Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][S:9][C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13]>>[CH3:8][S:9][C:10]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH:11][N+:12]([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Nc1cccnc1
Product: CSC(=C[N+](=O)[O-])Nc1cccnc1

Procedure:
3-Aminopyridine and 1,1-bis(methylthio)-2-nitroethylene were processed as in Example 54B to provide the desired product.
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.[C:40](=[O:42])=[O:41]>O1CCCC1.C1CCCCC1>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:6]1[CH2:7][CH2:8][CH2:9][C:10]2=[C:2]([C:40]([OH:42])=[O:41])[N:3]([CH3:20])[N:4]=[C:5]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Reactant: O=C=O
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3C(=O)O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (1-1; 1.46 g) and a few crystals of 1,10 phenanthroline were dissolved in 25 mL of dry tetrahydrofuran and chilled to −78° C. under an argon atmosphere. A 2.0 M solution of n-butyllithium in cyclohexane was added dropwise until the dark color of the phenanthroline/organolithium complex persisted. An additional 2.05 mL of the n-butyllithium solution was added. After 10 minutes, carbon dioxide, generated from dry ice, was bubbled through the reaction mixture for 5 minutes. After the reaction mixture had been stirred at −78° C. for 5 minutes, the cooling bath was removed and the mixture was allowed to warm for 5 minutes before being quenched by the addition of water. The mixture was partitioned between ethyl acetate and water, acidified with dilute hydrochloric acid. The ethyl acetate was dried with magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel eluting with an acetone/hexane gradient to provide 1.11 g of 5-1: mp 247.8-248.3° C.
Reaction SMILES: [S:1]([C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14](S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:37]([NH:39][CH2:40][CH3:41])[CH3:38]>>[CH2:37]([N:39]([CH2:40][CH3:41])[C:14]1[C:15]2[C:16](=[O:26])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23](=[O:25])[C:24]=2[C:11]([S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])=[CH:12][CH:13]=1)[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: CCNCC
Product: CCN(CC)c1ccc(S(=O)(=O)c2ccc(C)cc2)c2c1C(=O)c1ccccc1C2=O
Yield: 91 %

Procedure:
1-(diethylamino)-4-tosylanthraquinone was prepared by reaction of 1,4-ditosylanthraquinone with diethyl amine. The isolated and purified reaction product has the structure illustrated below (where "Ts" is ##STR11## The yield was 91% and the m.p. 140°-141° C. Mass spec m/e 449 (M+), 434 (M-CH3), 420 (M-C2H5), 294 (M-C7H7SO2), 266 (294-CO), 155 (C7H7SO2), 91 (C7H7): H-NMR (CD2Cl2)δ8.19-8.13 (m, 2H), 7.97-7.68 (m, 4H), 7.30-7.15 (m, 4H), 3.48-3.24 (q, 4H), 2.26 (s, 3H), 1.22-1.06 (t, 6H); IR (Nujol) 1172 cm-1 (symmetrical SO2 stretch), 945 cm-1, 872, 830, 820, 800, 785, 765 (S--O--C stretch); UV/VIS max (Xylenes) 506 nm (ε3650).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:22][CH2:23][OH:24])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[N:21]=1.Br[CH2:26][C:27]#[C:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[C:29]1([C:28]#[C:27][CH2:26][O:24][CH2:23][CH2:22][N:5]2[C:6]3[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([O:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:7]=3[N:21]=[C:4]2[CH3:3])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCO)c2c1C
Reactant: BrCC#Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
Sodium hydride (0.82 g, 20.48 mmol, 60% in mineral oil) and anhydrous N,N-dimethylformamide (20 mL) were combined and stirred for 5 minutes under nitrogen. A solution of 1-[2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]ethan-2-ol (5.8 g, 19.50 mmol) from Part G in N,N-dimethylformamide (30 mL) was then added to the sodium hydride over 5 minutes. After stirring the resulting reaction solution for 10 minutes at room temperature, a solution of 3-bromo-1-phenylpropyne (4.18 g, 21.45 mmol) from Part A in N,N-dimethylformamide (15 mL) was added to the reaction solution, and the resulting reaction mixture was stirred for 4 hours and 10 minutes. Sodium hydride (0.10 g, 60 % in mineral oil) and then 3-bromo-1-phenylpropyne (1 g) were added to the reaction mixture, and after stirring for 30 minutes, HPLC monitoring of the reaction mixture indicated about 7% starting material remaining. The reaction mixture was concentrated under reduced pressure, and the resulting oil was dissolved in dichloromethane. The dichloromethane solution was washed with saturated ammonium chloride (3×), water (3×), and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a brown solid, which was triturated with diethyl ether. The resulting solid was filtered off, and a second crop was collected from the mother liquor. The combined solids were passed through a column of silica (120 g, 40×200 mm) using 95/5 ethyl acetate/dichloromethane. A white solid (5.4 g) was isolated and carried on to the next step. HPLC analysis indicated the presence of about 9% starting material in the white solid.
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]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 87.4 %

Procedure:
The title compound (114 mg) was prepared as in Example 177, Steps C and D, using 208 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 211 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C15H18FN3, 259.15. found, m/z 260.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.41-7.35 (m, 2H), 7.32-7.26 (m, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.43-3.38 (m, 2H), 3.33-3.28 (m, 2H), 3.18-3.12 (m, 2H), 2.80-2.75 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:48])[C:23]([CH3:47])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:48])[C:23]([CH3:47])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
Piperidine (0.054 g, 0.634 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.182 g, 0.950 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.129 g, 0.317 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.060 g, 0.126 mmol, 40%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][C:29](O)=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:29](=[O:30])[CH2:28][N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:32])([F:1])[F:33])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:24]=[N:25]1
Reactant: O=C(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Reactant: CNC
Product: CN(C)C(=O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 240, (4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-acetic acid was reacted with dimethylamine to give 241. MS(ESI+) 504.1. 1H NMR (400 MHz, DMSO) δ 8.31-8.26 (m, 2H), 8.16 (s, 1H), 7.97 (s, 1H), 7.44 (dd, J=8.3, 1.6, 1H), 7.31 (d, J=1.4, 1H), 5.87 (q, J=8.7, 2H), 5.12 (s, 2H), 4.40 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 3.05 (s, 3H), 2.87 (s, 3H)
Reaction SMILES: [CH2:1]([OH:5])[C@@H:2]([OH:4])[CH3:3].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].N1C=CN=C1.CN(C)C=O>C(OCC)(=O)C>[Si:6]([O:5][CH2:1][C@@H:2]([OH:4])[CH3:3])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)CO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.1 %

Procedure:
A solution of (S)-propane-1,2-diol (1.9 mL, 26 mmol), tert-butyldimethylsilyl chloride (4.87 g, 32 mmol), and imidazole (4.5 g, 66 mmol) in anhydrous dimethylformamide (6.6 mL, 26 mmol) was allowed to stir at ambient temperature for 12 hours. The reaction mixture was poured into ethyl acetate (50 mL) and washed sequentially with saturated aqueous sodium bicarbonate (30 mL) and water (30 mL). The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5.2 g, 104%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:22][C@@H:23]2[CH2:25][O:24]2)(=O)=O)C=CC=1)([O-])=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:22][CH:23]2[CH2:25][O:24]2)=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Cc1ccc(O)cn1
Product: Cc1ccc(OCC2CO2)cn1

Procedure:
The title compound was prepared from 6-methyl-3-pyridinol and (2S)-oxiranylmethyl 3-nitrobenzenesulfonate in substantially the same manner as described in Example 123. The product was obtained as a brown oil; 1H NMR (400 MHz, DMSO-d6) δ 2.38 (s, 2.38, 1H), 2.68–2.70 (m, 1 H), 2.81–2.84 (m, 1 H), 3.30–3.34 (m, 1 H), 3.83–3.87 (m, 1 H), 4.34–4.38 (m, 1 H), 7.15–7.17 (m, 1 H), 7.28–7.31 (m, 1 H), 8.15–8.16m (m, 1 H); MS (ES) m/z: 165 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:20]O>OS(O)(=O)=O.CN(C=O)C>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc2[nH]c3cc(C(=O)O)ccc3c(=O)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(=O)c3cc(C)ccc3[nH]c2c1

Procedure:
A mixture of compound 138B (50 mg), MeOH (12 mL), Conc. H2SO4 (2 drops), and DMF (2 drops) was heated to reflux over 18 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give a brown oil (47.5 mg). HPLC retention time: 3.05 min., condition: A. M+: 268.
Reaction SMILES: [N:1]1([C:6]2(C#N)[CH2:9][O:8][CH2:7]2)[CH2:5]CCC1.[C:12]1(=O)[CH2:15][CH2:14][CH2:13]1.[NH:17]1CCOC[CH2:18]1>>[N:1]1([C:12]2([C:18]#[N:17])[CH2:15][CH2:14][CH2:13]2)[CH2:5][CH2:7][O:8][CH2:9][CH2:6]1
Reactant: O=C1CCC1
Reactant: C1COCCN1
Reactant: N#CC1(N2CCCC2)COC1
Product: N#CC1(N2CCOCC2)CCC1

Procedure:
The title compound, light yellow liquid, was prepared in accordance with the general method of intermediate A from cyclobutanone and morpholine.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([N:19]4[CH2:23]C[CH:21](OS(C)(=O)=O)[CH2:20]4)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH:37][CH3:38])[CH3:36].[CH3:39]N(C=O)C>>[CH2:35]([N:37]([CH3:39])[CH:38]1[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:11]3[C:10]4[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=4[N:8]=[C:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:30][CH:29]=2)[CH2:23]1)[CH3:36]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)OC1CCN(C(=O)c2ccc(Cn3c(-c4ccccc4)nc4ccccc43)cc2)C1
Reactant: CCNC
Product: CCN(C)C1CCN(C(=O)c2ccc(Cn3c(-c4ccccc4)nc4ccccc43)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methanesulfonic acid 1-[4-(2-phenyl-benzoimidazol-1-ylmethyl)-benzoyl]-pyrrolidin-3-yl ester (71 mg, 0.15 mmol) in DMF is treated with N-ethylmethylamine (0.038 mL, 0.45 mmol), stirred at room temperature overnight and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse-phase semi-preparative HPLC1 to give the title product as a white powder (6.4 mg), identified by HPLC2 and MS [439.6 m/e (M+H)], retention time 1.48 min.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Br[C:30]1[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:30]4[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Cn1cc(Br)ccc1=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2ccc(=O)n(C)c2)C3)cc1

Procedure:
The compound was prepared following the general procedure in Example 289, substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea and substituting 2-Bromo-6-benzyloxypyridine for 5-bromo-1-methylpyridin-2(1H)-one: LC-MS m/z=490 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([S:5][CH2:6][CH3:7])=[NH:4].C(=O)([O-])[O-].[K+].[K+].[P:15](=[S:21])(Cl)([O:18][CH3:19])[O:16][CH3:17]>C(#N)C>[CH3:17][O:16][P:15]([O:18][CH3:19])([N:4]=[C:3]([S:5][CH2:6][CH3:7])[N:2]([CH3:8])[CH3:1])=[S:21]
Reactant: CCSC(=N)N(C)C
Reactant: COP(=S)(Cl)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCSC(=NP(=S)(OC)OC)N(C)C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a mixture of 13.2 g of N,N-dimethylcarbamimidothioic acid, ethyl ester, 27.6 g of finely powdered potassium carbonate and 250 ml of acetonitrile, 16.1 g of phosphorochloridothioic acid, O,O-dimethyl ester was added. The mixture was stirred and heated to 40° C. for 4 hours. The salts were removed by filtration and the filtration concentrated in a rotary evaporator. The residue was taken up in methylene chloride, the methylene chloride solution washed thrice with 50 ml portions of water and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator, leaving 20.0 g of crude product. To remove some lower boiling impurity the sample was placed in a Kugelrohr (bath temperature 95° C., pressure 0.2 mm) for 2 hours. The residue was exhaustively extracted with hexane and the hexane solution concentrated under vacuum, leaving N'-(dimethoxyphosphinothioyl)-N,N-dimethylcarbamimidothioic acid, ethyl ester as a nearly colorless oil. The product has a refractive index of nd25 =1.5610. The IR and NMR spectra were in agreement with the structural assignment.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].C(N(C(C)C)CC)(C)C.[CH2:18]([O:25][CH2:26]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl.C(OCC)(=O)C>[CH2:18]([O:25][CH2:26][O:8][CH2:7][C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](C)CO
Reactant: ClCOCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)COCOCc1ccccc1
Reaction time: 1 h

Procedure:
Methyl (S)-(+)-2-methyl-3-hydroxypropionate (2.0 g; 16.9 mmole) and diisopropylethylamine (2.2 g; 17.1 mmole) were dissolved in dry dichloromethane (2 ml), and benzyloxymethyl chloride (2.7 g; 17.3 mmole) was dropwise added thereto, followed by stirring for 1 hour. 1N Hydrochloric acid (10 ml) and ethyl acetate (20 ml) were added thereto, and the aqueous layer was extracted with ethyl acetate. The extract was combined with the organic layer, washed with a sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give methyl (S)-3-benzyloxymethyloxy-2-methylpropionate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[I:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])/[C:9](/[S:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:24]\[C:23]2[CH:26]=[CH:27][C:20]([I:19])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: O=C(CSc1ccc(Br)cc1)c1ccc(Br)cc1
Product: O=C(/C(=C\c1ccc(I)cc1)Sc1ccc(Br)cc1)c1ccc(Br)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 1. A solution of 1-(4-bromophenyl)-2-(4-bromophenylthio)ethanone (10 mmol) and 4-iodobenzaldehyde (10 mmol) was subjected to the procedure described as Method B in part C of Synthesis Example 1 and the product obtained was purified by column chromatography. m.p. 128-130° C.
Reaction SMILES: [C:1]1([CH3:7])C=CC=CC=1.[N:8]1([C:13]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:14]=2C=O)[CH:12]=[CH:11][N:10]=[CH:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[C:36](=O)([OH:38])[O-:37].[Na+]>C(OCC)(=O)C.C(O)CO>[O:37]1[CH2:7][CH2:1][O:38][CH:36]1[C:18]1[CH:17]=[CH:14][C:13]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[C:20]([O:21][CH3:22])[CH:19]=1
Reactant: COc1cccc(C=O)c1-n1ccnc1
Reactant: O=C([O-])O
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: OCCO
Solvent: CCOC(C)=O
Product: COc1cc(C2OCCO2)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a toluene (70 mL) solution of 4-(1H-imidazol-1-yl-3-methoxybenzaldehyde (4.3 g) and ethylene glycol (6.5 g), para-toluenesulfonic acid monohydrate (4.8 g) was added, Dean-Stark equipment was attached and heat-refluxing was carried out for 4 hours. After allowing cool the reaction mixture to room temperature, a saturated sodium bicarbonate water and ethyl acetate were added, and the organic layer was partitioned. The organic layer was washed with a saturated salt solution and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system), and 3.15 g of the title compound was obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]=1[CH3:17]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:1][C@@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])=[CH:12][C:11]=1[CH3:17]
Reactant: CC[C@@H](O)C(=O)OC
Reactant: Cc1cc(O)ccc1Cl
Product: CC[C@H](Oc1ccc(Cl)c(C)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (R)-methyl 2-hydroxybutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 4-chloro-3-methylphenol instead of the m-cresol.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([OH:23])=[O:22])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH2:30](Cl)Cl>>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]([O:23][CH3:30])=[O:22])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: O=C(O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 8 h

Procedure:
Thionyl chloride (0.01 mole) was added to a mixture of intermediate (13) (0.0029 mole) in DCM (10 ml). The mixture was stirred for one minute overnight and then allowed to stand. The solvent was evaporated. The residue was dissolved in DCM (10 ml). Methanol (10 ml) was added. The mixture was allowed to stand for four hours, then poured out into a NaHCO3 solution and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in hexane/DIPE. The precipitate was filtered off and dried, yielding 0.9 g of (±)-methyl 1-(4-nitrophenyl)-α-phenyl-4-piperidineacetate (intermediate 14, melting point 124° C.).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:14][C:15]([F:33])([F:32])[C:16]([C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][C@H:24]([C:29](O)=[O:30])[CH2:23][CH2:22][C:21]=2[N:20]=1)([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:29]([CH:24]3[CH2:23][CH2:22][C:21]4[N:20]=[C:19]([C:16]([CH3:18])([CH3:17])[C:15]([F:33])([F:32])[F:14])[CH:28]=[CH:27][C:26]=4[CH2:25]3)=[O:30])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(N)cc21
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2ccc(NC(=O)C3CCc4nc(C(C)(C)C(F)(F)F)ccc4C3)cc21
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 64.1 %

Procedure:
To a mixture of 1-acetyl-6-amino-indoline (32 mg, 0.18 mmol), (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (40 mg, 0.14 mmol) was added HATU (79 mg, 0.21 mmol) in NMP (0.7 mL), followed by N,N-diisopropylethylamine (73 μL, 0.42 mmol). After 1.3 h, the reaction was heated to 60° C. After 25 h, the material was filtered and purified by reverse-phase HPLC (40-75% ACN in 0.1% HCO2H/H2O). The fractions were stirred with MP-carbonate resin (1.0 g, 3.0 mmol/g) overnight, filtered and concentrated to afford the amide (40 mg, 64%) as a solid foam. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.21 (d, J=1.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.38 (dd, J=1.8, 8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 4.09 (t, J=8.5 Hz, 2H), 3.08 (t, J=8.5 Hz, 2H), 3.02-2.85 (m, 4H), 2.85-2.74 (m, 1H), 2.18-2.12 (m, 1H), 2.16 (s, 3H), 1.93-1.82 (m, 1H), 1.55 (s, 6H); m/z=446.5 (M+1)+.