Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:42](O)[CH2:43][OH:44].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29][CH2:42][CH2:43][OH:44])=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: OCCO
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCCO)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg (0.1 mmol) of the compound of Example 47 in 0.3 ml dry dimethylformamide are added 48.6 mg (0.3 mmol) N,N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour, the reaction mixture is diluted with water and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is evaporated off in vacuo. To the residue are added 0.5 ml (555 mg, 8.95 mol) ethylene glycol and 10 μl (0.07 mmol) triethylamine. The reaction mixture is stirred at 100° C. for one hour. Then the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([O:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1nc2ccccc2[nH]1
Solvent: CC(=O)O
Product: CC(=O)OCc1nc2ccccc2[nH]1

Procedure:
A mixture of 1.0 g of 2-hydroxymethylbenzimidazole and 0.64 ml of acetic anhydride in 10 ml of acetic acid was heated to reflux for 1 hour. The solvent was removed in vacuo and the residue dissolved in chloroform and washed with a sodium bicarbonate solution. The organic layer was separated, dried and concentrated to give 1.2 g of the desired intermediate.
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17](=[O:22])[O:18]2)=[CH:13][C:12]=1[O:34][CH2:35][CH2:36][CH3:37].ClC(Cl)(Cl)C(=N)O[C@H:42]1[C@@H:47]2[O:48][C:49](=[O:51])[O:50][C@@H:46]2[C@@H:45]([O:52][CH3:53])[C:44]([CH3:55])([CH3:54])[O:43]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:53][O:52][C@H:45]1[C:44]([CH3:55])([CH3:54])[O:43][C@@H:42]([O:10][C:11]2[C:20]([CH3:21])=[C:19]3[C:14]([CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:17](=[O:22])[O:18]3)=[CH:13][C:12]=2[O:34][CH2:35][CH2:36][CH3:37])[C@@H:47]2[O:48][C:49](=[O:51])[O:50][C@H:46]12
Reactant: CCCOc1cc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c(C)c1O
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1cc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c(C)c1O[C@@H]1OC(C)(C)[C@H](OC)[C@H]2OC(=O)O[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
Boron trifluoride etherate (16.7 μL, 0.13 mmol) was added to 23b (170 mg, 0.44 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (643 mg, 1.77 mmol) in anhydrous CH2Cl2 (11.1 mL). After stirring at room temperature for 48 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 100:1→40:1 CH2Cl2:Acetone) to give 25b as a colorless foam (246 mg, 95%): 1H NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H), 7.35-7.27 (m, 5H), 6.84 (s, 1H), 5.96 (s, 1H), 5.15 (s, 2H), 4.99 (d, J=7.5 Hz, 1H), 4.59 (d, J=9.7 Hz, 1H), 4.23 (d, J=9.6 Hz, 1H), 3.97 (t, J=6.6 Hz, 1H), 3.82-3.75 (m, 2H), 3.37 (s, 3H), 1.84-1.79 (m, 2H), 1.51 (s, 3H), 1.41 (s, 3H), 1.18 (s, 3H), 1.00 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 157.8, 154.3, 152.2, 151.8, 146.7, 144.2, 142.9, 134.6, 127.8, 127.6, 127.5, 127.5, 127.2, 121.0, 120.9, 111.1, 105.3, 101.7, 91.6, 85.7, 82.8, 80.0, 69.8, 58.1, 54.8, 28.3, 28.2, 22.4, 21.3, 9.4; IR (film) νmax 2961, 2939, 2906, 2359, 2341, 1811, 1757, 1726, 1522, 1445, 1371, 1267, 1175, 1113, 1086, 825, 768 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C30H33NO11, 606.1952. found, 606.1950.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH3:14])[O:12][C:11](=[O:15])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Li]CCCC.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1C[O:41][CH2:40]C1>ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH3:14])[O:12][C:11](=[O:15])[N:10]2[C:40]([NH:37][CH2:36][CH2:35][CH2:34][N:31]2[CH2:32][CH2:33][CH:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:29][CH2:30]2)=[O:41])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CCOC1
Reactant: NCCCN1CCC(c2ccc(F)cc2)CC1
Reactant: C[C@@H]1OC(=O)N[C@H]1c1ccc(F)c(F)c1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: O
Product: C[C@@H]1OC(=O)N(C(=O)NCCCN2CCC(c3ccc(F)cc3)CC2)[C@H]1c1ccc(F)c(F)c1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
4(S)-(3,4-difluorophenyl)-5(S)-methyloxazolidin-2-one (2 g, 9.4 mmole) was dissolved in THF (20 ml) and cooled to −60° C. for the dropwise addition of n-BuLi (4 ml, 2.5 M in hexane). In a separate flask, p-nitrophenyl chloroformate was dissolved in 20 ml THF and cooled to −60° C. When the addition of n-BuLi was complete, the mixture was aged at −60° C. for 30 minutes. and then transferred via cannula to the p-nitrophenyl chloroformate solution. The reaction mixture was then allowed to warm to room temperature, and reaction progress was monitored by HPLC. After 2.5 hours, 3-(4-(4-fluorophenyl)piperidin-1-yl)propylamine (Example 1) (2.2 g, 9.4 mmole) in THF was added. After 3.5 hours at room temperature age, the solution was diluted with 100 ml water and extracted with 2×50 ml MTBE. The MTBE extractions were combined and washed with 2×50 ml 1M sulfuric acid. The aqueous washes were combined, rendered basic (pH=9-10) with 2 M sodium carbonate, and extracted with 2×100 ml MTBE. The MTBE layers were combined and concentrated, and the title compound was isolated by column chromatography on silica gel using 9:1 EtOAc:MeOH.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][S:17][C:18](SC)=[N:19]C#N.[N:24]1C=CC=C[CH:25]=1>>[C:25]([N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)[C:18](=[NH:19])[S:17][CH3:16])#[N:24]
Reactant: c1ccncc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CSC(=NC#N)SC
Product: CSC(=N)N(C#N)c1ccc(C2=NNC(=O)CC2C)cc1

Procedure:
(-)-6-(4-Aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (0.240 g) was stirred with dimethyl cyanodithioiminocarbonate (0.38 g) in dry pyridine (4 ml) under reflux for 6 hours. The reaction mixture was then evaporated down to an oily solid under vacuum at 50° C. Diethyl ether (approx. 20 ml) was added to the reaction mixture and stirred until a solid was obtained. The solid was then filtered and thoroughly washed with diethyl ether (approx. 20 ml) to give the corresponding 6-(4-(N-cyano-S-methylisothioureido)phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C@@H:8]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH:9]([CH3:11])[CH3:10].[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([CH2:33]O)[OH:32])[OH:30])[OH:28])[OH:26]>[Au].CO>[CH2:33]([NH:7][C@@H:8]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH:9]([CH3:11])[CH3:10])[C:31]1([O:23][CH2:24][C@@H:25]([OH:26])[C@@H:27]([OH:28])[C@@H:29]1[OH:30])[OH:32]
Reactant: CC(C)[C@@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Au]
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)[C@@H](NCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Reaction time: 2.5 h

Procedure:
300 ml of pyridine and 3 l of methanol were added to 10 g of D-valyl-aspartic acid and 50 g of anhydrous D-glucose, and the stirred mixture was boiled for 2.5 hours. The reactants gradually dissolved during this time, and the reaction mixture assumed a yellow-gold color. After the reaction was complete, the mixture was concentrated in vacuo and further processed as described in Example 9. Freeze-drying resulted in 13.5 g of amorphous N-(1-deoxyfructopyranos-2-yl)-D-valyl-aspartic acid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[F:14].C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30].C(=O)=O.CC(C)=O>O1CCCC1.O>[F:14][C:8]1[CH:9]=[C:10]([Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:11]=[CH:12][C:7]=1[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(Br)ccc1Br
Reactant: C[Si](C)(C)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2ccc([Si](C)(C)C)cc2F)OC1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A 2.5 M solution of n-butyllithium (3.5 mL, 8.5 mmol, 1.1 equiv) was added to a stirred solution of 1,4-dibromo-2-fluorobenzene (2.0 g, 7.9 mmol, 1.0 equiv) in tetrahydrofuran (26 mL) at −78° C. The resulting bright yellow solution was stirred at −78° C. for 15 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.8 mL, 8.7 mmol, 1.1 equiv) was added and the resulting pale yellow solution was stirred at −78° C. for 30 m. A 2.5 M solution of n-butyllithium (3.5 mL, 8.5 mmol, 1.1 equiv) was added and the resulting yellow/brown solution was stirred at −78° C. for 15 m. Chlorotrimethylsilane (2.2 mL, 17 mmol, 2.2 equiv) was added and the resulting pale yellow solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and stirred for 18 h. The reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a pale yellow powder (2.3 g, 99%): IR (thin film) 3058 (w), 2981 (s), 2932 (m), 1615 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J=7.5, 6 Hz, 1H), 7.26 (m, 1H), 7.16 (d, J=7.5 Hz, 1H), 1.34 (s, 12H), 0.23 (s, 9H).
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[N:14]=[N:13][C:12]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18][C:11]=2[CH:10]=1.[C:23]1(/[CH:29]=[CH:30]/B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:23]1(/[CH:29]=[CH:30]/[C:9]2[N:14]=[N:13][C:12]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[O:18][C:11]=3[CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1cc2c(nn1)Oc1ccccc1O2
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C(=C/c1cc2c(nn1)Oc1ccccc1O2)\c1ccccc1
Temperature: 120 °C
Reaction time: 14 h
Yield: 49.2 %

Procedure:
Toluene (10 ml) was added to 3-chloro[1,4]benzodioxino[2,3-c]pyridazine (600 mg), and (E)-2-phenylvinylboronic acid (480 mg), tetrakis(triphenylphosphine)palladium (315 mg) and 2M aqueous sodium carbonate solution (1.6 mL) were added at room temperature. The reaction mixture was stirred at 120° C. for 14 hr. Water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The obtained residue was washed with a mixed solvent of hexane and ethyl acetate and filtered. The obtained solid was dried under reduced pressure to give 3-[(E)-2-phenylvinyl][1,4]benzodioxino[2,3-c]pyridazine (386 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:14][OH:15]>N1C=CC=CC=1.CCO.C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[N:14][OH:15]
Reactant: NO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(O)c(C=NO)c1
Temperature: 20 °C
Reaction time: 10 h
Yield: 81 %

Procedure:
To a solution of 2-hydroxy-5-nitrobenzaldehyde (2.10 g, 12.6 mmol) in pyridine (31.0 mL) and EtOH (5.0 mL) was added hydroxylamine hydrochloride (1.75 g, 25.2 mmol). After stirring at 20° C. for 10 h, the mixture was diluted with CH2Cl2 (125 mL) and washed with water (4×70 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and evaporated. The residue was triturated with EtOH and filtered. The resulting solid was rinsed with ether and dried under vacuum to obtain the title compound (1.86 g, 81% yield) as a yellowish solid: MS (electrospray, +ions) m/z 183 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([CH3:34])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:32]#[N:33])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=1)[CH:14]=2)=[O:9])C.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:32]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:35])([CH3:34])[C:4]([OH:36])=[O:3])=[O:9])[N:11]=1)#[N:33]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-{[1-Cyano-4-hydroxy-7-(naphthalen-2-yloxy)-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (18 mg, 0.04 mmol) was dissolved in MeOH (3 mL) and 2 N NaOH (3 mL). After stirring for 4 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 10 mg. MS: (−) m/z 453.90 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C@@H:19]([OH:22])[CH2:20][Br:21])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C@@H:19]([O:22][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][Br:21])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
A solution of methyl 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]benzoate (71.05 g, 195 mmol), imidazole (18.52 g, 272 mmol), tert-butyldimethylsilyl chloride (32.23 g, 214 mmol) and 4-(dimethylamino)pyridine (0.44 g, 3.6 mmol) in DMF (270 ml) was left to stir at room temperature under a nitrogen atmosphere for a period of 24 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was separated and washed with 2N hydrochloric acid (2-fold 500 ml), saturated aqueous sodium bicarbonate (2-fold 500 ml) saturated sodium chloride (500 ml), dried (magnesium sulphate) and the solvent removed in vacuo to give the title compound as a colourless oil (91.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([N+:22]([O-:24])=[O:23])[C:17]([CH3:21])=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C(O)(C(F)(F)F)=O>C(O)(C)C>[CH3:21][C:17]1[C:16]([N+:22]([O-:24])=[O:23])=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[N:12][CH:13]=[CH:14]2
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1[N+](=O)[O-]
Temperature: 22 °C
Yield: 89.6 %

Procedure:
A mixture of 4-aminobenzonitrile (4.0 g, 34 mmol), isopropanol (50 mL) and 1-chloro-6-methyl-5-nitroisoquinoline (5.0 g, 22 mmol) was stirred at RT (22° C.) and treated with TFA (5.0 mL, 67 mmol). The reaction mixture was stirred at 80° C. for 17 h, and allowed to cool to RT. The thick slurry was diluted with isopropanol (100 mL) and the solid precipitate was collected by suction filtration. The solid was washed with saturated NaHCO3 (2×100 mL), water (50 mL), Et2O (50 mL), and hexane (100 mL) and dried in a vacuum oven at 70° C. overnight to provide 4-(6-methyl-5-nitroisoquinolin-1-ylamino)benzonitrile (6.0 g, 88% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 305 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=[O:8].CC1C=CC(S(O)(=O)=O)=[CH:14][CH:15]=1.C(=O)(O)[O-:21].[Na+]>C1(C)C=CC=CC=1>[O:8]1[CH2:15][CH2:14][O:21][CH:7]1[C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: Cn1ccnc1C=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1ccnc1C1OCCO1
Temperature: 120 °C

Procedure:
A mixture of 1-methyl-1H-imidazole-2-carbaldehyde (24 g, 218 mmol), p-TsOH (16.2 g, 87 mmol), glycol (27 g, 437 mmol), and toluene (700 mL) was heated to 120° C. in a Dean-Stark apparatus for 16 h. Then the mixture was cooled to room temperature, pH was adjusted to 9 with saturated sodium bicarbonate solution at 0° C., and the mixture was extracted with EtOAc (500 mL×2). The organic layers were washed with water (200 mL) and brine (100 mL), dried, filtered, then concentrated to give a red oil (12 g). MS (ESI): m/z 155.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:13]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:22]([CH2:25][C:26](=[O:28])[CH3:27])(=[O:24])[CH3:23]>C(O)(=O)C.Cl.O>[F:1][C:2]1[C:8]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][N:13]=[C:25]([C:26](=[O:28])[CH3:27])[C:22](=[O:24])[CH3:23]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1cccc(C(F)(F)F)c1F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of 2-fluoro-3-(trifluoromethyl)aniline (1.0 g, 5.58 mmol) in 8 mL of acetic acid and 1.3 mL of concentrated hydrochloride solution, sodium nitrite (462 mg, 6.69 mmol) in 2.1 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture were added sodium acetate (1.37 g, 16.8 mmol) and acetylacetone (726 mg, 7.26 mmol). The mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH/H2O (1/1) and hexane, and dried to give the title compound (900 mg, 55% yield). 1H NMR (400 MHz, CDCl3): δ ppm 2.51 (s, 3H), 2.63 (s, 3H), 7.30-7.34 (m, 1H), 7.38-7.41 (m, 1H), 7.94-7.96 (m, 1H), 14.66 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:22])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: NNC(=O)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1
Temperature: 100 °C
Yield: 75 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-{[4-(hydrazinocarbonyl)benzoyl]amino}benzoic acid. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 126 mg of the title compound (75%) as a orange solid in 83.3% purity by HPLC (Rt: 3.78, gradient of 8 min. MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].C([Li])CCC.[CH3:20][N:21]=[CH:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1>O1CCCC1.CCCCCC.C1(C)C=CC=CC=1>[CH3:20][NH:21][CH:22]([C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1]
Reactant: CN=Cc1ccsc1
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccsc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
To a chilled, solution (-50° C.) of 19.13 g of 2,2-dimethyl-N-[(2-methyl)phenyl]propanamide in 200 ml of tetrahydrofuran was added, dropwise over 1.5 hours, 88 ml of a 2.5M solution of n-butyllithium in hexane. Upon completion of the addition, the resultant solution was stirred for 2 hours with cooling. A solution of 15.0 g of 3-thiophene-carboxaldehyde methylimine in 30 ml of toluene, was then added, dropwise over 15 minutes, to the cooled solution. Upon completion of the 3-thiophenecarboxaldehyde methylimine addition, the reaction mixture was stirred for 20 minutes at 0° C., quenched by the addition of 300 ml of water, concentrated, and extracted with dichloromethane. The combined extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. HPLC of the oil (Water's Associates Prep LC/System 500; silica gel; methanol as the eluent) afforded a semipurified product which was subsequently chromatographed under otherwise identical conditions utilizing ethyl acetate, followed by methanol as eluents. Concentration of the appropriate fractions and trituration with hexane yielded 18.0 g of N-[2-[2-(methylamino)-2-(3-thienyl)ethyl]phenyl]-2,2-dimethylpropanamide. mp 81°-84° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5](C)[N:6]=1.[Li+].CC([N-]C(C)C)C.Cl[CH2:20][C:21]1[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23][O:24][C:25]=1[CH3:26]>C1COCC1>[CH3:26][C:25]1[O:24][N:23]=[C:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]=1[CH2:20][CH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[CH:5][N:6]=1
Reactant: Cc1onc(-c2ccccc2)c1CCl
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1CCc1ncc(C(=O)O)s1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (250 mg, 1.59 mmol) in THF (16 mL) at −78° C. and under argon was added LDA (1.6 mL of a 2M solution in THF, 3.2 mmol) dropwise. After 1.5 h a solution of 4-chloromethyl-5-methyl-3-phenyl-isoxazole (330 mg, 1.59 mmol) in THF (4 mL) was added dropwise. After 1 h the reaction mixture was quenched with HCl (1N, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (315 mg, 60%) as a light yellow gum. MS: m/e=329.1 [M+H]+.