Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[CH:50][N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>C1COCC1.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.[Cu]I>[N:51]1[CH:50]=[CH:49][N:48]2[C:43]([C:11]3[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]4[S:28][C:27]([CH2:29][N:30]5[CH2:35][CH2:34][CH:33]([N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)[CH2:32][CH2:31]5)=[CH:26][C:9]=4[N:10]=3)=[CH:44][CH:45]=[CH:46][C:47]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1
Reactant: Brc1cccc2nccn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCOCC5)CC4)cc3n2)n2ccnc2c1
Temperature: 140 °C
Yield: 42.3 %

Procedure:
A mixture of 4-morpholin-4-yl-6-(4-morpholin-4-ylpiperidin-1-ylmethyl)-2-(tributylstannanyl)thieno[3,2-d]pyrimidine (69 mg, 0.10 mmol), 5-bromoimidazo[1,2-a]pyridine (24 mg, 0.12 mmol), Pd(PPh3)4(11 mg, 0.01 mmol) and copper(I) iodide (23 mg, 0.12 mmol) in THF (1 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the product was eluted with 2 M NH3 in MeOH. The appropriate fractions were evaporated and the resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 3:97) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 70:30 to 2:98) to give 687 as a white solid (22 mg, 42%). LCMS (Method F): RT 3.90 min; [M+H]+ 520. 1H NMR (400 MHz, CHCl3-d): δ 9.23 (s, 1 H); 7.95 (dd, J=7.2, 1.2 Hz, 1 H); 7.77 (d, J=8.9 Hz, 1 H); 7.75 (d, J=1.2 Hz, 1 H); 7.35 (s, 1 H); 7.31 (dd, J=8.9, 7.2 Hz, 1 H); 4.07 (t, J=4.7 Hz, 4 H); 3.91 (t, J=4.7 Hz, 4 H); 3.84 (s, 2 H); 3.74 (t, J=4.4 Hz, 4 H); 3.05 (d, J=11.4 Hz, 2 H); 2.57 (t, J=4.4 Hz, 4 H); 2.29-2.19 (m,1 H); 2.15 (t, J=11.4 Hz, 2 H); 1.87 (d, J=12.5 Hz, 2 H); 1.65-1.59 (m, 2 H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH2:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[C:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[NH:26][C:27]3=[O:30])=[CH:22][CH:21]=2)[C:16]1=[O:41].[Cl-].[NH4+]>ClCCl>[O:41]=[C:16]1[CH:15]([CH2:14][O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18][N:17]1[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:38])[F:39])[NH:26][C:27]2=[O:30])=[CH:22][CH:21]=1
Reactant: O=C1C(CO)CCN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
Methanesulfonyl chloride (0.023 ml, 0.299 mmol) and triethylamine (0.03 ml, 0.299 mmol) were added at −20° C. to a dichloromethane solution (2 ml) that contained the 7-(3-hydroxymethyl-2-oxopyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (80 mg, 199 mmol) obtained in Example 1-46. The obtained mixture was stirred at −20° C. for 2 hours. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1->20:1), so as to obtain methanesulfonic acid 2-oxo-1-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]-pyrrolidin-3-ylmethyl ester (38 mg, 40%) in the form of a colorless oil substance.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=O)C.O.[NH2:18][NH2:19]>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[NH:19][N:18]=[C:4]([OH:3])[CH:5]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2cc(O)n[nH]2)cc1
Yield: 103.8 %

Procedure:
5-(4-Methoxy-phenyl)-1H-pyrazol-3-ol (30.8 g, 99%) was prepared as a white solid from 3-(4-methoxy-phenyl)-3-oxo-propionic acid ethyl ester (29.9 mL, 156 mmol) and hydrazine hydrate (14.6 mL, 468 mmol) by a procedure analogous to Example 22. C10H10N2O2: 1H NMR (D6-DMSO): δ 7.55 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.75 (s, 1H), 3.73 (s, 3H) ppm.
Reaction SMILES: I[CH:2]([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]>>[CH3:3][CH:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1ccccc1O
Reactant: CCCCC(C)I
Product: CCCCC(C)Nc1ccccc1O
Reaction time: 5.33 h

Procedure:
The same procedure as in Example 4 was repeated except for using 2-iodohexane in place of 2-iodobutane, to conduct the reaction. As a result, it was confirmed that the rate of conversion of o-aminophenol was 93%, the selectivity to the N-monoalkylated compound was 41% and the oxygen absorption initiation time as an index of determining an oxidation-inhibiting property thereof was 320 min.
Reaction SMILES: [N:1]#[C:2][NH2:3].C(N(C(C)C)CC)(C)C.[CH3:13][S:14]([NH:17][C:18]1[N:23]=[CH:22][C:21]([N:24]=[C:25]=[N:26][CH:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=1)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:13][S:14]([NH:17][C:18]1[N:23]=[CH:22][C:21]([NH:24][C:25]([NH:26][CH:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[N:3][C:2]#[N:1])=[CH:20][CH:19]=1)(=[O:15])=[O:16]
Reactant: CC(N=C=Nc1ccc(NS(C)(=O)=O)nc1)C(C)(C)C
Reactant: N#CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(NC(=NC#N)Nc1ccc(NS(C)(=O)=O)nc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
Cyanamide (172 mg, 4.1 mmol) and diisopropylethylamine (711 μl, 4.1 mmol) were added to 1 ml of a solution of N-(6-methanesulfonylamino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)carbodiimide (121 mg, 0.41 mmol) in chloroform and the mixture was stirred at room temperature for 16 hours. After an insoluble matter was removed by filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography [eluent: chloroform alone to chloroform:methanol =5:1 (v/v)] and subjected to recrystallization from chloroform-ether to obtain 97 mg of the intended product (yield: 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH3:19].[Cl:20]N1C(=O)CCC1=O.O.[OH-].[Na+]>CC(O)=O>[Cl:20][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:18][CH3:19])=[CH:4][C:5]=1[N:8]1[CH2:9][CH2:10][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:16][CH2:17]1
Reactant: COc1cc(N2CCC3(CC2)OCCO3)ccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCC3(CC2)OCCO3)c(Cl)cc1Cl
Temperature: 60 °C
Yield: 90.7 %

Procedure:
A mixture of 8-(4-chloro-3-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.67 g, 5.89 mmol, Example 13, step 1) and 1-chloropyrrolidine-2,5-dione (0.786 g, 5.89 mmol) in AcOH (15 mL) was heated at 60° C. overnight. The mixture was cooled and water was added. Upon completion of addition, the mixture was neutralized with 1N NaOH, extracted with EtOAc, dried (Na2SO4), and concentrated to give 8-(2,4-dichloro-5-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.7 g, 5.34 mmol, 91% yield) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([NH2:6])[CH2:3]1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19]([NH:6][CH:4]1[CH2:5][N:2]([CH3:1])[CH2:3]1)=[O:20]
Reactant: CN1CC(N)C1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
To a solution of 1-methylazetidin-3-amine (1 equiv) in dry DCM (0.13 M) was added triethylamine (1.8 equiv). A solution of 3-methoxy-4-nitrobenzoyl chloride (0.91 equiv) in dry DCM was added and the reaction was stirred at room temperature for 5 min. The mixture was then concentrated and purified by silica gel chromatography (5% MeOH in DCM) to afford the title compound (46.4% yield) as a yellow solid. MS (ESI) m/z 266.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH2:7][C:5]1[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=[C:2]([N:1]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1
Reactant: O=Cc1ccccc1
Reactant: CNC(=S)n1nc(N)nc1N
Solvent: CCO
Product: CNC(=S)n1nc(N=Cc2ccccc2)nc1N
Temperature: 60 °C
Yield: 47 %

Procedure:
The compound (3.00 g) obtained in Example 31, ethanol (100 ml), benzaldehyde (1.99 g) and DL-camphor-10-sulfonic acid (110 mg) were stirred with heating in an oil bath at 60° C. for 5 hours. After the reaction, the mixture was cooled to room temperature and the resulting crystals were collected by filtration, which were washed with ethanol and dried to give 2.13 g of pale-yellow crystals (yield 47%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCOCC1)OC2

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), morpholine (0.50 ml, 5.7 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 313 (M+, 1), 101 (6), 100 (bp), 77 (4), 56 (6).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[CH2:10]([C:17]1[O:18][C:19]2[CH:52]=[CH:51][CH:50]=[CH:49][C:20]=2[C:21]=1[C:22]1[CH:48]=[CH:47][C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][S:33][CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:28][CH:27]=2)=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C.C(OCC)(=O)C>[CH2:10]([C:17]1[O:18][C:19]2[CH:52]=[CH:51][CH:50]=[CH:49][C:20]=2[C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][S:33]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[C:36]([OH:38])=[O:37])(=[O:6])=[O:5])=[CH:28][CH:27]=2)=[CH:47][CH:48]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CS(=O)(=O)Cc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Sodium perborate tetrahydrate (320 mg, 2.1 mmol) was added as a solid to a stirred solution of (2R)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylamino-propionic acid (440 mg, 0.74 mmol) in acetic acid (10 mL) at 40° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 15% methanol in methylene chloride as eluent, afforded the title compound as a white solid (426 mg, 92%): mp. 202-203° C. Rf 0.40 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 7.84 (2H, d, J=9 Hz, Ar—H), 7.74 (2H, d, J=9 Hz, Ar—H), 7.60 (4H, m, Ar—H), 7.48 (2H, d, J=9 Hz, Ar—H), 7.29 (5H, m, Ar—H), 7.22 (2H, d, J=8 Hz, Ar—H), 6.58 (1H, br s, NH), 4.51 (2H, s, PhCH2), 4.27 (2H, s, PhCH2S), 4.16 (1H, m, CHN), 3.56 (1H, dd, J=15, 5 Hz, CHHCHN), 3.20 (1H, dd, J=15, 8 Hz, CHHCHN), 1.37 (9H, s, tBu); ESI-LCMS e/z calcd for C36H35NO7S 625.739, found 626 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](=[O:58])[N:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]3[N:35]=[CH:36][N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:38]=3)=[CH:29][N:28]=2)[CH:26]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24](=[O:58])[N:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]3[N:35]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH:4]=4)[CH:36]=[N:37][CH:38]=3)=[CH:29][N:28]=2)[CH:26]=1
Reactant: N#Cc1ccc(CO)cc1OCCc1ccccc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-phenethyloxy-benzonitrile from step 2 (65 mg, 0.26 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23 Step 5 (136 mg, 0.26 mmol) in CH2Cl2 (2 ml) was added DIEA (100 μl, 0.56 mmol) followed immediately by the addition of Tf2O (65 μl, 0.39 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (2 ml) and heated to 60° C. for several hours. The MeOH was then removed in vacuo and the residue treated with saturated aqueous NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:29]1[O:40][C:39]2[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH2:36])=[CH:32][C:31]=2[O:30]1.C(N(CC)CC)C>ClCCCl>[C:12]([O:11][C:9](=[O:10])[NH:1][C@@H:2]([C:6](=[O:8])[NH:36][CH2:35][CH2:34][C:33]1[CH:37]=[CH:38][C:39]2[O:40][CH2:29][O:30][C:31]=2[CH:32]=1)[CH:3]([CH3:4])[CH3:5])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Boc-D-Val-OH (282 mg, 1.30 mmol) was dissolved in DCE (5 mL), followed by addition of CDI (253 mg, 1.56 mmol). The reaction solution was stirred for 30 mins to activate the acid. After this period, 3,4-Methylenedioxyphenethylamine HCl (263 mg, 1.30 mmol) and triethylamine (363 μL) were added to the reaction vessel and it was stirred at room temperature for 16 hours. Next, the reaction mixture was concentrated under vacuum. The crude material was dissolved in DCM (50 mL), transferred to a separatory funnel, washed with sat. NaHCO3 (aq) (50 mL), dried over Na2SO4 and concentrated down to yield 447.1 mg (94.6%) of crude product, [1-(2-benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester, which was taken on crude. [M+H]+ 365.00.
Reaction SMILES: CC1N=C([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)C=CC=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=1.[C@@H]12NC[C@@H]1CCN(C(OC(C)(C)C)=O)C2>>[CH3:25][C:19]1[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=[C:17]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[N:18]=1
Reactant: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: Cc1nc(Cl)nc(C)c1C
Agent: CC(C)(C)OC(=O)N1CC[C@H]2CN[C@H]2C1
Product: Cc1nc(N2C[C@@H]3CCNC[C@@H]32)nc(C)c1C

Procedure:
(1R,6S)-8-(4,5,6-Trimethylpyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane was prepared in a manner analogous to Intermediate 40, using Intermediate 66 and Intermediate 39 as starting materials. MS (ESI) mass calcd. for C13H20N4, 232.17; m/z found, 233.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: CN1CCC(=O)CC1
Reactant: NCc1ccc(F)cc1
Product: CN1CCC(NCc2ccc(F)cc2)CC1

Procedure:
1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), 4-fluorobenzylamine (1.25 g, 1.0 eq.).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[N:11]=[C:12](O)[C:13]3[CH:19]=[N:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][C:14]=3[N:15]=2)[CH2:3]1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:41]>C(Cl)(Cl)Cl>[Cl:41][C:12]1[C:13]2[CH:19]=[N:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:27])[F:29])=[CH:16][C:14]=2[N:15]=[C:10]([CH2:9][N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)[N:11]=1
Reactant: CC1CN(Cc2nc(O)c3cnc(-c4ccccc4C(F)(F)F)cc3n2)CC(C)O1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CC1CN(Cc2nc(Cl)c3cnc(-c4ccccc4C(F)(F)F)cc3n2)CC(C)O1

Procedure:
Reflux a mixture of 2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido[4,3-d]-pyrimidin-4-ol (0.6 g), 2,6-lutidine (0.62 g), and POCl3 (1.1 g) in CHCl3 (15 mL) for 20 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido[4,3-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9]1[C:10]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:12]=[CH:13][CH:14]=1.[CH3:26]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9]1[C:10]([N:15]([CH3:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(c1ccccc1Cl)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Reactant: CI
Solvent: CN(C)C=O
Product: CN(c1ccccc1Cl)c1ccccc1N(C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Compound 4 (0.405 g, 1.14 mmol) was dissolved in 4 mL of dimethylformamide (DMF) and added to KH (0.46 g, 3.42 mmol). The mixture was stirred at room temperature for 10 min. To this, MeI (0.4 mL, 5.7 mmol) was added dropwise. The reaction was allowed to stir at room temperature for 30 min. The reaction was then quenched with deionized H2O and extracted 3 times with 15 mL dichloromethane. The organic layers were combined and washed 3 times with 15 mL of H2O, and 3 times with 15 mL of brine. The organic layers were dried with MgSO4, and solvent was removed under reduced pressure to give the desired product as a yellow powder without further purification (0.362 g, 86% yield). 1H NMR (300 MHz, CDCl3) δ 7.63 (1H, dd, J=8.0, 1.7 Hz), 7.36 (1H, ddd, J=8.8, 7.3, 1.8 Hz), 7.29-7.19 (2H, m), 7.12 (1H, dd. J=8.2, 1.7 Hz), 7.07-6.92 (5H, m), 6.88 (1H, ddd, J=8.2, 7.3, 1.2 Hz), 6.81 (1H, dd, J=7.8, 1.2 Hz), 3.32 (3H, s), 3.27 (3H, s); 13C (75 MHz, CDCl3) δ 146.5 (q), 143.5 (q), 142.1 (q), 138.8 (q), 132.7 (t), 131.0 (t), 128.7 (q), 127.6 (t), 126.2 (t), 124.2 (t), 124.1 (t), 123.7 (t), 123.1 (t), 120.4 (t), 118.8 (t), 38.5, 38.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.3 %

Procedure:
To 7-bromo-1,2,3,4-tetrahydroquinoline (1E) (1.0 g, 4.7 mmol) in DCM (30 mL) was added TEA (1.6 mL, 12 mmol), acetic anhydride (1.1 mL, 12 mmol), and pyridine (1.0 mL, 10.0 mmol). The reaction was allowed to stir at rt for 24 hours while monitoring by LCMS. To the reaction mixture was added TEA (1.6 mL, 12 mmol), acetic anhydride (1.1 mL, 12.0 mmol), and pyridine (1.0 mL, 10 mmol). The reaction was allowed to stir at rt for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 1.09 g (91%) of the desired product 1-(7-bromo-3,4-dihydroquinolin-1(2H)-yl)ethanone (1F): LC/MS (APCI): m/z 255.7 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38][CH2:39][CH2:40][CH:41](O)[CH3:42].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:38][CH2:39][CH2:40][CH:41]([N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:18])=[O:17])[CH3:42]
Reactant: CC(O)CCBr
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCBr)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 68.9 %

Procedure:
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (general procedure 10.2 g, 0.8 mmol) was dissolved in tetrahydrofuran (10 mL) and triphenylphosphine (0.54 g, 0.9 mmol) was added followed by 4-bromobutan-2-ol (0.14 g, 0.9 mmol) and diisopropyl azodicarboxylate (0.18 g, 0.9 mmol). The mixture was stirred for 18 hours at 23° C. The mixture was concentrated and purified via Isco chromatography (Redisep, silica, gradient 0-50% ethyl acetate in hexane) to afford 0.22 g of 1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.