Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH:40][C:11](=[O:12])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[C:22]([N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:36]2)[CH2:31][O:30]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(N3CCCC3)c2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(N3CCCC3)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.140 g, 0.37 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.090 g, 0.46 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.655 g, 1.48 mmol). The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 0% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.110 g, 53%) as a white solid: HR-ES-MS m/z calculated for C29H38FN5O5 [M+H]+ 556.2930, observed 556.2928, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.25 (s, 3H), 1.29, 1.31 (2×s, 3H), 1.35-1.64 (m, 2H), 1.66-1.83 (m, 1H), 1.84-1.95 (m, 4H), 3.29-3.39 (m, 4H), 3.73 (dd, J=8.3, 5.9 Hz, 1H), 4.00 (dd, J=8.3, 6.5 Hz, 1H), 4.04-4.14 (m, 2H), 4.18 (d, J=18.4 Hz, 1H), 4.25-4.41 (m, 1H), 4.56 (d, J=18.4 Hz, 1H), 4.84-4.93 (m, 2H), 6.43 (d, J=2.1 Hz, 1H), 6.59-6.70 (m, 2H), 7.03 (t, J=8.2 Hz, 1H), 7.60 (br. s., 1H), 10.79 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].OO.C(OCC)(=[O:14])C.CCCCCC>C(O)(=O)C.CO>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccn1
Reactant: CCOC(C)=O
Agent: OO
Solvent: CCCCCC
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)c1cccc[n+]1[O-]
Yield: 33 %

Procedure:
To a solution of 2-acetylpyridine (0.3 mol) in 150 ml of glacial acetic acid was added with stirring 30% hydrogen peroxide (0.32 mol) and the mixture was allowed to react at 60°-65° C. for 16 hours. An additional 3.3 ml of 30% hydrogen peroxide was added, and the mixture was allowed to react at 70° C. for 2 hours. After cooling, the water was removed by evaporation at reduced pressure to leave a crude liquid residue which was taken up in an equal volume of 50:50 ethyl acetate and hexane, and the components were separated by chromatography on 330 g of silica gel. Gradient elution starting with 50:50 ethyl acetate/hexane to 100% ethyl acetate and then to 5% methanol gave 13.48 g (33% yield) of 2-acetyl-pyridine-N-oxide. 1H NMR (CDCl3): 2.81 (singlet (s), 3H, CH3), 7.34 (multiplet (m), 2H, H4 and H 5), 7.71 (doublet (d), 1H, H3), and 8.22 ppm (d, 1H, H5); 13C NMR (CDCl3): 31.3 (CH3), 125.9, 127.4, 128.6, 141.2, and 195.7 ppm (C=O); mass spectrum (DCl) M+H=138 m/e; IR (film) λmax 1686 cm-1 (C=O).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:16][NH2:17].C(N(CC)CC)C>C(O)C>[NH:16]([C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1)[NH2:17]
Reactant: O=C(c1ccc(Cl)nc1)N1CCOCC1
Reactant: NN
Solvent: CCN(CC)CC
Solvent: CCO
Product: NNc1ccc(C(=O)N2CCOCC2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To (6-chloro-pyridin-3-yl)-morpholin-4-yl-methanone (0.649 g, 2.86 mmoles) in ethanol (6 mL) was added 0.270 uL (3.0 equivalents) of hydrazine, followed by triethylamine 438.9 uL (1.1 equivalents). The reaction was stirred overnight at 100° C. to give (6-hydrazino-pyridin-3-yl)-morpholin-4-yl-methanone. The reaction was filtered and then concentrated to dryness. The crude residue, (6-hydrazino-pyridin-3-yl)-morpholin-4-yl-methanone, weighed 0.372 g (76% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[C:10]=2[OH:18])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CC(C)=O>[CH3:7][CH2:2][CH2:3][CH:4]([CH3:8])[CH3:5].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[C:10]=2[O:18][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1csc(Cc2cccc(Cl)c2)c1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(C)C
Product: COC(=O)c1csc(Cc2cccc(Cl)c2)c1OCCO[Si](C)(C)C(C)(C)C
Yield: 93.2 %

Procedure:
A mixture of methyl 5-[(3chlorophenyl)methyl]-4-hydroxythiophene-3-carboxylate (11 g), potassium carbonate (5.45 g) and (2-bromoethoxy)(1,1-dimethylethyl)dimethylsilane (10 g) was dissolved in acetone (250 m) and heated at reflux for 36 hours and then allowed to cool. The mixture was filtered, concentrated and purified by chromatography, eluting with 10:1 ethyl acetate:isohexane, to give the sub-title compound (8 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[N:38](C)[CH3:39])[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(O[C:45]([CH2:47][CH2:48]C1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C=CSC=2)C=1)C(O)=O)=O)C.C1(N)CCC1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[NH:38][CH:39]3[CH2:48][CH2:47][CH2:45]3)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Agent: NC1CCC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NC3CCC3)cc(-c3ccsc3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(3-dimethylcarbamoyl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid and cyclobutylamine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)(=[O:14])[CH3:13]
Reactant: OCCSCc1ccncc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCSCc1ccncc1
Reaction time: 8 h

Procedure:
4-(2-Hydroxyethylthiomethyl)pyridine (1.0 g.) was refluxed with 10 ml. of acetic anhydride for 3 hours. After standing overnight at room temperature, the acetic anhydride was evaporated in vacuo, the residue diluted with 10 ml. of water, made basic with sodium bicarbonate, and the product extracted into chloroform (four times 50 ml.). The chloroform was carbon treted, dried and concentrated to an oil (1.47 g.). The oil was chromatographed on 60 g. of silica gel with 5% methanol/chloroform as eluant. Fractions containing only product (Rf 0.6 on thin layer silica gel chromatography eluted with 18:1 chloroform:methanol) were combined and concentrated to yield 4-(2-acetoxyethylthiomethyl)pyridine [300 mg. of oil; pnmr/CDCl3 /TMS/τ: 7.9 (s, 3H), 7.3 (t, 2H), 6.3 (s, 2H), 5.8 (t, 2H), 2.7 (d, 2H), 1.4 (d, 2H)].
Reaction SMILES: C([B-:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#N.[Na+]>CO>[B:3]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#C[B-](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: c1ccc(B(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.25 g of the product from c) was dissolved almost completely in 5 ml of methanol. 0.45 g of sodium cyanotriphenylborate was added. The mixture was stirred at room temperature for 17 h, during which the product gradually became crystalline. This product was filtered off with suction and washed with 25 ml of methanol, 25 ml of water and again with 25 ml of methanol. Drying gave 0.15 g (59% of theory) of a pate grey powder of the formula (LXXIV) with X−=NC—B(C6H5)3−.
Reaction SMILES: C(OC([P:9]([CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH3:16])(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](C)(C)Cl>ClCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([CH3:16])=[CH:14][PH:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:22][CH:21]=1
Reactant: CCOC(C)(OCC)P(=O)(C=C(C)c1ccc(Cl)cc1)OCC
Agent: C[Si](C)(C)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCO[PH](=O)C=C(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 14.42 g of ethyl (1,1-diethoxyethyl)-2-(4-chlorophenyl)prop-1-enylphosphinate in 50 ml of anhydrous dichloromethane containing 10% of absolute ethanol is treated with 6.518 g of trimethylchlorosilane. After stirring at room temperature for 24 hours the volatile material is removed under reduced pressure. Chromatography of the resulting oil on silica-gel gives ethyl 2-(4-chlorophenyl)prop-1-enylphosphinate as a colourless oil; 1H-NMR (CDCl3): δ(ppm)=7.35 (4H, m, Ph), 7.05 (1H, d, t, J=549 and 1.5 Hz, P--H), 5.56 (1H, d, CH), 5.30 (1H, d, CH), 4.20-3.97 (2H, q, CH2OP), 3.07 (2H, d, t, J=17+1.5 Hz, P--CH2), 1.27 (3H, t, CH3).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:16])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]=[C:14]=[S:15])[CH:7]=2)[CH2:3][CH2:2]1.[NH3:17]>CO>[CH:1]1([NH:4][C:5](=[O:16])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14]([NH2:17])=[S:15])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: N
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N=C=S
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A suspension of N-cyclopropyl-3-isothiocyanato-4-methyl-benzamide 3B (7.45 g) in a 7N solution of ammonia in methanol (40 mL) was stirred at room temperature for 1 hr. The mixture was concentrated, then redissolved in MeOH and reconcentrated to give the desired product as white solid (6.1 g, 60% for two steps).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH2:11]C=O)=N)=[CH:5][CH:4]=1.[NH2:16][C:17]([NH2:19])=[O:18].[CH2:20](O)C>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:11]=[N:16][C:17]([OH:18])=[N:19][CH:20]=2)=[CH:7][CH:8]=1
Reactant: CCO
Reactant: NC(N)=O
Reactant: N=C(CC=O)c1ccc(C(F)(F)F)cc1
Product: Oc1ncc(-c2ccc(C(F)(F)F)cc2)cn1

Procedure:
By the procedure described in Example 4, (p-trifluoromethylphenyl)formimidoylacetaldehyde is reacted with urea to give the product of the Example (recrystallized from ethanol), m.p. 271°-273° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[N:4]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].O>O1CCCC1>[F:14][C:2]([F:1])([F:13])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:22](=[O:23])[O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[CH:11][C:5]=2[N:4]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2[nH]c(C(F)(F)F)nc2c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2[nH]c(C(F)(F)F)nc2c1)OCC(Cl)(Cl)Cl
Yield: 68.4 %

Procedure:
To a solution of 2-(trifluoromethyl)-1H-benzimidazol-5-amine (1.00 g, 4.97 mmol) and pyridine (0.473 ml, 5.97 mmol) in tetrahydrofuran (17 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.826 ml, 5.97 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 1.28 g (68.5%) of the desired product as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl.[Na+].[I-:23]>N1C=CC=CC=1.CC(C)=O.O>[I:23][CH2:8][CH2:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCc1ccco1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: ICCCc1ccco1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 3-furan-2-yl-propan-1-ol (6.3 g, 50 mmol) in pyridine (40 mL) at −15° C. was added p-toluenesulfonyl chloride (11.4 g, 60 mmol) in portions and the reaction was stirred for 3 h. Water (10×0.5 mL) was added and the mixture was poured into a mixture of concentrated HCl (65 mL) and ice (200 gm). The product was extracted into Et2O and the organic solution was dried over MgSO4, filtered, and concentrated to provide a yellow oil. The oil was added to a mixture of NaI (9 g, 60 mmol) in acetone (70 mL) and the reaction was stirred for 15 h. The insolubles were removed by filtration and the filtrate was concentrated in vacuo. Purification by flash chromatography (hexanes) provided the title compound (7.2 g). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.28 (m, 1H), 6.04 (m, 1H), 3.19 (t, 2H), 2.75 (t, 2H), 2.14 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)=[O:11])[N:9]=1)(=[O:3])[CH3:2].[ClH:27]>CO.C(OCC)(=O)C>[ClH:27].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[O:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C(=O)Nc2ccc(NC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(N)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl)amino}phenylcarbamate (85 mg) in methanol (1 ml) was added 4N hydrogen chloride in ethyl acetate (1 ml), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo. The solid residue was collected and washed with ethyl acetate to give 2-(acetylamino)-N-(4-aminophenyl)-1,3-thiazole-4-carboxamide hydrochloride (70 mg).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+].[Na+].[C:7](=[O:10])([O-:9])[O-:8].[Ca:11].[Sr:12]>>[C:1](=[O:2])([O-:4])[O-:3].[Sr+2:12].[C:7](=[O:8])([O-:10])[O-:9].[Ca+2:11]
Reactant: [Sr]
Reactant: [Ca]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: [Ca+2]
Product: [Sr+2]

Procedure:
To determine the effect of sodium carbonate excesses, carbonate reaction times and various levels of muds recycle on the removal of strontium and calcium from brine, separate runs are made in which 200 ml. samples of raw brine containing 25 weight percent sodium chloride, 228 ppm calcium (calculated as elemental calcium) and 15 ppm strontium compounds (calculated as elemental strontium) are contacted with the selected quantity of sodium carbonate and stirred in a 250 ml. container at approximately 300 rpm for the selected period of time to provide reaction of the sodium carbonate with dissolved calcium and strontium impurities to form strontium carbonate and calcium carbonate solids. In each run, sodium carbonate was added in an amount to provide the desired excess sodium carbonate over that stoichiometrically required to react with the dissolved strontium and calcium impurities. In the runs which employed muds recycle, a selected quantity of muds having the following analysis (dry basis) are added along with the sodium carbonate to the brine:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16]([S:20]([C:23]4[S:27][C:26]5[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=5[CH:24]=4)(=[O:22])=[O:21])[CH2:15][CH:14]3[C:33](O)=[O:34])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C[N:37]1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16]([S:20]([C:23]4[S:27][C:26]5[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=5[CH:24]=4)(=[O:21])=[O:22])[CH2:15][CH:14]3[C:33]([NH2:37])=[O:34])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCOCC1
Reactant: Nc1ncnc2cc(CN3C(=O)CN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a mixture containing (±)-1-(4-amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid (45 mg, 0.08 mmol), EXAMPLE 800, N-methylmorpholine (18 mg, 0.18 mmol), and HATU (35 mg, 0.09 mmol) in anhydrous DMF (1 mL) is added NH3 (7N in MeOH, 2 drops, approx. 0.5 mmol). The heterogeneous mixture is stirred 16 h at ambient temprature and then concentrated to dryness. The residue is dissolved in water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 25 mg (46%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.63 (d, J=16.0 Hz, 1H), 4.01 (m, 4H), 5.17 (d, J=16.6 Hz, 1H), 7.58 (m, 3H), 8.08 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.74 (s, 1H), 9.63 (br s, 2H) ppm; MS (ISP loop): m/z 531 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([OH:32])[CH2:5]2.[H-].[Na+].I[CH2:36][CH3:37]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([O:32][CH2:36][CH3:37])[CH2:5]2
Reactant: CCI
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1[C@@H]1c2ccc(Br)cc2C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H]1Cc2cc(Br)ccc2[C@H]1N1CCN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a solution of tert-butyl 4-{(3S)-4-[(1R,2R)-5-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (564 mg, 1.1 mmol) in tetrahydrofuran (20.00 mL) was added sodium hydride (448 mg, 17.75 mmol) at room temperature. After stirring for 10 min, iodoethane (1.42 mL, 17.75 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with saturated aqueous ammonium chloride solution (20 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×30 mL). The combined extracts were splashed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the crude product (488 mg, 82%). LC-MS [M+1]=536.3, 538.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH2:6][O:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH3:16])[N:9]=1.Cl.C([N:37]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:25][C:26]=1[CH3:27])[CH2:6][O:7][C:8]1[C:12]([C:13]([NH2:37])=[O:15])=[CH:11][N:10]([CH3:16])[N:9]=1
Reactant: COc1cc(COc2nn(C)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(C)cc2C(N)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylic acid (0.90 g), 1-hydroxy-1H-1,2,3-benzotriazole ammonia complex (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g) and N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxamide (0.71 g, yield 79%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 168-169° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8]([O:10]CC)=O.O.[NH2:30][NH2:31]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:10])[NH:31][NH:30][C:13](=[O:14])[C:6]=2[C:5]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[N:4][C:3]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1c(-n2cncn2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ccccc2)nc(-n2cncn2)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 15 ml of ethanol was dissolved 0.215 g of 3-amino-4,5-diethoxycarbonyl-2-phenyl-6-(1,2,4-triazol-1-yl)pyridine, whereto 1 ml of hydrazine monohydrate was added. The mixture was heated under reflux for 7 hours. After cooling, the resulting yellow crystals were collected by filtration and washed with ethanol. The crystals were suspended in 20 ml of water and the suspension was acidified by addition of 1 ml of acetic acid. Thereafter, the crystals were collected by filtration, washed with water and dried to give 0.11 g of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C1O[CH2:38][CH2:37]OCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1Cl>[CH:2]1[C:3]2[N:20]([C:38]3[CH:37]=[CH:21][CH:9]=[C:10]([N:20]4[C:19]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[C:13]5[C:21]4=[CH:9][CH:10]=[CH:11][CH:12]=5)[CH:11]=3)[C:19]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Ic1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Reaction time: 12 h

Procedure:
To a solution of 1,3-diiodobenzene (50.0 g, 0.152 mol), carbazole (55.0 g, 0.329 mol), Cu (40.0 g, 0.630 mol) and 18-crown-6 (0.5 g) in 1,2-dichlorobenzene (200.0 ml) was added potassium carbonate (150.0 g, 1.085 mol) under nitrogen and stirring. The reaction was carried out at 190° C. for 12 hours. After cooling, the reaction mixture was filtrated. The solid residues were carefully washed with THF. Then, THF and 1,2-dichlorobenzene were evaporated from the combined filtration solution. The crude product was purified by recrystallization from acetone/methanol to give 47.0 g (75.7%) in yield.