Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH:27](=[N:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:28][CH3:29].[CH:37](=[N:40][S:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42])[CH2:38][CH3:39].[Cl-].[NH4+]>C(OCC)C.C1(C)C=CC=CC=1>[F:13][C:12]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:6]=[CH:7][C:2]=1[C@@H:27]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:28][CH3:29].[F:13][C:12]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:6]=[CH:7][C:2]=1[C@H:37]([NH:40][S@:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42])[CH2:38][CH3:39]
Reactant: CCC=NS(=O)C(C)(C)C
Reactant: FC(F)(F)c1cc(C(F)(F)F)c(Br)cn1
Reactant: CCC=N[S@@](=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC[C@@H](N[S@@](=O)C(C)(C)C)c1cnc(C(F)(F)F)cc1C(F)(F)F
Product: CC[C@H](N[S@@](=O)C(C)(C)C)c1cnc(C(F)(F)F)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 14 %
Yield: 15 %

Procedure:
To a solution of 5-bromo-2,4-bis-trifluoromethyl-pyridine (200 mg, 0.685 mmol) in dry diethyl ether (1.5 ml) at −78° C. was added a 2.5 M solution of n-butyllithium in hexane (0.25 ml, 0.685 mmol) and the mixture was stirred at −78° C. for 15 min. A solution of (S)-2-methyl-propane-2-sulfinic acid propylideneamide (Comp. No. 13b) (85 mg, 0.527 mmol) in dry toluene (1 ml) was added at −78° C., the mixture was stirred for 5 min at −78° C. and then poured into a saturated aqueous ammonium chloride solution. The mixture was extracted 3 times with dichloromethane, dried over sodium sulfate, and after evaporation of all solvents the crude product was purified by flash chromatography (silica gel, elution with heptane/ethyl acetate) to give 27 mg (14%) of (S)-2-methyl-propane-2-sulfinic acid [(S)-1-(4,6-bis-trifluoromethyl-pyridin-3-yl)-propyl]-amide (LC/MS (method 2; MS ionization method ES−): Rt=1.3 min; m/z=375.1 (M+1−)) and 29 mg (15%) of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(4,6-bis-trifluoromethyl-pyridin-3-yl)-propyl]-amide (LC/MS (method 2; MS ionization method ES−): Rt=1.3 min; m/z=375.12 (M+1−)).
Reaction SMILES: FC(F)(F)C(O)=O.N[CH:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([NH2:12])=[O:11].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.C([N:29](CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[NH2:12][C:10]([CH:9]([C:21]1[CH:22]=[C:17]([CH3:26])[CH:18]=[CH:19][C:20]=1[C:23]([NH2:29])=[O:24])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)C(N)C(N)=O
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(N)=O)c(C(C(N)=O)C(C)(C)C)c1
Reaction time: 6 h
Yield: 80.3 %

Procedure:
A solution of Example 22C (489 mg, 3.76 mmol) and p-toluoyl chloride (0.560 mL, 4.14 mmol) in CH2Cl2 (8 mL) at 0° C. was treated with triethylamine (0.520 mL, 3.76 mmol). After 6 hours, the mixture was diluted with ethyl acetate (25 mL) and washed sequentially with 1M HCl (10 mL), saturated aqueous NaHCO3 solution (10 mL), water (15 mL), and brine (10 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to provide an oily residue which was purified by flash chromatography (elution with 50% ethyl acetate/hexanes) to provide 750 mg of the desired product as a sticky white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.BrC1C=CC(OC2C=CC=CC=2)=C(Cl)C=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)ccc1O
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Clc1cc(Br)ccc1Oc1ccccc1
Solvent: CC#N
Product: Cc1cc(Br)ccc1Oc1ccccc1
Yield: 35 %

Procedure:
The title compound was prepared in a 35% yield from 4-bromo-2-methylphenol and phenyl boronic acid in a manner similar to that described for the preparation of 4-bromo-2-chloro-1-phenoxybenzene: 1H NMR (DMSO-d6, 400 MHz) δ 7.54(s, 1H), 7.35(m, 3H), 7.12(t, 1H), 6.93(d, 2H), 6.82(d, 2H), 2.18(s, 3H); RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 mmin) tr 14.25min.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([NH2:28])[CH3:27]>>[ClH:19].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([NH:28][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:27]
Reactant: CC(N)c1ccccn1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NC(C)c3ccccn3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 40 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (1-pyridin-2-yl)ethylamine as described in Step 5, Example 24 to give the title compound as a solid (40% yield). LC/MS: RT 2.40 min; m/e 404 (M+H); 1H NMR (δ, ppm): 11.82 (1H, br s), 8.81 (1H, d), 8.60 (1H, d), 8.06 (1H); 7.66 (3H, m); 7.23 (1H, s), 7.04 (1H, d), 4.64 (1H, m), 2.38 (2H, q), 2.30 (3H, s), 1.37 (3H, d), 1.10 (3H, t).
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13](=[NH:17])OCC.[CH3:18][NH2:19].[CH2:20](O)C>>[ClH:1].[CH3:18][NH:19][C:13](=[N:17][CH3:20])[CH2:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1
Reactant: CN
Reactant: CCOC(=N)Cc1ccc2ccccc2c1
Reactant: CCO
Agent: Cl
Product: CN=C(Cc1ccc2ccccc2c1)NC
Temperature: 2 °C
Reaction time: 21 h
Yield: 85 %

Procedure:
In a 100 ml. reaction vessel, equipped with a stirrer, thermometer, a pressure-equalizing addition funnel, and a reflux condenser fitted with a drying tube, 11.95 grams (0.048 mol.) of ethyl 2-naphthaleneethanimidate hydrochloride was placed. A solution of 21.20 grams (0.683 mol.) of methylamine in 35 ml. of absolute ethanol was rapidly added to the reaction mixture. The temperature quickly rose to 65° C. and dropped to about 30° C. after all of the solution was added. The reaction mixture was kept between about 50°-53° C. for 21 hours. The reaction mixture was cooled to 2° C. and the white crystalline product was filtered off. The product was washed with toluene and dried to give 10.2 grams (85% yield) of the title compound. The crude product was recrystallized from absolute ethanol to yield 8.97 grams of the title compound. The melting point was 225.5°-227° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N>CO.[Ni]>[N:1]1([C:7]2[C:8]([CH2:13][NH2:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1ncccc1N1CCOCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ncccc1N1CCOCC1
Yield: 94.1 %

Procedure:
A solution of 3-morpholin-4-yl-pyridine-2-carbonitrile (0.500 g, 2.64 mmol) in MeOH (10 mL) was added to a flask charged with Raney Ni (pre-washed with methanol) (0.5 g) in MeOH (10 mL). After saturated with NH3 gas the mixture was shaken under H2 (40 psi) for 3 h. The reaction mixture was then filtered through a celite cake, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (500:25:6 CH2Cl2/MeOH/NH4OH), affording C-(3-morpholin-4-yl-pyridin-2-yl)-methylamine as a pale yellow oil (0.480 g, 94%). 1H NMR (CDCl3) δ 2.90-2.93 (m, 4H), 3.85-3.90 (m, 4H), 4.02 (s, 2H), 7.16 (dd, 1H, J=4.5, 8.1 Hz), 7.35 (dd, 1H, J=1.2, 8.1 Hz), 8.33 (dd, 1H, J=1.2, 4.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[S-:12][C:13]#[N:14].[K+].[Cl:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>C(#N)C.O>[Cl:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:13]([NH:14][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=1)=[S:12]
Reactant: N#C[S-]
Reactant: NCc1ccc(F)cc1Cl
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(NC(=S)NCc1ccc(F)cc1Cl)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
To a solution of 3,4-diflorobenzoyl chloride (45 mL, 358 mmol) in acetonitrile (1.43 L) was added solid potassium thiocyanate (KNCS) (38.2 g, 393 mmol). The suspension was stirred to 0° C. for 10 min and then the cooling bath was removed. The suspension was stirred at room temperature for an additional 20 min. A solution of 2-chloro-4-fluorobenzylamine (57.1 g, 358 mmol) in acetonitrile (150 mL) was added over 5 minutes. The resulting suspension was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (1.4 L) and stirred for 1 hour. The suspension was filtered, rinsed with water (150 mL) and dried in vacuo at 60° C. to afford N-((2-chloro-4-fluorobenzyl)carbamothioyl)-3,4-difluorobenzamide as a yellow solid (98.3 g, 77% yield). 1HNMR (400 MHz, DMSO-d6) δ 11.56 (bs, 1H), 11.12 (t, 1H, J=5.7 Hz), 8.00 (m, 1H), 7.79 (m, 1H), 7.54 (m, 1H), 7.44 (m, 2H), 7.19 (m, 1H), 4.85 (d, 2H, J=5.7 Hz).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[N:11]1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22](S(O)(=O)=O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[N:10]1([CH:1]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:2]([CH3:7])([CH3:3])[CH2:29][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[N:11]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(Cc1ccccc1)C(NC(=O)c1ccncc1)n1nnc2ccccc21

Procedure:
The product from Example 18A, isonicotinamide, benzotriazole, and p-toluenesulfonic acid in toluene were processed as described in Example 18B to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[N:7]([O:9]CCC(C)C)=O.[ClH:15]>>[Cl:15][C:2]([CH3:6])([CH3:1])[C:3](=[N:7][OH:9])[CH2:4][OH:5]
Reactant: CC(C)CCON=O
Reactant: CC(C)=CCO
Reactant: Cl
Product: CC(C)(Cl)C(CO)=NO
Temperature: -5 °C

Procedure:
3-Methyl-2-buten-1-ol (8.6 g, 100 mmol) was mixed with isoamyl nitrite (28 g, 240 mmol) at room temperature. The solution was cooled to -5° C. in an ice-salt bath and concentrated HCl (11 mL, 100 mmol) was added dropwise. The reaction temperature was maintained between -5° to 0° C. during the addition. The reaction mixture was stirred in the ice-salt bath for 60 min, filtered and washed with cooled ether to give a white solid. Yield 4.5 g (30%). mp: 114°-115° C. MS (m/z): 305 (2M+2+H)+, 303 (2M+H)+, 154 (M+2+H)+, 152 (M+H)+. 1H NMR (DMSO-d6): δ1.56 (d) and 1.80 (s) [6H, (CH3)2CCHNO and (CH3)2CC=NOH)], 4.10 (m) and 4.26 (s) [2H, HOCH2CH (NO) and HOCH2C=NOH], 5.2 (b, 1H, HOCH2), 5.93 (t) and 11.28 (b) [1H, CHN=O and C=NOH]. 13C (DMSO-d6) δ29.9 [(CH3)2CCHNO], 31.5 [(CH3)2CC=NOH], 53.7 [(CH3)2CCHNO], 59.7 [(CH3)2CC=NOH], 69.4 [HOCH2CH(NO)], 74.1 [HOCH2C=NOH], 160.2 [CHN=O and C=NOH].
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[C:12]([C:16]([O:18]C)=[O:17])([CH2:13]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Cl>C1COCC1.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH:14]3[C:12]([C:16]([OH:18])=[O:17])([CH2:13]3)[C:11]2=[O:20])=[CH:8][CH:9]=1
Reactant: COC(=O)C12CC1CN(c1ccc(F)cc1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C12CC1CN(c1ccc(F)cc1)C2=O
Reaction time: 1 h
Yield: 88.6 %

Procedure:
LiOH (0.2 g, 8.4 mmol) was added into a suspension of methyl 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylate (1.2 g, 4.8 mmol) in THF (20 mL) and water (1 mL). The reaction was allowed to stir for 1 hour. The reaction mixture was poured into water and neutralized with 1M HCl. The mixture was extracted with EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated to afford the title compound (1 g, 79% yield) as a light brown solid. LRMS (APCI pos) m/e 235.9 (M+1). 1H NMR: (DMSO-d6, 400 MHz): δ 12.70 (br s, 1H), 7.57-7.62 (m, 2H), 7.17-7.23 (m, 2H), 4.06 (dd, 1H), 3.70 (dd, 1H), 2.50-2.56 (m, 1H), 1.76-1.81 (m, 1H), 1.29-1.33 (dd, 1H).
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[F:20][C:21]([F:26])([F:25])C(O)=O.N1C=CC=CC=1>ClCCl.CN(C=O)C>[F:13][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][C:10](=[O:12])[C:21]([F:26])([F:25])[F:20])[CH2:6][CH2:7]1
Reactant: O=C(O)CCC1CCC(F)(F)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCC1CCC(F)(F)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
3-(4,4-Difluorocyclohexyl)propionic acid (500 mg, 2.60 mmol) obtained in step 3 of Example 34 was dissolved in dichloromethane (5.0 mL), and the solution was stirred at room temperature for 30 minutes after adding oxalyl chloride (0.430 mL, 5.12 mmol) and DMF (0.010 mL). The solvent was then evaporated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and the mixture was cooled to −10° C., and stirred at room temperature for 2 hours after adding anhydrous trifluoroacetic acid (2.20 mL, 15.8 mmol) and pyridine (1.70 mL, 21.3 mmol). Upon being cooled to −10° C., the mixture was extracted with dichloromethane after gently adding water in a manner that keeps the internal temperature at or below 0° C. The organic layer was washed with 3 mol/L hydrochloric acid and a saturated sodium hydrogen carbonate aqueous solution, and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=70/30) to give 4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (204 mg, yield 35%).
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[B:4]([OH:7])([OH:6])[OH:5].C1(C)C(C)=CC=CC=1.CO>CCCCCC>[B:4]([O-:7])([O-:6])[O-:5].[Ca+2:2].[B:4]([O-:7])([O-:6])[O-:5].[Ca+2:2].[Ca+2:2]
Reactant: OB(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: [O-]B([O-])[O-]
Temperature: 60 °C

Procedure:
200 g of the same neutral calcium alkylsalicylate (A) as used in Example 1, 26 g of calcium hydroxide (B), 43.4 g (2.0 moles per mole of the calcium hydroxide) of orthoboric acid (C) and 400 g of xylene (F) were put in a 1000-ml four-necked flask fitted with a condenser and heated to 60° C. while agitating. To this mixture was added 120 g of methanol, and the resulting mixture was heated up to a refluxing temperature (66° C.) under agitation and reacted for 4 hours to obtain a reaction product. The reaction product was further heated to 140° C. for 1.5 hours to distill out the methanol, reaction water and xylene. Finally the reaction product was diluted twofold with hexane and filtered to remove any residual solids present, and the hexane was distilled out to obtain a calcium borate overbased alkylsalicylate. However, the thus obtained calcium borate overbased alkylsalicylate caused its gelation and was found generally unusable as an additive for petroleum products.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH3:29])[C:10]([CH3:28])([O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23]C(C)(C)C(C)(C)[O:20]2)=[CH:15][CH:14]=1)[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>Cl.O1CCCC1.O>[Si:5]([O:8][CH:9]([CH3:29])[C:10]([CH3:28])([CH3:11])[O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]([OH:20])[OH:23])=[CH:15][CH:14]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(C)(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)C(C)(C)Oc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl{1,2-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propoxy}dimethylsilane (5.8 g) was dissolved in 1 M hydrochloric acid (20 mL)-tetrahydrofuran (20 mL)-water (20 mL), sodium periodate (5.9 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the title compound as a pale-yellow solid (1.1 g, 23%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:52])[N:20]([CH2:39][C:40]([CH3:51])([CH3:50])[CH2:41][O:42][Si](C(C)(C)C)(C)C)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:52])[N:20]([CH2:39][C:40]([CH3:50])([CH3:51])[CH2:41][OH:42])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(CC(C)(C)CO)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.17 g), sodium hydrogen carbonate (1.88 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3.7 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was extracted with 1 M hydrochloric acid and ethyl acetate, and the ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.24 g, 48%).
Reaction SMILES: CCN([CH2:6][CH3:7])CC.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9].[OH2:20]>C(Cl)Cl>[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:20][C:6]2([CH3:7])[CH2:15][CH:14]2[CH2:18][CH2:19][CH2:11][CH:12]=[CH2:13])=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O
Solvent: ClCCl
Product: C=CCCCC1CC1(C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To a solution of 1,6-heptadiene (19.65 g, 204 mmol), in THF (341 ml) was added EtOAc (6.67 ml, 68.1 mmol), and chlorotitanium triisopropoxide (68.1 ml, 68.1 mmol). Cyclohexylmagnesium chloride (2M, 153 ml, 306 mmol) was then added slowly over 2 hours. After an additional 1 hour of stirring at RT, the reaction mixture was filtered through CELITE. The filtrate was then concentrated in vacuo and purified on SiO2 (15% EtOAc/hexanes) to yield the title compound as a mixture of enantiomers. To a solution of the enantiomers (5.5 g, 39.2 mmol) in anhydrous DCM, at 0° C. and under N2, was added Et3N (10.9 mL, 78 mmol) and 4-nitrobenzoyl chloride (8.7 g, 47.1 mmol). The reaction was stirred for 2 hours, diluted with H2O (70 mL) and extracted with DCM (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (gradient elution, 0 to 50% EtOAc in hexane) to yield (1R,2R and 1S,2S)-1-methyl-2-(pent-4-en-1-yl)cyclopropyl 4-nitrobenzoate. The benzoate enantiomers (12 g, 41.5 mmol) were separated by chiral chromatography on an AD-H column, eluting with 10% CO2 in MeOH. The desired peak fractions were concentrated to give (1R,2R)-1-methyl-2-(pent-4-en-1-yl)cyclopropyl 4-nitrobenzoate. To a solution of (1R,2R)-1-methyl-2-(pent-4-en-1-yl)cyclopropyl 4-nitrobenzoate (4.87 g, 16.83 mmol) in MeOH (67 mL) was added K2CO3 (4.65 g, 33.7 mmol). The mixture was stirred for 1 hour, filtered, and concentrated in vacuo. The material was purified on SiO2 (gradient elution, 0-50% ether/hexanes) to give the title compound. 1H NMR (500 MHz) (CDCl3) δ 5.82 (m, 1H), 4.99 (m, 2H), 2.09 (m, 2H), 1.78 (s, 1H), 1.55 (m, 2H), 1.41 (s, 3H), 1.32 (m, 1H), 1.14 (m, 1H), 0.97 (m, 1H), 0.84 (m, 1H), 0.06 (m, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH2:7].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O.C1(C)C=CC=CC=1>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH:7][C:11](=[O:12])[O:13][CH2:14][CH3:15]
Reactant: COC(CN)OC
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NCC(OC)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
A solution of NaOH (578.4 g, 14.46 mol) in H2O (2 L) was added to a solution of 2,2-dimethoxyethanamine (800 g, 7.6 mol) in toluene (2 L) and the resulting mixture was cooled to 0° C. using an ice bath. Ethyl chloroformate (825 g, 7.6 mol) was added dropwise while keeping the temperature near 10° C. The mixture was then stirred at r.t. overnight. The phases were then separated and the aqueous solution was saturated with solid NaCl. This solution was then extracted with toluene (1.25 L×3). The combined organic solutions were dried (Na2SO4) and concentrated in vacuo to give the title compound (1.123 kg, 83%) as colorless oil; 1H NMR: (CDCl3) 1.17 (3H, t), 3.14 (2H, s), 3.32 (6H, s), 4.02-4.07 (2H, m), 4.30 (1H, t).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:12]([C:13]1[CH:21]=[CH:20][C:18]([O:19][C:2]2[N:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=2)=[C:15]([O:16][CH3:17])[CH:14]=1)=[O:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: NC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Yield: 97.7 %

Procedure:
Dissolve 5-chloropyrazine-2-carboxamide (Example 387, Part A) (0.374 g, 2.34 mmol) and vanillin (0.361 g, 2.34 mmol) in DMF (23.7 mL). Add K2CO3 (0.821 g, 8.94 mmol) and heat at 100° C. for 1.5 hours. Concentrate the reaction mixture. Take the solid up in water (50 mL) and extract with dichloromethane (3× 100 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.625 g, 96.4%): TOF MS ES+ 274.1 (M+H)+, HRMS calcd for C13H12N3O4 274.0828 (M+H)+, found 274.0829, time 0.55 min; HPLC [YMC-Pro pack C—IS (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95 over 19 min], tR=10.2 min, 98.1% purity.