([NH:39][C:40](=[O:47])[O:41][C@H:42]([CH2:44][CH2:45][CH3:46])[CH3:43])=[C:24]([O:23][CH3:22])[CH:29]=3)[N:3]=2)[CH2:13][CH2:14]1)[CH3:21]
Reactant: CCC[C@H](C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN(C)C)CC1
Product: CCC[C@H](C)OC(=O)Nc1ccc(-c2nc([C@H]3CC[C@H](CN(C)C)CC3)n3ccnc(C)c23)cc1OC

Procedure:
1-((Trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N,N-dimethylmethanamine (26 mg) and (S)-pentan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (27 mg) were used according to the procedure described in example 4 step 4c and the crude product was purified by prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and made basic with aqueous sodium hydrogencarbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give (S)-pentan-2-yl 4-(3-((trans)-4-((dimethylamino)methyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate (9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Na+].CO.O>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cc(F)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-chloro-5-fluorobenzoate (23, 35.0 g, 185.6 mmol) in dry THF (150 mL) was added NaBH4 (21.2 g, 557 mmol). Methanol (40 mL) was added dropwise at RT. After the addition, the mixture was stirred at RT for 1 h. Water (300 mL) was slowly added. The mixture was extracted with CH2Cl2 (200 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give (2-chloro-5-fluorophenyl)methanol (24).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=1)([O-:25])=[O:24].[H-].[Na+].O>CN(C=O)C>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]3[C@H:8]4[C@H:18]([CH2:19][CH2:20][C@:3]23[CH3:4])[C@:16]2([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]2)[CH2:10][CH2:9]4)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc([N+](=O)[O-])cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 17β-hydroxy-4-methyl-5α-4-azaandrostan-3-one (1.07 g, 3.5 mmole) and p-nitrofluorobenzene (2.0 ml, 14 mmole) in DMF (15 ml) under N2 was added 95% NaH (180 mg, 7 mmole) in two portions during 10 mins. The mixture was stirred for 3 hours at room temperature and poured onto ice (50 g) and water (50 ml). The mixture was extracted with CH2Cl2 (30 ml×2). The organic layer was washed with brine and dried (Na2SO4). Removal of solvent gave the crude product which was purified via a flash silica gel column eluting with 1:1 ethyl acetate-CH2Cl2 to give the desired title product. Mp. 183°-184° C. (recrystallized from CH2Cl2 -hexane).
Reaction SMILES: [ClH:1].C(OCC)C.[F:7][C:8]1([F:24])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[CH2:10][CH2:9]1>>[ClH:1].[ClH:1].[F:24][C:8]1([F:7])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH2:16])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(F)(F)CC1
Agent: Cl
Solvent: CCOCC
Product: NCCN1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.9 ml of a 2 N solution of hydrogen chloride in diethyl ether (13.8 mmol, 10 equivalents) were added to 500 mg of tert-butyl [2-(4,4-difluoropiperidin-1-yl)ethyl]carbamate (Example 166A, 1.38 mmol, 1 equivalent), and the mixture was stirred at RT overnight. The solvent was decanted off, the residue was triturated three times with diethyl ether, the diethyl ether was decanted off and the product obtained in this manner was dried under reduced pressure. This gave 448 mg (100% of theory; purity 73%) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][C:28]=1[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[O:13][CH2:14][C:15]1[S:16][C:17](/[C:20](/[CH2:24][CH3:25])=[CH:21]/[C:22]#[CH:23])=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[F:43][C:44]([F:52])([F:51])[C:45]([C:47]([F:50])([F:49])[F:48])=[O:46]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][C:28]=1[CH2:29][O:30][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[O:13][CH2:14][C:15]1[S:16][C:17](/[C:20](/[CH2:24][CH3:25])=[CH:21]/[C:22]#[C:23][C:45]([C:47]([F:50])([F:49])[F:48])([OH:46])[C:44]([F:52])([F:51])[F:43])=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#C/C=C(\CC)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC/C(=C\C#CC(O)(C(F)(F)F)C(F)(F)F)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1.7 g (3 mmol) of 2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-5-((E)-1-ethyl-but-1-en-3-ynyl)thiophene are dissolved in 50 mL of THF and the mixture is cooled to −78° C. 1.3 mL (3.3 mmol) of 2.5 M butyllithium are then added. After stirring for 15 minutes at the same temperature, a gentle flow of hexafluoroacetone (gas) is introduced into the reaction medium. After reaction for 20 minutes at −78° C., the flow of gas is stopped and the reaction medium is treated in the usual manner. The residue obtained is purified by chromatography on silica gel. The desired product is obtained in the form of a yellow oil (1 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[C:3]=1[NH:17][CH3:18].[H-].[Na+].[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29]Cl)(=[O:23])[CH3:22]>CS(C)=O>[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][N:5]1[C:4](=[O:16])[C:3]([NH:17][CH3:18])=[C:2]([NH2:1])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]1=[O:15])(=[O:23])[CH3:22]
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: CNc1c(N)n(Cc2ccccc2)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1c(N)n(Cc2ccccc2)c(=O)n(CCCC[C@@H](C)OC(C)=O)c1=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
6-Amino-1-benzyl-5-methylaminouracil (11 g, 43 mmol) was added to a suspension of sodium hydride (1.032 mg, 43 mmol) in anhydrous dimethylsulfoxide (75 ml). After stirring for 30 minutes, (R)-5-acetoxy-1-chlorohexane (7.675 g, 43 mmol) was added. The mixture was heated at 70-80° C. for 12 hours. After cooling to room temperature, the reaction was quenched by the addition of water (150 ml) and extracted with ethyl acetate (3x 125 ml). The combined extracts were washed with water (2x 50 ml), with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-3-(5-acetoxyhexyl)-6-amino-1-benzyl-5-methylaminouracil (7.89 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.BrBr>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Cl)cc2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1

Procedure:
A 283 g. portion of 6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Example 1 of U.S. Pat. No. 3,689,652) is suspended in 2500 ml. of acetic acid at room temperature with stirring. A 227 g. (72.7 ml.) portion of bromine is dissolved in 300 ml. of acetic acid and 20% of this solution is added to the reaction mixture which is then heated on a steam bath until the bromine color disappears. The balance of the bromine solution is added portionwise, over a 1/2 hour period to the heated solution. The reaction mixture is heated for an additional hour and then poured into crushed ice. The resulting solid is recovered by filtration, washed with water and dried yielding an off-white solid, m.p. 269°-272° C., 6-(p-chlorophenyl)-3(2H)-pyridazinone.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[C:4](=[O:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)O1>>[CH3:25][C:10]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:9][CH2:8][N:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=3)=[CH:39][CH:40]=2)=[CH:3][C:4]1=[O:26])[C:11]([NH:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[O:12]
Reactant: CC(CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: CC1(C)OB(c2ccc(-c3ccncc3)cc2)OC1(C)C
Product: CC(CCn1ccc(-c2ccc(-c3ccncc3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O

Procedure:
(+/−)-4-(4-Iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be prepared as in Preparation 2A and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine were converted to the title product following the general procedure outlined for (+/−)-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide in Example 33, Step A. The title compound was obtained as a white solid (161 mg, 61%) LC-MS m/z 526.7 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][C:5]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>CCOCC>[CH3:13][O:12][CH:3]([O:2][CH3:1])[CH2:4][C:5]1([CH2:10][NH2:11])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(CC1(C#N)CCCC1)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(CC1(CN)CCCC1)OC
Temperature: 25 °C
Yield: 88 %

Procedure:
54 mmol of the product obtained in Stage A, in 100 ml of ether, are added dropwise to 109 mmol of lithium aluminum hydride suspended in 200 ml of ether stirred at room temperature under a nitrogen atmosphere. When all the nitrile has disappeared, 10 ml of ethyl acetate are added to the mixture, followed by 10 ml of water. The mixture is stirred for 1 hour, filtered and dried over MgSO4 and the solvent is evaporated off. The expected product is obtained in an 88% yield.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][CH:7]([NH:9][C:10](=[O:21])[CH2:11][CH2:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:8].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][CH2:11][C:10]([NH:9][CH:7]([CH3:8])[CH3:6])=[O:21])=[S:4]
Reactant: CC(C)NC(=O)CCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)NC(=O)CCC(=NNC(N)=S)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
Thiosemicarbazide (2.08 g, 22.8 mmol) was added to a solution of N-(1-methylethyl)-4-oxo-4-phenyl-butyramide (5.0 g, 22.8 mmol), prepared in the previous step, in 80 ml of methanol plus 6.2 ml of 1 N HCl plus 6.2 ml of water and the reaction stirred at room temperature for 2 days. An additional 1.04 g (11.4 mmol) of thiosemicarbazide was added and the reaction stirred at room temperature for 24 hours. The reaction was cooled in an ice bath and a white solid precipitated. The solid was collected by filtration and dried. Recrystallization of the solid from isopropyl alcohol gave the title compound (4.73 g, 53%) as a white solid, mp 66-71° C.
Reaction SMILES: [C:1]([C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]3[CH:25]=[CH:24][C:23]4[NH:22][C:21]5[CH2:26][CH2:27][N:28](C(OCC6C=CC=CC=6)=O)[CH2:29][C:20]=5[C:19]=4[CH:18]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].Br.CC(O)=O.C(N(CC)CC)C.[F:54][C:55]([F:67])([F:66])[C:56]1[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[CH:58][CH:57]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]3[CH:25]=[CH:24][C:23]4[NH:22][C:21]5[CH2:26][CH2:27][N:28]([S:62]([C:59]6[CH:58]=[CH:57][C:56]([C:55]([F:54])([F:66])[F:67])=[CH:61][CH:60]=6)(=[O:64])=[O:63])[CH2:29][C:20]=5[C:19]=4[CH:18]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:40][CH:41]=1)#[N:2]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(CN2CCC(NC(=O)c3ccc4[nH]c5c(c4c3)CN(C(=O)OCc3ccccc3)CC5)CC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc4[nH]c5c(c4c3)CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC5)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 8-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (4a, 50 mg, 91 μmol) in DCM (dichloromethane) (1.0 mL) was added dropwise a solution of HBr/AcOH (48% w/v, 1.0 mL). After the resulting brown reaction mixture was stirred for 30 min, the volatiles were evaporated, MeOH (2 mL) was added and the volatiles evaporated again. The resulting brown residue was dissolved in DMF (1.0 mL) and triethylamine (0.5 mL, 0.36 g, 3.6 mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (45 mg, 0.2 mmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, then poured into saturated sodium bicarbonate solution (20 mL) to give a brown precipitate which was filtered and purified by reverse phase HPLC to provide Compound 24 upon trituration with ethyl ether (18 mg, 31%). 1H NMR (DMSO-d6, 300 MHZ) 11.21 (br s, 1H), 11.18 (br s, 1H), 9.75 (br s, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.07 (d, J=8.3 Hz, 2H), 7.98 (d, J=7.7 Hz, 4H), 7.71 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.5 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 4.40 (d, J=8.3 Hz, 4H), 3.55-3.06 (m, 7H), 2.92-2.82 (m, 2H), 2.07 (d, J=10.5 Hz, 2H), 1.78 (q, J=11.3 Hz, 2H) ppm; MS (ES) 622 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[CH2:20][CH2:19][CH2:18][C:17]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:36])[C:28]1[CH:33]=[C:32](I)[CH:31]=[CH:30][C:29]=1[NH2:35])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[C:28]1[C:29]([NH2:35])=[CH:30][CH:31]=[C:32]([C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:33]=1)[CH3:25]
Reactant: CCOC(=O)c1cc(I)ccc1N
Reactant: Cc1ccc(OCc2ccccc2)c(C2=C(B(O)O)CCC2)c1
Product: CCOC(=O)c1cc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)ccc1N

Procedure:
Prepared by general procedure C(iii) but using 2-(2-benzyloxy-5-methylphenyl)cyclopentene-1-boronic acid instead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and 2-amino-5-iodobenzoic acid ethyl ester instead of 2-chloropyrimidine-4-carboxylic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH:30]2[CH2:36][C:37]([O:39][CH3:40])=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:23]([C:19]1[CH:18]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[N:22]=[CH:21][N:20]=1)=[O:24])[CH2:31][CH:30]2[CH2:36][C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)CC1CNc2ccc(F)cc21
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC1CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccc(F)cc21

Procedure:
150 mg (0.441 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 105 mg (0.500 mmol) methyl (5-fluoro-2,3-dihydro-1H-indol-3-yl)-acetate, 148 mg (0.460 mmol) TBTU and 112 μL (0.80 mmol) triethylamine in 2 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by preparative HPLC-MS without any further working up. The product fractions were combined and lyophilised.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][O:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:18]([N:20]([CH3:22])[CH3:21])=O.N1C=CC=CC=1.[OH-].[Na+]>O>[CH3:15][O:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:18]([N:20]([CH3:22])[CH3:21])=[S:2]
Reactant: COC(C(=O)N(C)C)c1ccccn1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: COC(C(=S)N(C)C)c1ccccn1

Procedure:
Phosphorus pentasulfide (4 g.) is added to 9.7 g. of 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide in 25 ml. of pyridine. The mixture is heated on a steam bath for 2 hours, then 250 ml. of water and 10 ml. of 5% aqueous sodium hydroxide solution are added. The mixture is extracted with chloroform and the extracts are dried and concentrated and the residue is recrystallized to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)-thioacetamide.