Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[S:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[Cl:17][CH:2]([Cl:1])[S:3]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1cc(SC(Cl)Cl)c(=O)c2ccc(F)cc21
Solvent: ClCCl
Product: Cn1cc(S(=O)C(Cl)Cl)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
665 mg (2.276 mmol) of the 3-dichloromethylthio-7-fluoro-1-methyl-4-quinolone (Compound 2, FIG. 1), as prepared in Step A, was dissolved in 20 ml of DCM at 0° C. to form a solution. To this solution was added 505.7 mg (2.345 mmol) of 80% MCPBA to form a mixture. This stirred mixture was then allowed to warm to room temperature and was stirred for 1 hour. An additional 25 mg of MCPBA was added and the mixture and stirred for 1 hour. The mixture was washed with 5% aqueous Na2CO3. The aqueous layer was extracted with DCM, and the combined DCM extracts were dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel with hexane-ethyl acetate (gradient 4:1,2:1,1:1) to give 352 mg (50%) of the product (Compound 3, FIG. 1) as a white solid, that was approximately 98% pure according to 1H NMR, CDCl3; d=3.96 s, 3H, N—CH3; 7.09 s, 1H, CHCl2; 7.22 dd, 1H, J=10.2 & 2.4 Hz, H at C8, 7.27 ddd, 1H, J=9.0, 7.6 & 2.2 Hz, H at C6; 8.03 s, 1H, H at C2; 8.43 dd, 1H, J=8.8 & 6.1 Hz, H at C5. This white solid product was further purified by recrystallization from methanol to give 252 mg of white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([Cl:20])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
3,5-Di-t-butylbenzoic acid, purchased from Aldrich Chemical Co., (10 g, 0.042 mol) was dissolved in 50 mL thionyl chloride and the light yellow solution was refluxed for 3 h under argon. The reaction was cooled to room temperature and excess SOCl2 was evaporated under vacuum (liq. N2 trap). The resulting oil was dissolved in dry toluene (100 mL) and the resulting solution was evaporated under vacuum to give the 3,5-di-t-butylbenzoyl chloride as a light brown oil (10.5 g, 99%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])[C:18]([CH:11]1[C:10](=[O:21])[C@@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1cc(Cl)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
Triethylamine (26 mL, 186.5 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 13.33 g, 62.1 mmol) in dichloromethane (150 mL), yielding a thick suspension. This was stirred for 3 min and then N′-(2,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 34; 13.00 g, 46.9 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 10 min, then in an oil-bath at 50° C. for 4 h. The reaction mixture was cooled to room temperature, then added to water (200 mL) and extracted with dichloromethane (3×150 mL). The combined organic layers were washed with brine (200 mL), dried (magnesium sulfate), filtered, and evaporated to give N′-(2,5-dichloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (29.55 g, 138% of the expected amount) as a brown oil. This was used directly in the next step without further purification.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:43]([Cl:46])(=[O:45])[CH3:44].C([O-])(O)=O.[Na+].[ClH:52]>C1COCC1>[ClH:46].[ClH:52].[O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][N:33]([C:43](=[O:45])[CH3:44])[CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)cs2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
A 20 mL vial was charged with 3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine (80 mg, 0.15 mmol), triethylamine (0.043 mL, 0.31 mmol), and THF (2 mL). Acetyl chloride (0.011 mL, 0.15 mmol) was added and stirred at ambient temperature for 10 minutes. The reaction was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (5 to 10% methanol in EtOAc) to afford the title compound (35.1 mg, 35.9% yield) as a yellow solid after HCl salt formation. 1H NMR (d6-DMSO) δ 8.65 (d, 1H), 8.48 (d, 1H), 8.46 (d, 1H), 7.77 (d, 1H), 7.54 (d, 1H), 7.41 (m, 2H), 7.18 (m; 4H), 6.82 (s, 1H), 4.43 (m, 1H), 3.88 (m, 1H), 3.14 (m, 1H), 2.89 (m, 1H), 2.64 (m, 1H), 2.01 (s, 3H), 1.96 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci) m/z=560.4 (M+H-2HCl).
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[F:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[C@@H:34]1[CH2:44][CH2:43][C:42](=O)[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[C@H:35]1[NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>C1(C)C=CC=CC=1>[C:49]([O:48][C:47]([NH:46][C@@H:35]1[C:36]2[C:37](=[N:38][CH:39]=[CH:40][CH:41]=2)/[C:42](=[CH:6]/[C:1]([O:3][CH2:4][CH3:5])=[O:2])/[CH2:43][CH2:44][C@H:34]1[C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[F:26])=[O:53])([CH3:51])([CH3:52])[CH3:50]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2C(=O)CC[C@H]1c1cccc(F)c1F
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C1\CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2cccnc21
Yield: 58.8 %

Procedure:
A mixture of (carbethoxymethylene)triphenylphosphorane (0.214 g, 0.614 mmol) and tert-butyl (5S,6S)-6-(2,3-difluorophenyl)-9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (0.199 g, 0.512 mmol) in toluene (5 mL) was heat to reflux for 18 h. The solvent was removed via vacuum and the crude residue was loaded onto a silica gel column directly. Purification was performed by elution with ethyl acetate in hexane from 0 to 65% to afford the desired product (138 mg, 59%): MS(ESI)[M+H+]=459.22; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.53 (1H, dd, J=4.8, 1.3 Hz), 7.70 (1H, d, J=7.5 Hz), 7.32 (1H, dd, J=7.8, 4.8 Hz), 7.15-7.24 (1H, m), 7.05-7.13 (2H, m), 6.39 (1H, t, J=2.3 Hz), 5.21-5.31 (1H, m), 4.89-4.99 (1H, m), 4.19 (2H, q, J=7.1 Hz), 3.32-3.43 (1H, m), 3.17-3.32 (1H, m), 3.12 (1H, d, J=2.3 Hz), 1.87 (2H, d, J=4.5 Hz), 1.14-1.38 (13H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18](Br)[CH2:17]1)[CH3:12]>C(O)C>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:17]1)[CH3:12]
Reactant: Sc1ccc(Cl)cc1
Reactant: CCOC(=O)CC1CCC(=O)C(Br)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CCC(=O)C(Sc2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
58 G. of 4-chlorothiophenol and a solution of 26.5 g. of 85% potassium hydroxide in 1500 ml. of ethanol were each placed in a 3 l. three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 105 g. of crude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotary evaporator), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue, weighing 128 g., was distilled in vacuo. A forerun weighing 28.7 g. was collected at 100°-190° (1 mm.), while 76.4 g. of a main fraction collected at 190°-222° (1 mm.). A gas chromatographic determination of the main fraction showed that 3-(4-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester was present.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: COc1ccc(-c2cn(C)c3cc(S(=O)(=O)Nc4ncns4)ccc23)c(OC)c1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (2,4-dimethoxyphenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(2,4-dimethoxyphenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 3.80 (s, 3H) 3.87 (s, 3H) 6.59-6.68 (m, 2 H) 7.35 (d, J=8.25 Hz, 1 H) 7.43 (dd, J=8.42, 1.43 Hz, 1 H) 7.52-7.60 (m, 1 H) 7.85 (s, 1 H) 7.94 (br. s., 1 H). m/z (ESI) 430.1 (M+H)+.
Reaction SMILES: [O-:1][P:2]([O-:5])([O-:4])=[O:3].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].Cl.[P:23](=O)(O)(O)[OH:24]>>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:15][P:23]([O:9]3)([O:4]1)=[O:24])(=[O:13])[O:1]2)=[O:8]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=P(O)(O)O
Agent: Cl
Agent: [Ca+2]
Agent: [F-]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3

Procedure:
In the same manner as in Ex. 1-3, phosphate rock from Zin, Israel of the same analysis and particle size as before was heated at various temperatures and for various times. The treated rock was reacted with hydrochloric acid as before and in separate experiment with a sulphuric/phosphoric acid mixture and the colour of the liquid noted and organic and P2O5 content of the liquid obtained. The sulphuric/phosphoric acid was a mixture of 200 g of 20% P2O5 thermal phosphoric acid and enough 56% sulphuric acid to combine with 98% of the calcium content of the phosphate rock used, the amount of which was such as to contain 40 g P2O5. The specified amount of rock was mixed with stirring with 200 g of phosphoric acid at 60° C. When foaming ceased the sulphuric acid was added and the mixture stirred for 2 hrs at 70° C. to give a suspension of gypsum in phosphoric acid. The suspension was filtered hot and the filter cake washed three times with 50 cc cold tap water. All the filtrates were combined to give the product acid which was analysed for P2O5, total carbon and oxidizable carbon contents. The rock before and after the heating was also analysed for F. The results were as follows. (see Table 2). The Zin rock before heat treatment contained acid insoluble iron sulphide in amount of 250 ppm (expressed as S).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].FC(F)(F)C(O)=O.[NH2:13][C@H:14]1[CH2:17][O:16][C:15]1=[O:18].[OH-].[Na+]>O>[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:17][C@@H:14]([C:15]([OH:18])=[O:16])[NH2:13]
Reactant: NCCS
Reactant: N[C@H]1COC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCSC[C@H](N)C(=O)O

Procedure:
To 2-aminoethanethiol hydrochloride (201 mg, 1.77 mmol) in degassed H2O (3.0 mL) was added (S)-3-amino-2-oxetanone trifluoroacetic acid salt (produced from BOC-L-serine β-lactone (151 mg, 0.807 mmol)) in H2O (1.0 mL). The pH of the stirred solution was maintained at 5.0-5.5 by dropwise addition of 1N NaOH. When additions of base were no longer required to maintain the pH at 5.5 (~35 min), the mixture was applied to a column of BioRad AG50-X8 (trademark) (80 mL, 3 cm dia., H+ form) and eluted with a linear gradient (0 to 0.2M over 1.0 L) of aqueous HC1 (2 mL/min). Lyophilization of the chromatographically pure fractions yielded 138 mg 85%) of S-(aminoethyl)-L-cysteine hydrochloride which was recrystallized from EtOH/acetone (85% recovery) for elemental analysis: mp 193°-194° C. (dec) (lit. mp 192°-192.5° C., 205°-207° C.); [α]D 25 +7.2 (c 1.0, H2O) (lit. [α]D +7.2 (c 1, H2O)); IR (KBr disk) 3650-2100 (s, br), 2000 (W, br), 1622 (s), 1587 (s), 1516 (s), 1494 (s), 1463 (s), 1427 (s), 1415 (s), 1400 (s), 1348 (s), 1303 (s), 560 (m) cm-1 ; 1H-NMR (300 MHz, D2O)δ 4.00 (dd, 1H, 4.8, 6.0 Hz, CH), 3.27 (t, 2H, 6.5 Hz, CH2NH3+), 3.16 (dd, 1H, 4.8, 14 Hz, CHCHHS), 3.14 (d, 6.0, 14 Hz, CHCHHS), 2.94 (t of d, 1H, 6.5, 14 Hz, SCHH), 2.92 (t of d, 1H, 6.5, 14.0 Hz, SCHH). Anal. Calc. for C5H13N2O2SCl: C, 29.92; H, 6.54; N, 13.96; Cl, 17.66; S, 15.97. Found: C, 29.59; H, 6.44; N, 13.98; Cl, 17.40; S, 15 88; POSFAB-MS (glycerol/HC1) 165 (MH+), 329 (M2H+); Rf~0.20 (System A).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)=[O:11].S([O-])([O-])(=O)=S.[Na+].[Na+].C[N:26](C=O)C>>[NH2:26][N:16]1[CH:15]=[CH:14][N:13]=[C:12]1[C:10]([NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:17])=[O:11]
Reactant: Cc1ccccc1NC(=O)c1ncc[nH]1
Reactant: CN(C)C=O
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1NC(=O)c1nccn1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
240 mg (6.02 mmol) of sodium hydride (60% dispersion in mineral oil) were added to a 0° C. cooled solution of N-o-tolyl-1H-imidazole-2-carboxamide (0.93 g, 4.63 mmol) in DMF (120 mL). The mixture was stirred at 0° C. for 30 minutes and DPPONH2 (1.51 g, 6.49 mmol, available from Sigma Aldrich®, cat. no. 5994-87-6) was added portionwise. The mixture was stirred at room temperature for 2 hours and then it was poured into 200 mL of a saturated aqueous solution of sodium thiosulphate and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography (20% to 50% AcOEt/Hexanes) to yield 0.55 g (55%) of the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[N+:25]([O-])([OH:27])=[O:26]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:25]([O-:27])=[O:26])[C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC(C)C)cc12
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate (6.16 g, 18.76 mmol) in chloroform (22 mL) at −15° C. was added dropwise a cold solution of 70% nitric acid (11 mL, 172 mmol) in chloroform (22 mL). After stirring at 0° C. for 1 hour, the reaction mixture was washed with water (50 mL) and the organic phase was separated by hydrophobic filter tube then evaporated under vacuum to afford a brown solid. The solid was triturated in methyl tert-butyl ether (25 mL) and the resulting pale yellow powder was filtered off, washed with heptane and dried under vacuum to give methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-6-nitro-1-benzofuran-3-carboxylate. LCMS (m/z, ES+)=764 (2M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ccc(Cl)c(Br)n1
Temperature: 80 °C

Procedure:
To a solution of 6-bromopyridin-2-amine (10 g, 58 mmol) in acetonitrile (150 mL) was added 1-chloropyrrolidine-2,5-dione (8.1 g, 60 mmol) and the mixture was heated at 80° C. for 10 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water. The organic phase was concentrated and purified by column chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. LCMS: 208 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:12]1[C:21]2[C:16](=[C:17]([CH3:23])[CH:18]=[C:19]([Cl:22])[N:20]=2)[C:15](=[O:24])[C:14]([C:25]([O:27]CC)=[O:26])=[CH:13]1.O.[OH-].[Li+]>O1CCOCC1>[Cl:22][C:19]1[N:20]=[C:21]2[C:16]([C:15](=[O:24])[C:14]([C:25]([OH:27])=[O:26])=[CH:13][NH:12]2)=[C:17]([CH3:23])[CH:18]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)cc(C)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)nc2[nH]cc(C(=O)O)c(=O)c12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of Example 65D (0.200 g) in 1.4-dioxane (5 mL) was treated with lithium hydroxide monohydrate (0.100 g), stirred for 16 hours, and concentrated. The concentrate was dissolved in trifluoroacetic acid (8 mL), heated at 60° C. for 12 hours, and concentrated; and this concentrate was purified by reverse phase HPLC to afford the desired product. NMR (300 MHz, DMSO-d6) δ 14.95 (s, 1H), 13.79 (s, 1H), 8.72 (s, 1H), 7.57 (s, 1H), 2.89 (s, 3H).
Reaction SMILES: N[C:2]1[C:11]2[C:10](=[O:12])[C:9]([CH3:13])=[N:8][N:7]([CH3:14])[C:6]=2[N:5]=[C:4]([NH2:15])[N:3]=1.[OH-:16].[Na+]>>[NH2:15][C:4]1[NH:3][C:2](=[O:16])[C:11]2[C:10](=[O:12])[C:9]([CH3:13])=[N:8][N:7]([CH3:14])[C:6]=2[N:5]=1
Reactant: [OH-]
Reactant: Cc1nn(C)c2nc(N)nc(N)c2c1=O
Agent: [Na+]
Product: Cc1nn(C)c2nc(N)[nH]c(=O)c2c1=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 5,7-diamino-1,3-dimethylpyrimido-(4,5-c)pyridazin-4(1H)-one (0.50 g) and 1.5 N aqueous sodium hydroxide (35 ml) was stirred at reflux for 24 hours after which time a small amount of solid was removed by filtration of the hot mixture. On cooling, the yellow filtrate deposited white needles which were collected by filtration and dissolved in warm water (20 ml). Adjustment of this aqueous solution to pH 5 by dropwise addition of 6 N hydrochloric acid and subsequent cooling to room temperature provided a very finely divided white precipitate which was collected, washed with water and dried under vacuum at 70° C. to give 7-amino-1,3-dimethylpyrimido-(4,5-c)pyridazine-4,5(1H, 6H)-dione (0.38 g; 76% of theoretical yield). The u.v., i.r., and n.m.r. spectra of this compound were identical to those of the sample made according to the procedure of Example 2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3C2CCCCO2)=[C:5]([C:26](OCC)=[O:27])[N:4]([CH2:31][C:32]2[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][NH:11]3)=[C:5]([CH2:26][OH:27])[N:4]([CH2:31][C:32]2[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=2)[N:3]=1
Reactant: CCOC(=O)c1c(-c2cc(C(F)(F)F)cc3c2cnn3C2CCCCO2)c(C)nn1Cc1cnn(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nn(Cc2cnn(C)c2)c(CO)c1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
A 100 mL round bottom flask was charged with ethyl 3-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazole-5-carboxylate (0.745 g, 1.442 mmol) in THF (10 mL). The mixture was cooled to 0° C. A 1M solution of lithium aluminum hydride (4.33 mL, 4.33 mmol) in ether was added, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction was quenched with 1N HCl (6 mL) at 0° C. and the product was extracted into EtOAc. The organic phase was washed with brine and dried over Na2SO4. The volatiles were removed by evaporation. The crude residue was dissolved in MeOH (5 mL). HCl (0.5 mL) was added and the mixture was stirred for 2 hours. The product was purified by LCMS, eluting with 30% ACN in H2O (containing 10 mM NH4HCO3) over a period of 10 minutes. The product-containing fractions were combined and the volatiles were evaporated using a GeneVac™ to give the title compound (0.178 g, 31.6%). 1H NMR (400 MHz, CD3OD) δ ppm 2.27 (s, 3H), 3.88 (s, 3H), 4.51 (s, 2H), 5.30 (s, 2H), 7.37 (d, J=1.26 Hz, 1H), 7.52 (s, 1H), 7.65 (s, 1H), 7.88 (s, 1H), 7.94-8.02 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C18H17F3N6O, 391.15. found 391.13.
Reaction SMILES: Br.[CH:2]1([O:7][C:8]2[CH:9]=[CH:10][C:11](/[C:16](/[C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)=[CH:17]/[C@@H:18]3[N:22](CC4C=CC(OC)=CC=4OC)[C:21](=[O:34])[CH2:20][CH2:19]3)=[N:12][C:13]=2[O:14]C)[CH2:6][CH2:5][CH2:4][CH2:3]1.O>O1CCOCC1>[CH:2]1([O:7][C:8]2[C:13](=[O:14])[NH:12][C:11](/[C:16](/[C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=3)=[CH:17]/[C@H:18]3[CH2:19][CH2:20][C:21](=[O:34])[NH:22]3)=[CH:10][CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(F)(F)F)cc2)c2ccc(OC3CCCC3)c(OC)n2)c(OC)c1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](/C=C(\c2ccc(C(F)(F)F)cc2)c2ccc(OC3CCCC3)c(=O)[nH]2)N1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
48% hydrobromic acid (3 mL) was added to a solution of (5R)-5-{(E)-2-[5-(cyclopentyloxy)-6-methoxypyridin-2-yl]-2-[4-(trifluoromethyl)phenyl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (184 mg) in 1,4-dioxane (2 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A solution of the residue in trifluoroacetic acid (4 mL) and anisole (2 mL) was stirred at 80° C. for six hours. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1→4:1) and powdered with ethyl acetate-diethyl ether-hexane to give the title compound as a colorless amorphous (59 mg, 47%).