Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].O.C(=O)(O)[O-].[C:15](O)(=[O:26])[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.Cl>COCCOC>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:15]([NH:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:26]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: NC(=O)[C@H](CC(=O)O)NC(=O)c1ccc2ccccc2n1
Yield: 69.1 %

Procedure:
To a solution of 0.50 g (3.78 mmol) of L-isoasparagine in 5.0 mL H2O containing ~45 mg (1.5 eq) of solid bicarbonate. To this was added a suspension of 1.02 g (3.78 mmol) quinaldic acid, N-hydroxysuccinamide ester in ethylene glycol dimethylether, and the suspension was solubilized by the addition of 10 mL of dimethyfformamide. After 3 hours the solution was acidified by the addition of 5% HCl (aqueous) and the product was filtered and washed with water, dried under vacuum to yield 750 mg (70% yield) of N-(2-quinolinylcarbonyl)-L-isoasparagine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:9]([NH:1][C@@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC[C@@H](C)N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC[C@@H](C)NCc1ccccc1
Temperature: 0 °C
Reaction time: 28 h

Procedure:
A sample of 0.65 mL (4.4 mmol) of (R)-(−)-2-aminoheptane (R-44) 0.44 mL (4.4 mmol) of benzaldehyde and 0.1 mL of HOAc were combined in 40 mL of CH2Cl2 and then cooled to 0° C. To the reaction mixture was added 2.75 mg (13 mmol) of sodium triacetoxyborohydride in one portion, which was stirred under argon at room temperature for 28 hours. The reaction mixture was diluted with 30 mL of CH2Cl2, cooled in an ice bath and 80 mL of 5% NaOH (in water) was added. Fractions were separated, organics (Na2SO4) dried and evaporated to 638 mg (71%) of (R)-15. 1H NMR (CDCl3) δ 0.88 (m, 3H), 1.08 (d, 3H J=6.6 Hz), 1.20-1.39 (m, 6H), 1.41-1.67 (m, 2H), 3.62-3.77 (m, 1H), 3.75 (p, 2H, J=12 Hz), 7.17-7.41 (m, 5H); MS (APCI+) m/z (rel): 206 (100); [α]D=+6.9° (c=1.0, MeOH).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:20][CH:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: C[C@]12CCC(OCc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
3β-Benzyloxyandrost-5-en-17β-thiol is obtained starting from dehydroepiandrosterone. The dehydroepiandrosterone is reacted with one equivalent of sodium hydride and benzyl chloride by standard procedures for making benzyl ethers to give 3-benzyloxyandrost-5-en-17-one. This benzyloxy compound is then reacted with Lawesson's reagent (4-methoxyphenylthiophosphine sulfide dimer) according to the procedure described in M. Feiser, "Feiser and Feiser's Reagents for Organic Synthesis", John Wiley & Sons, New York, 1980, p. 327; also B. S. Pedersen et al., Bull. Soc. Chim. Belg., 87, 223 (1978). This gives 3β-benzyloxyandrost-5-ene-17-thione and this thione is then reduced with lithium aluminum hydride by standard procedures to give the desired 17β-thiol. Then, to a solution of cyclopropanone in dichloromethane under nitrogen at -50° C., there is added rapidly 1.1 equivalent of the above thiol in dichloromethane. The temperature is allowed to rise to -30° C. and, after 16 hours, most of the solvent is evaporated. Dry ether is added to precipitate by-product polyketene. The by-product is removed by filtration, the solvent is distilled from the filtrate, and the residue is purified by flash chromatography to give 3β-benzyloxy-17β-(1-hydroxycyclopropylthio)androst-5-ene.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCc1cccc(C(=O)OC)c1C(=O)OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Triethylamine (1.57 g, 18.5 mmol) was added to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The mixture was cooled in an ice bath to 4° C. Ethyl chloroformate (1.0 g, 9 mmol) was added slowly keeping the mixture at 4-6° C. After addition was complete, the mixture was stirred in an ice bath for 30 minutes and then warmed to room temperature for 2 hours. The mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the residue was purified by flash chromatography (dichloromethane/ethyl acetate 95 to 5) to give 1.59 g (70%) of the product as an oil: 1H NMR (CDCl3) δ 7.87 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 5.30 (b, 1H), 4.32 (d, J=6.3 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[Br:17]Br>[Zn].CC(O)=O>[Br:17][C:7]1[CH:8]=[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([NH2:1])=[N:5][CH:6]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ncccc1Sc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1Sc1ccccc1
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
mL 2-Nitro-3-(phenylthio)pyridine (16.3 g, 70.2 mmol) and AcOH (250 mL) were cooled in a water bath. Zinc (22.9 g, 351 mmol) was slowly added and stirred for 5 minutes. Filtered through celite and the cake washed with CH2Cl2. The CH2Cl2 was removed and to the solution was added bromine (3.6 mL, 70.2 mmol). After 10 minutes, the HOAc was removed and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (1.5 L SiO2 and 30% EtOAc in hexanes) to afford the title compound (18.2 g, 92.21% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)O1.[Br:37][C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[CH:40][CH:39]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)cc1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(-c4ccc(Br)cc4)cc3)cc2)cc1
Temperature: 95 °C
Yield: 69.9 %

Procedure:
A mixture of compound 8 (3.0 g, 6.3 mmol), 1-bromo-4-iodobenzene (3.57 g, 12.6 mmol), Pd(PPh3)4 and potassium carbonate (1.74 g, 12.6 mmol) in dioxane/water (40 ml/8 ml) was degassed and heated at 95° C. for 24 hours. After being cooled to RT, a yellow solid precipitated and was collected by filtration. The solid was recrystallized in dichloromethane/methanol to give a pale yellow solid (2.22 g). The filtrate was loaded on silica gel and purified by flash column to give additional amount of yellow solid 9 (0.42 g). The total amount of solid was 2.64 g, in 83% yield.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:21]([CH:18]([N:13]1[C:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccccc1
Product: CCC(CC)n1nc2c(c1-c1ccccc1)CCNCC2
Yield: 42.9 %

Procedure:
The title compound (40 mg) was prepared as in Example 177, Steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 120 mg of phenylboronic acid. MS (ESI): exact mass calculated for C18H25N3, 283.20; found, m/z 284.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.48-7.38 (m, 3H), 7.24-7.19 (m, 2H), 3.77-3.70 (m, 1H), 3.36-3.31 (m, 2H), 3.24-3.19 (m, 2H), 3.14-3.09 (m, 2H), 2.71-2.65 (m, 2H), 1.85-1.75 (m, 2H), 1.68-1.58 (m, 2H), 0.61 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C)C=O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:10]=[CH:11][C:12]([C:15](=[O:17])/[CH:16]=[CH:22]/[N:23]([CH3:25])[CH3:24])=[CH:13][CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(-c2nc3cc(Br)ccc3[nH]2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)c1ccc(-c2nc3cc(Br)ccc3[nH]2)cc1
Temperature: 100 °C

Procedure:
Subsequently, 1-[4-(5-bromo-1H-benz[d]imidazol-2-yl)phenyl]-1-ethanone (592 mg) and N,N-dimethylformamide dimethyl acetal (468 μL) were dissolved in N,N-dimethylformamide (10 mL), followed by heating at 100° C. for 2 hours. The reaction mixture was concentrated, and the residue was subjected to flash chromatography. Fraction eluted by dichloromethane-methanol (15:1) were concentrated under reduced pressure, followed by recovering the solid through filtration by use of isopropyl ether, to thereby yield a 1:1 mixture (116 mg) of (E)-1-[4-(5-bromo-1H-benz[d]imidazol-2-yl)phenyl]-3-dimethylamino-2-propen-1-one and (E)-1-[4-(6-bromo-1H-benz[d]imidazol-2-yl)phenyl]-3-dimethylamino-2-propen-1-one.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N+:8]([CH3:13])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[Na+].[Na+].[C:20]1(=[O:33])[N:24]([CH2:25][CH2:26][Br:27])[C:23](=[O:28])[C:22]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:21]12>C(#N)C>[Br-:27].[CH3:13][N+:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH2:26][CH2:25][N:24]3[C:20](=[O:33])[C:21]4=[CH:32][CH:31]=[CH:30][CH:29]=[C:22]4[C:23]3=[O:28])[CH:4]=2)[CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: C[n+]1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Product: C[n+]1ccc2cc(OCCN3C(=O)c4ccccc4C3=O)ccc2c1

Procedure:
6-Hydroxy-2-methylisoquinolinium bromide (2.4 g.), sodium carbonate (5 g.) and phthalimidoethyl bromide (2.6 g.) in acetonitrile (100 ml) were heated under reflux for 9 days. The mixture was filtered hot and the filtrate evaporated to give an oily solid. It was washed with chloroform, and light petroleum ether (b.p. 40°-60°) was added to give an oil that solidified on trituration, m.p. 165°-169°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(Cl)cc4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccc(Cl)cc3)C2)n1
Temperature: 150 °C
Yield: 30.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-chlorophenyl)-3-piperidinecarboxamide (190 mg, 0.421 mmol), 3 mL of EtOH, Hunig's base (0.22 mL, 1.26 mmol), and hydrazine anhydrous (0.053 mL, 1.69 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH at 50° C., EtOAc was used to triturate. When the solution turned slightly cloudy, it was cooled down to room temperature to get pure crystallized light yellow title compound (59 mg). LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (m, 1H), 1.64-1.85 (m, 2H), 1.99 (m, 1H), 2.55 (m, 1H), 2.78-3.07 (m, 2H), 4.38-4.82 (m, 2H), 5.37 (s, 2H), 6.10 (s, 2H), 6.64-6.74 (m, 1H), 7.31-7.40 (m, 2H), 7.53-7.76 (m, 4H), 7.97 (s, 1H), 10.18 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1Br.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28]C)[CH:22]=[O:23])C>>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1[CH:22]([OH:23])[C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:16])[CH:20]=1
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: COC(OC)c1cc2c(cc1Br)OCO2
Product: COc1ccc(C(O)c2cc3c(cc2C(OC)OC)OCO3)cc1OC
Yield: 76 %

Procedure:
2-bromo-4,5-methylenedioxybenzaldehyde dimethylacetal and 3,4-diethoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(3,4-dimethoxy-α-hydroxybenzyl)-4,5-methylenedioxybenzaldehyde dimethylacetal is obtained as colorless syrup. Yield 76%
Reaction SMILES: [OH:1][C@@H:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[C:16]([NH:26][C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([NH:26][C@H:27]([C:31]([O:1][C@@H:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)[C@H](C)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4methoxybenzyl (S)-(+)-2-hydroxypropionate (7.6 g, 36 mmole), N-CBZ-L-valine (10.05 g, 40 mmole) and DMAP (0.98 g, 8 mmole) in 150 ml dichloromethane was added a solution of DCC (8.3 g, 40 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled to about 5° C. and the urethane was filtered. The filtrate was evaporated and the product was isolated by silica gel column chromatography. Yield: 14.4 g=90%
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([N:6]([CH2:9][CH2:10]Cl)[CH2:7][CH3:8])[CH3:5].[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:24])[C:15]2=[CH:25][S:26][CH:27]=[C:14]12>CN(C)C=O>[CH2:4]([N:6]([CH2:7][CH3:8])[CH2:9][CH2:10][N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:13]([CH3:12])[C:14]2=[CH:27][S:26][CH:25]=[C:15]2[C:16]1=[O:24])[CH3:5]
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.60 g. of diethylaminoethylchloride hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.4 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The chloroform extracts are concentrated under reduced pressure to an oil, which is chromatographed on silica gel preparative thin layer chromatographic (tlc) plates using 10:1 benzene:methanol as eluent. The oily product is crystallized from hexane to give white crystals, m.p. 92°-93°C.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(Cl)Cl.CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])c4ccccc34)ccn2)CC1
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(N)c4ccccc34)ccn2)CC1

Procedure:
A solution of the urea product, obtained above, (130 mg, 0.32 mmol) in DCM/MeOH (1:1 v/v, 40 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 70 mm, 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was partitioned between DCM (10 mL) and sat. aq NaHCO3 and the organic layer was separated and washed with brine (10 mL), dried and evaporated in vacuo to afford the title compound, Intermediate D6, as a red solid (87 mg, 69%); Rt 1.05 min (Method 2); m/z 378 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cc(F)ccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cc(F)ccc4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 22 (0.8 g, 1.78 mmol) was demethylated using pyridine hydrochloride (8.0 g, 69.0 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:14](C)=O)[CH:4]=1.FC(F)(F)[C:19]([O:21][C:22](=O)[C:23](F)(F)F)=O>ClCCl>[CH3:19][O:21][C:22]1[CH:23]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:14][S:14][C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:4]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccnc(-c2sccc2S(C)=O)c1
Solvent: ClCCl
Product: COc1ccnc(-c2sccc2SSc2ccsc2-c2cc(OC)ccn2)c1

Procedure:
The product of step (d) above (1.61 g) and trifluoroacetic anhydride (1.79 ml) were heated under reflux in dichloromethane (50 ml) producing a copious white precipitate during 1.5 hour. The solvent was evaporated off and the residue was heated under reflux with methanol (10 ml) and triethylamine (10 ml) for 0.5 hour. Evaporation to dryness in vacuo, aqueous work-up, extraction in ethyl acetate and chromatography gave the sub-title compound as a gum. MS (FAB) 445 (M+1), (5%), 222 (100%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=1>C1COCC1>[O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=2)[CH2:2]1
Reactant: Nc1nccc(Cl)n1
Reactant: O[C@H]1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1nccc(O[C@H]2CCOC2)n1
Reaction time: 0.08 h

Procedure:
(S)-tetrahydrofuran-3-ol (612 mg, 6.95 mmol) was treated at room temperature with KHMDS (1 M in THF, 5.09 ml, 5.09 mmol). The reaction mixture was stirred for 5 min. Then, the mixture was added to a solution of 4-chloropyrimidin-2-amine (300 mg, 2.32 mmol) in THF (10 ml). The resulting brown solution was stirred at room temperature for 5 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted 2× with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 0.31 min; ESI-MS 182.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][N:22]3[CH2:25][CH2:24][CH2:23]3)[CH:16]=[C:17](Br)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[CH3:36].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][N:22]3[CH2:25][CH2:24][CH2:23]3)[CH:16]=[C:17]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[C:28]([CH3:36])[CH:29]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCN2CCC2)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 4-[1-(2-Azetidin-1-yl-ethyl)-4-bromo-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (8800.00 mg; 21.29 mmol; 1.00 eq.), 4-fluoro-3-methylphenylboronic acid (3932.91 mg; 25.55 mmol; 1.20 eq.) and Cs2CO3 (13872.97 mg; 42.58 mmol; 2.00 eq.) in doxane (80 ml) and water (8 ml) was purged by argon for 10 min, then Bis(tri-t-butylphosphine)palladium(0) (435.20 mg; 0.85 mmol; 0.04 eq.) was added under argon flow and purged by argon for 1 min. The resulting mixture was stirred at 50 C overnight. The reaction solution was diluted with ethyl acetate 250 ml, washed with brine-100 ml×2. The organic layer was dried and concentrated to afford the crude product which is purified by biotage Ki-Sil column to yield 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (9370.00 mg; 99% yield).