Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[O:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: O=C1CCOCC1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (21 mg, 0.046 mmol, racemic intermediate from Example 2, Step 1)), tetrahydro-4H-pyran-4-one (from Aldrich, 4.6 μL, 0.050 mmol), and triethylamine (20 μL, 0.14 mmol) in methylene chloride (0.32 mL) was added resin of sodium triacetoxyborohydride (40 mg, 0.091 mmol). The resulting mixture was stirred overnight at rt. The mixture was filtered and concentrated and then purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C24H32ClN6O2 (M+H)+: m/z=471.2; Found: 471.2.
Reaction SMILES: C[N:2]([C:8](OC(C)(C)C)=O)[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:30]1([C:36]#[C:37][C:38]2[N:43]=[C:42]([NH2:44])[CH:41]=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN1C(=O)CCC1>[CH3:8][NH:2][CH:3]([CH3:7])[C:4]([NH:44][C:42]1[CH:41]=[C:40]([C:45]([F:47])([F:46])[F:48])[CH:39]=[C:38]([C:37]#[C:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:43]=1)=[O:6]
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Nc1cc(C(F)(F)F)cc(C#Cc2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(C)C(=O)Nc1cc(C(F)(F)F)cc(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (620 mg, 3.05 mmol) and N,N′-dicyclohexylcarbodiimide (315 mg, 1.53 mmol) in DCM (4 ml) is stirred at RT for 30 minutes. This mixture is added to 6-(2-phenylethynyl)-4-(trifluoromethyl)pyridin-2-amine B3b (100 mg, 0.38 mmol) and DIPEA (73 μl; 0.42 mmol) in NMP (5 ml). After stirring for 6 days at 50° C. the reaction mixture is concentrated in vacuo and the boc-protected product purified by NP chromatography. The boc-protected product is treated with DCM:TFA (9:1, 4 ml) for 1.5 h at RT. This mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 10.2 mg (8%). HPLC-MS: M+H=348; tR=1.46 (*Method—1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][CH:8]([N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](=[O:38])[C:28]([C:39]#[N:40])=[C:27]([CH3:41])[N:26]=1)[CH:22]([CH3:24])[CH3:23])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:13])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:50][C:51](OC(C)=O)=[O:52]>CC(O)=O.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6](=[O:42])[NH:7][CH:8]([N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](=[O:38])[C:28]([CH2:39][NH:40][C:51](=[O:52])[CH3:50])=[C:27]([CH3:41])[N:26]=1)[CH:22]([CH3:23])[CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:13])[CH2:9][CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(NC(=O)OC(C)(C)C)N(C(=O)c1ccc(C)cc1)C(c1nc(C)c(C#N)c(=O)n1Cc1ccccc1)C(C)C
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCC(NC(=O)OC(C)(C)C)N(C(=O)c1ccc(C)cc1)C(c1nc(C)c(CNC(C)=O)c(=O)n1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
To a stirred solution of {1-[{1-[5-Cyano-3-benzyl-6-methyl-4-oxo-3,4-dihydro-pyrimidin-2-yl]-2-methyl-propyl}-(1-p-tolyl-methanoyl)-amino]-propyl}-carbamic acid tert-butyl ester (350 mg, 0.6 mMol) in HOAc (10 mL) was carefully added 10% Pd/C (150 mg). The reaction was hydrogenated under a balloon of H2 for 18 h at RT, filtered through a pad of Celite®, rinsed with HOAc and evaporated under vacuum. To the crude amine (˜34% pure by LCMS, MS (ES) m/e 576.4 (M+H)+) in CH2Cl2 (10 mL) was added with stirring Et3N (280 uL, 2 mMol) and Ac2O (114 uL, 1.2 mMol). After stirring at RT for 2 h the reaction was concentrated under vacuum, taken up in EtOAc, washed with 1 N Na2CO3, 1 N HCl, brine, dried (MgSO4), filtered and evaporated under vacuum. Purification by flash chromatography (80% EtOAc/hexane) gave the title compound (0.10 g, 27%) as an off-white solid: MS (ES) m/e 618.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19]([CH3:27])([CH3:26])[C:20]#[C:21]/[CH:22]=[CH:23]/[CH2:24]Br.C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[CH2:24]/[CH:23]=[CH:22]/[C:21]#[C:20][C:19]([O:18][CH3:17])([CH3:27])[CH3:26])[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COC(C)(C)C#C/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C/C=C/C#CC(C)(C)OC)P(=O)(OCC)OCC
Reaction time: 5 h
Yield: 55.8 %

Procedure:
3.36 g of diethylphosphonoacetic acid ethyl ester is dissolved in 40 ml of ethanol, 0.60 g of 60% oily sodium hydride is added under ice cooling and stirring, 1.09 g of (E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide is added dropwise, and the mixture is stirred under ice cooling for 1 hour and then at room temperature for 5 hours. 15 ml of acetic acid is added to the reaction solution, the solvent is distilled off under reduced pressure, and the residue is extracted with a system of water and ethyl acetate. The organic layer is post-treated in a conventional manner, and the product is purified by silica gel column chromatography [Wako gel C-200, 100 g; hexane/ethyl acetate=1/2] and medium pressure liquid chromatography [Lobar column, size B, Lichroprep Si 60F (produced by Merck Co.); hexane/ethyl acetate=1/1→1/2] to obtain 1.01 g of (E)-diethylphosphono(6-methoxy-6-methyl-2-hepten-4-ynyl)acetic acid ethyl ester as colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[NH2:8][CH2:9][CH2:10][OH:11].[S-:12][C:13]#[N:14].[K+].II>>[C:2]([C:3]1[S:12][C:13](=[NH:14])[N:8]([CH2:9][CH2:10][OH:11])[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: N#C[S-]
Reactant: NCCO
Reactant: CC(C)(C)CC=O
Agent: II
Agent: [K+]
Product: CC(C)(C)c1cn(CCO)c(=N)s1

Procedure:
Commercially available 3,3-dimethylbutanal (Aldrich), 2-aminoethanol (Aldrich), potassium thiocyanate (Aldrich) and iodine (EMD chemicals) were processed using the method described in Example 315A to afford the title compound. MS (ESI+) m/z 201 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=O)=[C:6]([CH:15]=1)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.O>CC(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:7][C:8]3[C:13]([N:16]=2)=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=3)[CH:15]=1
Reactant: O=Nc1ccc(Br)cc1Nc1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2nc3cc(Br)ccc3nc2c1
Yield: 16 %

Procedure:
5-bromo-N-(4-bromophenyl)-2-nitrosoaniline (13-1) (10 g, 28.1 mmol) in AcOH (300 mL) was heated under reflux for 1.5 h. Water (400 mL) was then added and the brown precipitate formed was collected by filtration after washing with water (2×200 mL). The product was purified by silica gel chromatography (SiO2, hexanes/DCM=1/1 (v/v)) to afford a brown solid, 2,7-dibromophenazine 13-2 (1.52 g, 16% yield). 1H NMR (CDCl3) δ 8.43 (2H, dd, J 2.2, 0.4 Hz), 8.10 (2H, dd, J 9.2, 0.4 Hz), 7.91 (2H, dd, J 9.2, 2.2 Hz) ppm. LC-MS (ESI): m/z 338.6 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH:9](O)=[O:10]>>[CH:9]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:10]
Reactant: O=CO
Reactant: CC(C)[C@H](N)C(=O)O
Product: CC(C)[C@H](NC=O)C(=O)O
Reaction time: 17 h

Procedure:
To valine (11.7 g, 0.10 mole) in 88% formic acid (40 ml) is added acetic formylanhydride (26.3 g, 0.30 mole) over 0.5 hr at 5°. The reaction mixture is warmed to 24° and stirred for 17 hours. The reaction is worked up by distilling off (bath temp. 45°-50°) the solvent, excess anhydride and acetic acid, to give, as a white solid, N-formylvaline, recrystallized from hot ethanol, m.p. 143°-145°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:27])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:30]>C(OCC)(=O)C>[ClH:30].[ClH:30].[CH3:27][C:17]1[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[S:20][C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(tert-butoxycarbonyl)-4-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]piperazine (6.40 g) were added methanol (30 ml) and 4N hydrochloric acid in ethyl acetate (30 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was washed with ether and dried under reduced pressure to give powders of the title compound (5.8 g).
Reaction SMILES: [Cl:1][C:2](Cl)=[CH:3][C:4](=[O:14])[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7].Cl(O)(=O)(=O)=O.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[O:7][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][C:4](=[O:14])[CH:3]=1
Reactant: O=C(C=C(Cl)Cl)CC(=O)N1CCOCC1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1cc(Cl)oc(N2CCOCC2)c1
Temperature: 90 °C
Yield: 75.4 %

Procedure:
To a suspension of 5,5-Dichloro-1-morpholin-4-yl-pent-4-ene-1,3-dione (11.3 g, 44.9 mmol) in dioxane was added perchloric acid (11.4 ml, 0.14 mol) and the reaction was heated at 90° C. under N2 for 1 h. The reaction was cooled, neutralised with 2M NaOH (75 ml) and filtered. The aqueous layer was extracted with dichloromethane (4×30 ml) and the organic layers were combined and dried over MgSO4. The organic layer was further treated with charcoal and filtered through celite. The dark yellow filtrate was evaporated in vacuo, and the resulting solid was triturated with hexane (50 ml) and dried to give the desired compound (7.3 g, 75%) as a light yellow powder. m/z (LC-MS, ESP): 216 (M++1). 1HNMR (300 MHz, DMSO-d6): 3.3 (t, 4H), 3.65 (t, 4H), 5.4 (d, 1H), 6.25 (d, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH:13]=O>[Pd].CO.O>[CH2:13]([N:1]([CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH3:10])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])[CH2:12][C:11]([CH3:16])([CH3:15])[CH3:10]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CC(C)(C)CC=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(C)CCN(CCC(C)(C)C)[C@@H](CC(=O)O)C(=O)O

Procedure:
To a slurry of L-aspartic acid (4 g, 0.03 mol) in 1:1 methanol/water (80 mL) was added neat 3,3-dimethylbutyraldehyde (3 g, 0.03 mol), followed by Pd/C (4%, 50% wet, 0.5 g). The mixture was hydrogenated using H2 (50 psi) at room temperature for 2 days. The resulting reaction mixture was filtered through a Celite® bed, and the bed washed with methanol (50 mL) The filtrate and washings were combined and the methanol removed using a rotary evaporator under reduced pressure at 40-50° C. to provide the N,N-di-neohexyl L-aspartic acid as a solid precipitate in water. The solid was filtered, washed with water (2 mL) and dried in a vacuum oven at 50° C. for 4 hrs to provide 3.2 g of N,N-di-neohexyl L-aspartic acid (36%), M.P. 197-198° C., [α]D -3 (c=1, methanol). Anal. Calc'd. for C16H31NO4 ; C, 63.78; H, 10.29; N, 4.65. Found: C, 63.43; H, 10.29; N, 4.70
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[C:19]2[NH:20][C:21]3[C:22]([N:27]=2)=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.C(=O)([O-])[O-:31].[K+].[K+]>C(O)(=O)C.O>[C:1]1([S:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[C:19]2[NH:20][C:21]3[C:22]([N:27]=2)=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCSc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCS(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.8 gm (0.0074 mol) of 2-[2-(2-phenylthioethoxy)-4-methoxyphenyl]imidazo[4,5-b]pyridine in 40 ml of glacial acetic acid was admixed with 0.84 gm of hydrogen peroxide (30%), and the mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was diluted with 20 ml of water, neutralized with potassium carbonate, extracted three times with 50 ml each of methylene chloride, and dried over magnesium sulfate. The purification was carried out on 70 gm of silicagel with methylene chloride/acetone (100:0 to 80:20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=2[CH:27]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][C:39]=1[C:47]([O:49][CH2:50]C)=[O:48]>>[CH3:50][O:49][C:47]([C:39]1[CH:40]=[C:41]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=4[CH:27]=3)([OH:14])[C:10]([F:11])([F:12])[F:13])=[C:2]([Cl:1])[CH:3]=2)[CH:42]=[CH:43][C:38]=1[Cl:37])=[O:48]
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)cc21
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(Cl)c(C(=O)OC)c4)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 64, step 7, trifluoromethanesulfonic acid 3-chloro-4-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 64, step 6) was reacted with 4-chloro-3-(ethoxycarbonyl)phenylboronic acid (70° C., 5.5 h) to give title compound as a white solid. MS (m/e)=596.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:32])[C:17]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:34][C:35]#[N:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH3:32])[C:17]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:34][C:35]#[N:36]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.5 %

Procedure:
A mixture N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-N-methyl-1-benzofuran-3-carboxamide (1.60 g, 3.25 mmol), prepared in the previous step, bromoacetonitrile (272 μL, 3.90 mmol) and potassium carbonate (2.25 g, 16.3 mmol) in 25 mL of DMF was stirred under nitrogen at room temperature for 23 h. The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-2-butyl-N-methyl-1-benzofuran-3-carboxamide (1.65 g, 95%) as a brown foam, MS (ESI) m/z 531 [M+H]+. Elemental Analysis for C29H27BrN2O3. Calc'd: C, 65.54; H, 5.12; N, 5.27. Found: C, 65.37; H, 5.14; N, 5.21.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].I[CH3:25]>COCCOC>[CH2:20]([O:19][C:17]([N:15]1[CH2:14][CH2:13][C:10]2[N:11]([CH3:25])[C:12]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]=2[CH2:16]1)=[O:18])[CH3:21]
Reactant: CI
Reactant: CCOC(=O)N1CCc2[nH]c3c([N+](=O)[O-])cccc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CCOC(=O)N1CCc2c(c3cccc([N+](=O)[O-])c3n2C)C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 108.9 %

Procedure:
Ethyl 6-nitro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (0.33 g, 1.12 mmol) was combined with KOH (0.31 g, 5.6 mmol) and iodomethane (1.3 g, 8.96 mmol) in ethylene glycol dimethyl ether (5.6 mL) and stirred at 90° C. for 16 h. The inorganic solid was filtered and the filtrate evaporated to give ethyl-5-methyl-6-nitro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (0.37 g) as an orange oil in near quantitative yield. 1H NMR (CDCl3, 300 MHz) δ 7.74 (d, 1H, J=7.7 Hz), 7.67 (d, 1H, J=7.7 Hz), 7.12 (t, 1H, J=8.0 Hz), 4.70 (s, 2H), 4.22 (q, 2H, J=7.0 Hz), 3.91 (br. s, 2H), 3.62 (s, 3H), 2.84 (t, 2H, J=5.5 Hz), 1.30 (t, 3H, J=7.0 Hz) ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N=C=N.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][N:34]([C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)[CH2:33][CH2:32]1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(C3CCN(C(=O)Cc4ccc(C(C)C)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
To a solution of 4-isopropylphenylacetic acid (36 mg, 0.2 mmol) in anhydrous DCM (1 mL) was added PS-carbodiimide (100 mg, 0.3 mmol) and the mixture was shaken at rt for 15 min. Then, a solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (27.5 mg, 0.1 mmol), as prepared in Example 1d, in anhydrous DMF (1 mL) was added to the mixture and it was shaken overnight at rt. It was then filtered and the resin was washed with THF/DCM and the combined filtrate and washings were concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to yield 13.4 mg (31%) of pure 1-[4-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-1-yl]-2-(4-isopropyl-phenyl)-ethanone. 1H-NMR (300 MHz, CDCl3): δ 9.06 (s, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 7.23-7.19 (m, 4H), 4.82 (d, 1H), 4.17-4.00 (m, 7H), 3.76 (m, 2H), 3.57 (m, 1H), 3.23 (m, 1H), 2.96-2.80 (m, 2H), 2.06-1.80 (m, 4H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 433.2, found 434.4 (MH)+.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[Br:16]Br.C(OCC)(=O)C.CCCCCC>C(O)C>[Br:16][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=2)[NH:2][N:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccc2[nH]ncc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]nc(Br)c2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.9 %

Procedure:
ethyl 1H-indazole-5-carboxylate hydrochloride (146 g, 0.645 mol) was dissolved in ethanol (4 L, anhydrous). Bromine (113.3 g, 0.709 mol) in 200 ethanol was added at room temperature. The reaction mixture was allowed to stir for 17 hours at room temperature. TLC (30% ethyl acetate/hexane) indicated that starting material was left. Bromine (40 g in 100 mL of ethanol) was added at room temperature. After 1 hour, TLC indicated no starting material was left. Ethanol was evaporated (2 L removed) and the mixture was poured into ice-water (8 L). The purple solid was stirred and 750 mL of saturated Na2S2O3 and NaOH solution was added to adjust the pH to 10-11. Total volume was 10 L. The mixture was stirred for 30 minutes and the solid were filtered and washed with 1.5 L of water and dried in a vacuum oven to obtain 170 gram of product as yellow solid.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16]C1C(C(O)=O)=C(I)C=CC=1.N1C=CN=N1>>[CH3:16][C:10]1[CH:2]=[CH:3][CH:4]=[C:5]([N:11]2[N:12]=[CH:13][CH:14]=[N:15]2)[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1cccc(I)c1C(=O)O
Agent: c1c[nH]nn1
Product: Cc1cccc(-n2nccn2)c1C(=O)O

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 6-methyl-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 204 [M+1]+.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)C(O)C(C)(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of-(2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4R)-4-amino-2,2-dimethyl-hexan-3-ol (52 mg, 3.41 eq, 0.36 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 6.3 mg (15%). (55% de 4R,3S: 45% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 1.00-1.03 (m, 12H, —NHCH(CH2CH3) CH(C(CH3)3OH), 1.56 & 0.58 (2×d, 6H, J=6.63 & 6.63 Hz, —CH(CH3)2), 1.69-1.89 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.56 (d, 1H, J=1.89 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.72-3.84 (m, 1H, —NHCH(CH2CH3) CH(C(CH3)3) OH), 4.58-4.70 (m, 1H, —CH(CH3)2), 4.88-4.98 (m, 2H, —HNCH2-Pyr), 5.22-5.39 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 6.70-6.80 (m, 1H —HNCH2-Pyr), 7.18-7.24 (m, 1H, Pyr-H), 7.38 (d, 1H, J=7.90, Pyr-H), 7.57 (s, 1H, —N═CH—N—), 7.63-7.70 (m, 1H, Pyr-H), 8.61 (d, 1H, J=4.90 Hz, Pyr-H). FABMS m/z (relative intensity): 412 ([M+H]+, 100), 324 (70). Accurate Mass (M+H): Actual: 412.2825, Measured: 412.2835.