Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([OH:23])=O)=[CH:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])=[CH:17]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C(=O)O)[nH]c23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C(=O)Nc4ccccc4)[nH]c23)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 55 %

Procedure:
A mixture of 7-{[(4-methylphenyl)sulfonyl]amino}-1H-indole-2-carboxylic acid (110 mg), aniline (38 μL), ethyldiisopropylamine (0.29 mL), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (180 mg) and N,N-dimethylformamide (4 mL) was stirred at 60° C. for 7 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (75 mg, yield 55%) as colorless crystals. melting point 247-248° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](Cl)=[O:20])=[CH:11][N:10]=1>C(Cl)Cl>[Cl:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:20])=[CH:11][N:10]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cnc(Cl)nc2C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
N-Methylpiperazine (0.11 mL, 1 mmol) was added to a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carbonyl chloride (0.24 g, 1 mmol) in DCM (4 mL) at 0° C. The mixture was stirred at that temperature for 1 hr, and the solvent was then removed under vacuum to give (2-chloro-4-trifluoromethylpyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone as a solid.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:38]=[CH:37][C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[N:28]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[S:25][CH:26]=[C:27]([C:29]4[CH:38]=[CH:37][C:32]5[NH:33][C:34](=[O:36])[O:35][C:31]=5[CH:30]=4)[N:28]=3)=[O:19])=[CH:21][CH:22]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1nc(-c2ccc3[nH]c(=O)oc3c2)cs1
Product: O=C(Nc1nc(-c2ccc3[nH]c(=O)oc3c2)cs1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (200 mg, 0.63 mmol) was treated with 6-(2-aminothiazol-4-yl)benzo[d]oxazol-2(3H)-one (198 mg, 0.55 mmol) using method C. The residue was purified using flash chromatography eluting with 0-70% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 73 mg (22%). 1H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.84-7.74 (m, 4H), 7.69 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.24-7.19 (m, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.13-7.07 (m, 2H), 3.85-3.78 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.67-1.58 (m, 2H).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1.[CH3:34][C:35]#[N:36]>>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:33][C:35]([CH3:34])=[N:36][CH:32]=2)=[CH:27][CH:26]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CC#N
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: Cc1ncc(-c2ccc(Br)cc2)o1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic acid (6.6 ml) was added to a flask containing iodobenzene diacetate (12.2 g) and MeCN (200 ml) at rt. After 25 min. a solution of 4′-bromoacetophenone (5 g) in MeCN (50 ml) was added and the resultant mixture heated at reflux for 6 h. The reaction was allowed to cool to rt before the solvent was evaporated and the residue partitioned between saturated aqueous Na2CO3 (150 ml) and EtOAc (150 ml). The organic phase was washed with saturated brine (150 ml), dried (MgSO4) and evaporated to give an orange solid. The crude product was purified by column chromatography (silica gel, 50% EtOAc in hexane) to give the title compound (D38) as a pale yellow solid (3.5 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19]C)[CH:14]=3)[C:9]=2[OH:21])[CH:5]=[CH:6][CH:7]=1.F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:21][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:17]([CH3:18])=[CH:16]2
Reactant: COc1ccc2c(O)c(-c3cccc(F)c3)c(C)cc2c1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(C=O)c(C(F)(F)F)c2)c1-c1cccc(F)c1
Temperature: 110 °C
Yield: 67 %

Procedure:
Compound (283) (1.77 g, 5.43 mmol) was dissolved in HCl (4 N in 1,4-dioxane) (15 mL) and the solution was stirred at RT under N2 for 30 min. The reaction mixture was concentrated to give crude 2-(3-fluorophenyl)-3-methyl-6-(methyloxy)-1-naphthalenol (284) as a gold-yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 3.84 (s, 3H), 6.99-7.44 (m, 6H), 8.04 (d, J=9.3 Hz, 1H), 8.75 (s, 1H). Compound 284 (˜1.50 g, 5.32 mmol) was immediately treated with 4-fluoro-2-trifluoromethylbenzaldehyde (1.53 g, 7.96 mmol) and Cs2CO3 (2.59 g, 7.98 mmol) in DMF (5 mL). The mixture was heated at 110° C. for 16 h, cooled to RT and diluted with 100 mL each H2O and EtOAc. The organic layer was washed with 100 mL each water and brine, dried (Na2SO4) and concentrated to 2.92 g of an amber oil. The oil was purified by column chromatography with 10% EtOAc/hexanes to yield 1.57 g (65%) of the title compound 285 as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.88 (s, 3H), 6.96 (dd, J1=2.3 Hz, J2=8.6 Hz, 1H), 7.01-7.14 (m, 4H), 7.17 (d, J=2.5 Hz, 1H), 7.23-7.38 (m, 1H), 7.39 (d, J=2.5 Hz, 1H), 7.93 (d, J=9.1 Hz, 1H), 7.79 (s, 1H), 7.90 (d, J=8.7 Hz, 1H), 10.02 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[N:7]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:13])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]1[CH:29]=[CH:28][N:27]([CH3:30])[C:26](=[O:31])[CH:25]=1.[Cl-].[Li+]>CC(N(C)C)=O.CS(C)=O>[OH:2][C:3]1[N:7]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:13])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]1[CH:29]=[CH:28][N:27]([CH3:30])[C:26](=[O:31])[CH:25]=1
Reactant: COc1c(-c2ccn(C)c(=O)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: Cn1ccc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)cc1=O
Yield: 17.1 %

Procedure:
Combined 6-(5-methoxy-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (24 mg, 0.057 mmol) and lithium chloride (12.01 mg, 0.283 mmol) in DMA (0.5 mL) and heated at 50° C. for 26 h. The reaction mixture was diluted with 0.5 mL DMSO and purified by prep HPLC using acetonitrile/water with ammonium hydroxide to give the title compound (4 mg, 17.24% yield) as a yellow solid. MS m/z 410 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH2:13]1)([CH3:10])[CH3:9].[CH:47](=O)[CH3:48].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([N:11]([CH2:47][CH3:48])[C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:39])=[O:40])[CH2:13]1)([CH3:10])[CH3:9]
Reactant: CC=O
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)C)[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.33 h
Yield: 32.2 %

Procedure:
To a solution of Example 48 (25 mg, 44 μmol) in 1,2-dichloroethane (3.0 mL) was added acetaldehyde (13 μL, 222 μmol) and acetic acid (30 μL, 0.14 mmol). The resulting mixture was stirred for 20 min, then sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added. After stirring for 2 h, the mixture was diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by preparative TLC (70:30 CH2Cl2/MeOH). After concentrating the material in vacuo, the resulting oil was dissolved in CH3CN/H2O/TFA and lyophilized to provide the title compound (10 mg, 34%) as a white solid and mixture of diastereomers: ESI MS m/z 591 [C30H37F3N4O3S+H]+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][O:43][CH2:44][CH3:45])=[CH:34][CH:33]=3)[CH:22]=[C:23]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:24]=2)=[CH:15][C:14]=1[F:46])C1C=CC=CC=1.C1C[O:50][CH2:49]C1>[Pd]>[F:46][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[C:21]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][O:43][CH2:44][CH2:45][O:50][CH3:49])=[CH:36][CH:37]=3)[CH:22]=[C:23]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:24]=2)[CH:17]=[CH:18][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: C1CCOC1
Reactant: CCOCOCCOc1ccc(-c2cc(OCOCCOC)cc(-c3ccc(OCCCOCc4ccccc4)c(F)c3)c2)cc1
Agent: [Pd]
Product: COCCOCOCCOc1ccc(-c2cc(OCOCCOC)cc(-c3ccc(OCCCO)c(F)c3)c2)cc1

Procedure:
2.60 g (4.20 mmol) 4″-(3-benzyloxy-propoxy)-3″-fluoro-5′-(2-methoxy-ethoxymethoxy)-4-(2-ethoxymethoxy-ethoxy)-[1,1′;3′,1″]terphenyl are hydrogenated in 50 ml THF on 1.0 g Pd/activated charcoal until the reaction is completed. The catalyst is filtered off and the solvent is removed in vacuo. 3-{3″-fluoro-5′-(2-methoxy-ethoxymethoxy)-4-[2-(2-methoxy-ethoxymethoxy)-ethoxy]-[1 1′;3′,1″]terphenyl-4″-yloxy}-propane-1-ol is obtained as colourless oil, which is used for the next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:30][C:29](=[O:31])[C:28]([CH3:32])=[C:27]([OH:33])[C:26]=1[CH3:34].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:30][C:29](=[O:31])[C:28]([CH3:32])=[C:27]([O:33][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:26]=1[CH3:34]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Pyridine (64 μl) and benzoyl chloride (45 μl) were added to a suspension of 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in CH2Cl2 (5 ml), and the mixture was stirred at room temperature for 50 minutes. The reaction solution was poured into a KHSO4 aqueous solution and extracted with AcOEt, and the organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→4/1) to obtain 6-(benzofuran-2-yl)-4-benzoyloxy-3,5-dimethyl-2H-pyran-2-one.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3([CH3:31])[CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:26]([O:28]CC)=[O:27])[CH:21]=4)[O:16]3)=[CH:11][CH:10]=2)[S:3]1.Cl>C(O)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3([CH3:31])[CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:26]([OH:28])=[O:27])[CH:21]=4)[O:16]3)=[CH:11][CH:10]=2)[S:3]1
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Solvent: CC(=O)O
Product: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CC(=O)c2cc(C(=O)O)ccc2O1
Yield: 68.6 %

Procedure:
A mixture of 530 mg of ethyl 2-[4-(2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl]-2-methyl-4-oxochroman-6-carboxylate (prepared as described in Example 14), 4 ml of acetic acid and 2 ml of 3N aqueous hydrochloric acid was heated under reflux for 5 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and the residue was dissolved in diethyl ether. The resulting solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The resulting residue was washed with warm water to afford 342 mg of the title compound as a pale yellow powder, softening at 105°-108° C.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl>CN1CCCC1=O>[C:2]1([O:1][CH:4]=[CH:5][C:6]2[CH:7]=[CH:8][C:13]([CH3:12])=[CH:14][CH:15]=2)[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2c(O)cccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(C=COc2cccc3c2C(=O)c2ccccc2C3=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.1 mol of 1-hydroxyanthraquinone is dissolved hot in 100 ml of N-methylpyrrolidone in a 1 liter brown glass flask with a mechanical stirrer, thermometer and condenser. After the mixture has been cooled to room temperature, 0.1 mol of NaH suspension is added in portions. When the evolution of gas has ended, 0.11 mol of a mixture of 3- and 4-vinylbenzyl chloride is added and the mixture is stirred at 100° C. for 5 hours. Stirring is continued overnight at room temperature. 100 ml of 0.1N HCl are then added and the suspension thus formed is extracted several times by shaking with methylene chloride. After the extract has been neutralised with sodium bicarbonate solution and dried with Na2SO4 and the methylene chloride has been stripped off, an oil remains, from which a yellow crystalline product is precipitated with water. Crude yield: 33.7 g (99% of theory). The crude product is purified by column chromatography with methylene chloride; yield of m-/p-methylstyryl 1-anthraquinonyl ether=58% of theory, melting point: 88°-90° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[OH-].[Na+].C1(C)C=CC=CC=1>[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCS(=O)(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(NCCS(=O)(=O)O)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Taurine (1 g; 8 mmol) was dissolved in 2N NaOH (4.3 mL) and, after cooling on ice/water bath, 4N NaOH (2.14 mL) and a solution of benzyloxycarbonyl chloride (3.27 mL; 8 mmol) in toluene (3 mL) were dropped at same time. After the additions, the mixture was left stirring at T=0-5° C. for 1 h. The reaction was quenched by adding diethyl ether. The mixture was debated and the phases were separated. The aqueous one was cooled to 0-5° C. and 37% HCl was added to pH=2. The acidic phase was extracted with ethyl acetate (3×10 mL) and the collected organic extracts were washed with water (2×15 mL) and brine (15 mL), dried over Na2SO4 and evaporated under vacuum to give 2-(N-benzyloxycarbonylamino)ethanesulfonic acid as crude product purified by trituration in diethyl ether to give the pure product as white solid (1.46 g; 5.64 mmol Yield=70.5%)
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[C:32]1[N:37]=[C:36]([CH3:38])[N:35]=[C:34]([S:39][CH3:40])[N:33]=1.[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[N:46][CH:47]=1.C1COCC1>[NH4+].[Cl-].O.C(OCC)(=O)C>[CH3:49][O:48][C:45]1[N:46]=[CH:47][C:42]([NH:41][C:12]2[N:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:14][C:13]=2[C:32]2[N:37]=[C:36]([CH3:38])[N:35]=[C:34]([S:39][CH3:40])[N:33]=2)=[CH:43][CH:44]=1
Reactant: COc1ccc(N)cn1
Reactant: CSc1nc(C)nc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc(SC)n2)cn1
Reaction time: 1 h
Yield: 48.8 %

Procedure:
LiHMDS (1.519 mL, 1.0 M in THF, 1.519 mmol) was added to a stirred solution of tert-butyl 4-((6-fluoro-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.220 g, 0.506 mmol) and 5-amino-2-methoxypyridine (0.094 g, 0.759 mmol) in THF (3.00 mL, 36.6 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with NH4Cl (aq) and water (10 mL each) and diluted with ethyl acetate (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (ISCO Combiflash system, Teledyne ISCO, Lincoln, Nebr., hexanes to 50% ethyl acetates in hexanes) to give tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.133 g, 49%) as a yellow solid. LCMS (API-ES) m/z 538 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 11.42 (s, 1H) 8.81 (br. s., 1H) 8.36 (d, J=2.74 Hz, 1H) 8.27 (br. s., 1H) 8.10 (dd, J=8.71, 2.64 Hz, 1H) 6.79 (d, J=8.80 Hz, 1H) 3.95 (s, 3H) 3.50 (s, 2H) 3.43 (br. s., 4H) 2.67 (s, 3H) 2.66 (br. s., 3H) 2.42 (br. s., 4H) 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24]3)=[CH:21][CH:22]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3]1.Cl.[NH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1([F:32])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:25]=[CH:24]3)=[CH:21][CH:22]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:13])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: O=C(O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Reaction time: 16 h
Yield: 11.5 %

Procedure:
Dimethylformamide (0.270 mL) was added to a vial containing crude 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzoic acid (24.0 mg, approximately 0.120 mmol pure), ethyl 3-aminopropanoate hydrochloride (16.3 mg, 0.110 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (40.3 mg, 0.110 mmol). Diisopropylethylamine (0.046 mL, 0.270 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-60% ethyl acetate in heptane) afforded ethyl 3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoate (7.00 mg) as an oil. MS (M+1): 552.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].C(CN)O>O.C(O)(=O)C.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[F:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1I
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccccc1CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and 9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hours, add 1-fluoro-2-iodo-benzene (2.3 g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0 mL) and dilute the mixture with water. Extract with ethyl acetate and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellow oil in acetic acid/methanol (1:9) and apply to an SCX column. Wash the column with methanol followed by 2N ammonia in methanol to give the title compound: mp 62–66° C.; mass spectrum (ion spray): m/z=389.4 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)[CH:2]=[CH2:3].[CH3:12][NH:13][CH2:14][CH:15]=[O:16]>C1C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH:15]=[O:16])[C:10]([NH:9][C:7]1[S:8][C:4]([CH2:1][CH:2]=[CH2:3])=[N:5][N:6]=1)=[O:11]
Reactant: C=CCc1nnc(N=C=O)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: C=CCc1nnc(NC(=O)N(C)CC=O)s1

Procedure:
A mixture of 5-allyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-allyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.