Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([CH:35]=O)[C:32]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:41][CH:40]=3)=[N:31]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([CH2:35][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:32]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:41][CH:40]=3)=[N:31]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (2.74 ml) in tetrahydrofuran (50 ml), sodium hydride (60%, oily, 552 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. To the reaction mixture, a solution of 1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-carbaldehyde (6.31 g) in tetrahydrofuran (100 ml) was added slowly, and the solution was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The obtained crystals were collected by filtration, and ethyl 3-[1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-yl]propionate (6.79 g, yield: 95%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: [I:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([CH:12]([CH3:14])[CH3:13])=[C:6]([CH:11]=1)[O:7][CH2:8][C:9]#[N:10].C(O[CH:22]([N:26]([CH3:28])[CH3:27])[N:23]([CH3:25])[CH3:24])(C)(C)C>CN(C=O)C>[CH3:28][N:26]([CH3:27])[CH:22]([N:23]([CH3:24])[CH3:25])[CH:8]([O:7][C:6]1[CH:11]=[C:2]([I:1])[C:3]([O:15][CH3:16])=[CH:4][C:5]=1[CH:12]([CH3:14])[CH3:13])[C:9]#[N:10]
Reactant: COc1cc(C(C)C)c(OCC#N)cc1I
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(OC(C#N)C(N(C)C)N(C)C)cc1I
Temperature: 100 °C

Procedure:
To a solution of (5-iodo-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (250 g, 0.75 mol) in 500 ml of DMF, t-butoxybis(dimethylamino)methane (167 g, 0.96 mol) was added. The mixture was heated to 100° C. for 4 hours, then cooled to 25° C. to provide a DMF solution of 3,3-bis-dimethylamino-2-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-propionitrile (not isolated). To this solution was added aniline hydrochloride (225 g, 1.7 mol), and the resultant mixture was heated to 100° C. for 11 hours. After cooling to 60° C., 100 ml of isopropanol was added, followed by 1 L of water, at a rate to maintain an internal temperature of 50° C. The resulting slurry was cooled to 20° C. and aged. Precipitated 2-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-3-phenylamino-acrylonitrile was collected by filtration, washed with isopropanol until the filtrate was colorless, and dried in a vacuum oven (50° C., 24 inches Hg) to give 310 g of 2-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-3-phenylamino-acrylonitrile, 93% yield: Melting Point: 170° C.; 1HNMR (CDCl3) δ=1.3 (d, 6H), 3.3 (m, 1H), 3.85 (s, 3H), 6.6 (d, 2H), 6.75 (s, 1H), 6.9 (d, 2H), 7.05 (t, 1H), 7.15 (d, 1H), 7.3 (t, 3H)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].C(N(CC)CC)C>O1CCCC1>[CH3:2][C:1]([NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([Br:5])[CH:7]=1)=[O:3]
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
A solution of acetyl chloride (44.0 ml, 0.619 mol) in tetrahydrofuran (20 ml) was added dropwise to a 0° C. solution of 3-bromoaniline (101.5 g, 0.590 mol) and triethylamine (87.4 ml, 0.625 mol) in tetrahydrofuran (550 ml). The resulting mixture was stirred 16 h at room temperature. The reaction mixture was quenched with ice/water (500 ml), acidified to pH 1 with 5N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate extracts were washed with 1N hydrochloric acid, water, brine, then dried over sodium sulfate. The solvent was removed under reduced pressure to give 125.5 g of a red solid. Recrystallization from ethyl acetate/hexanes gave 69.2 g of an off white powder. Filtered a second crop of product to give 26 g of a tan powder. Total yield=75%.
Reaction SMILES: [C:1]([S:7][CH2:8]/[C:9](=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[O:12]=[C:10]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])/[C:9](/[CH2:8][S:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)O
Product: CCOC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(=O)C(C)(C)C
Yield: 73 %

Procedure:
The (E)-2-pivaloylthiomethyl-3-phenylpropenoic acid described in Example 8 (step B) is coupled with ethyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 73% (after flash chromatography, eluent: ether/petroleum ether 55/45)-oil IR: 3300, 1710, 1650, 1620 cm-1 1H NMR (CDCl3): 7.20 (s, 5H); 6.75 (s, 1H); 6.0 (broad t, 1H); 3.95 (q, 2H, J=7.5 Hz); 3.80 (s, 2H); 3.40 (q app., 2H, J. app=6.40 Hz); 2.35 (t, 2H, J=5.9 Hz); 1.30 to 0.95 (m, 12H). Microanalysis: C20H27NO4S Calc. % C=63.63 H=7.21 N=3.71 Found. % C=63.35 H=7.16 N=3.52
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40]O)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:64].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][Br:64])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CBr)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 3 h
Yield: 62.6 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (1 g) is dissolved in methylene chloride (20 ml), then thereto are added triphenylphosphine (855 mg) and carbon tetrabromide (1.35 g), and the mixture is stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→4:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(bromomethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (690 mg). MS (m/z): 676/678 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.N1C=CC=CC=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>CO>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CO
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 8.2 %

Procedure:
To a mixture of ethyl 7-amino-5-(2-methoxyethoxy)-1H-indole-2-carboxylate (2.00 g) and pyridine (30 mL) was added thiophene-2-sulfonyl chloride (1.57 g) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction methanol (98:2-95:5, volume ratio) to give the title compound (250 mg, yield 27%) as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
3.01 g of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted via Procedure O to give tert-butyl 2-chloro-4-(methylsulfonylmethyl)benzoate. 1.2 g of tert-butyl 2-chloro-4-(methylsulfonylmethyl)benzoate was treated with 10 mL of 4N HCl in Dioxane at 45° C. and concentrated upon completion to give crude 2-chloro-4-(methylsulfonylmethyl)benzoic acid. 775 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1 g of 2-chloro-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 435 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6](Br)[CH:5]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[C:7]([C:10]#[N:11])=[CH:8][CH:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(C#N)c(Br)c1
Reactant: COc1ccccc1B(O)O
Product: COC(=O)c1ccc(C#N)c(-c2ccccc2OC)c1
Yield: 74.8 %

Procedure:
By following procedures described in General procedure C (Suzuki), 3-bromo-4-cyano-benzoic acid methylester (0.205 g, 0.85 mmol) and 2-methoxy phenyl boronic acid (0.156 g, 1.02 mmol) were used to obtain the title compound (0.170 g, 62%), following SiO2 chromatography (hexanes/EtOAc=6:1). MS(ESI) m/z 268.0 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([O:27][CH3:28])=[CH:17][C:10]=3[N:11]([CH3:16])[C:12](=[O:15])[CH2:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]#[CH:31]>>[C:36]([O:35][C:33](=[O:34])[NH:32][CH2:29][C:30]#[C:31][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:9]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([O:27][CH3:28])=[CH:17][C:10]=3[N:11]([CH3:16])[C:12](=[O:15])[CH2:13][N:14]=2)[CH:3]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COc1cc2c(cc1-c1ccccc1)C(c1cccc(Br)c1)=NCC(=O)N2C
Product: COc1cc2c(cc1-c1ccccc1)C(c1cccc(C#CCNC(=O)OC(C)(C)C)c1)=NCC(=O)N2C
Yield: 22 %

Procedure:
Prepared from 5-(3-bromo-phenyl)-8-methoxy-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one Example 62 using the same method described for Example 35 using propargyl Boc-amine instead of hex-1-yne. The title compound (51 mg) was obtained as a beige solid, (yield=22%).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:20][O:21][CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)[C:9]2[C:10]([CH2:20][O:21][CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1nn(-c2ccccc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: COCc1nn(-c2ccccc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 45.7 %

Procedure:
Using cyclohexyl[3-(methoxymethyl)-1-phenyl-1H-pyrazol-4-yl]methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.39 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.37 g, 46%) was obtained as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)(Cl)Cl>[N+:20]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCCCCNC(=O)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Yield: 84.3 %

Procedure:
Triethylamine (1 eq.) was added to a suspension of 4-chloro-3-nitroquinoline hydrochloride (13 g, 53 mmol) in chloroform. A suspension of N-(5-aminopentyl)benzamide (11 g, 53 mmol) in chloroform was added and the reaction mixture was heated to reflux. Progress of the reaction was monitored by HPLC. The reaction mixture was concentrated under vacuum. The residue was diluted with toluene, heated to reflux and then filtered while still hot. The filtrate was allowed to cool. The resulting precipitate was isolated by filtration to provide 16.9 g of N1-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide as a yellow solid, m.p. 130-132° C. 1H NMR (500 MHz, DMSO-d6) δ9.07 (s, 1H), 9.02 (broad s, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.43 (t, J=6.0 Hz, 1H), 7.89 (dd, J=8.0, 1.2 Hz, 1H), 7.83 (dt, J=8.0, 1.2 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.57 (dt, J=8.0, 1.2 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 3.63 (q, J=6.0 Hz, 2H), 3.25 (q, J=6.0 Hz, 2H), 1.77 (quintet, J=7.0 Hz, 2H), 1.55 (quintet, J=7.0 Hz, 2H), 1.39 (quintet, J=7.0 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][SH:11].[Na]>>[CH3:10][S:11][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CS
Agent: [Na]
Product: CSCC(=O)OC(C)(C)C
Yield: 96.5 %

Procedure:
Under ice cooling, 33.4 g of tert-butyl bromoacetate was gradually added to 80.0 g of 15% sodium methylmercaptan aqueous solution and the resulting mixture was reacted at room temperature overnight. After completion of the reaction, the reaction mixture was extracted 4 times with ethyl acetate and the extract was washed with saturated sodium chloride aqueous solution. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off to give 26.8 g of crude tert-butyl (methylthio)acetate.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:26])[NH:17][C@H:18]([C:23](F)=[O:24])[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:26])[NH:17][C@H:18]([C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)F)C(C)(C)C
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCCS)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (83.6 mg, 1.0 mmol) in 4.9 mL water was added 2-aminoethanethiol hydrochloride (60.7 mg, 0.53 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25i (113.3 mg, 0.48 mmol) in 4.9 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 26i as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][CH3:20])(=[O:18])=[O:17])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:24]=1[NH2:25].O>C(O)C.Cl>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][CH3:20])(=[O:18])=[O:17])=[N:4][C:5]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:23]=2[O:22][CH3:21])=[N:6][CH:7]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Reactant: COc1ccc(N)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(OC)cc2OC)ncc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (300 mg, 0.79 mmol), 2,4-dimethoxyaniline (181.5 mg, 1.18 mmol) in ethanol (3 mL), 1 N hydrochloric acid (0.03 mL) is added and stirred under reflux condition for 5 hours. The reaction mixture is cooled to room temperature, poured into water and extracted twice with ethyl acetate. The organic layer is successively washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to afford the title compound.
Reaction SMILES: C(O[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[N+:14]([O-:16])=[O:15])C.[N:17]12[CH2:24][CH2:23][CH2:22][C:21]1([CH2:25][NH2:26])[CH2:20][CH2:19][CH2:18]2>>[N:17]12[CH2:24][CH2:23][CH2:22][C:21]1([CH2:25][NH:26][C:4]1[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=1[N+:14]([O-:16])=[O:15])[CH2:20][CH2:19][CH2:18]2
Reactant: NCC12CCCN1CCC2
Reactant: CCOc1ccc2ccccc2c1[N+](=O)[O-]
Product: O=[N+]([O-])c1c(NCC23CCCN2CCC3)ccc2ccccc12
Yield: 39.1 %

Procedure:
2-Ethoxy-1-nitronaphthalene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 39.1%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH:13]([CH2:17]Br)[C:14]([NH2:16])=[O:15]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:17][CH:13]1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)C(Br)CBr
Reactant: CNCCNc1ccccc1
Product: CN1CCN(c2ccccc2)CC1C(N)=O

Procedure:
In a manner similar to preparation 1, react N-methyl-N'-phenyl-1,2-ethanediamine with 2,3-dibromopropanamide to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[S:17][C:18]([CH3:21])=[N:19][N:20]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=2)O1.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>[CH3:21][C:18]1[S:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:32]5[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=5)[CH:23]=[CH:22][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:20][N:19]=1
Reactant: Cc1nnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)s1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)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: Cc1nnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a degassed solution of 6-bromo-2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazole (450 mg, 1.094 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (406 mg, 1.313 mmol) and potassium carbonate (454 mg, 3.28 mmol) in dioxane (9 mL) and water (3.0 mL) was added Pd(Ph3P)4 (63 mg, 0.055 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to rt, diluted with water (20 mL), and extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 30 to 100% EtOAc) to afford tert-butyl 4-(2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (443 mg, 0.862 mmol, 79% yield) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.59-7.65 (2H, m), 7.41 (1H, dd, J=8.5, 1.7 Hz), 6.00-6.11 (1H, m), 5.41-5.48 (1H, m), 4.07-4.12 (2H, m), 3.75-3.83 (2H, m), 3.66 (2H, t, J=5.5 Hz), 3.52-3.59 (2H, m), 2.60 (3H, s), 2.53-2.58 (2H, m), 2.19-2.27 (2H, m), 2.06-2.14 (2H, m), 1.50 (9H, s). LCMS (m/z)=514 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:31])=[CH:26][CH:25]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1)C(=O)OC
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (1.0 g), 3-oxo-2-[4-(pyrrolidine-1-carbonyl)benzyl]pentanoic acid methyl ester (1.9 g), polyphosphoric acid (6.0 g) and dioxane (20 mL) was heated at 120° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and methanol (9:1:0 to 0:9:1 by volume) to afford title compound, 0.079 g.