Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12]CC(O)=O)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:30]CC1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][OH:30])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCn1ccc2ccc(Br)cc21
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OCCn1ccc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a 250 mL round bottom flask equipped with a stir bar was added compound (i), above, (3.0 g; 10.6 mmol) and THF (50 mL). The mixture was cooled to 0° C. and diisobutylaluminium hydride (1M in toluene)(42.5 mL; 42.5 mmol) added. The reaction mixture was stirred at room temperature for 2 h, cooled to 0° C. and the quenched with sodium sulfate decahydrate. The resulting thick gel was refluxed for 1 h, after which it was filtered through a pad of celite. Upon removing the solvent in vacuo a yellow oil was isolated, which was subjected to column chromatography on silica gel using hexanes:ethyl acetate (90:10) to yield the title compound as a bright greenish-yellow oil (1.8 g; 71%). 13C NMR (CDCl3): δ136.9, 129.1, 127.5, 122.8, 122.3, 115.3, 122.5, 101.8, 61.7, and 48.7.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:12][C:13]([OH:15])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(Br)cc1F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C=Cc1ccc(Br)cc1F
Yield: 85 %

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (12.4 g, 61 mmol), malonic acid (12.7 g, 122 mmol) and 4-dimethylamino pyridine (0.75 g, 6.1 mmol) in 20 mL of DMF was heated at 100 degrees Celsius for 2 hrs. After cooling, the reaction mixture was diluted with 300 mL water, and filtered. The solid was collected, and triturated in hexane. The solid was collected and dried in vacuum to give 12.7 g (85%) of a white solid. MS: calc'd 243 (M−H), exp 243 (M−H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[N:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30]([C:27]4[N:26]=[CH:25][C:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)=[CH:29][N:28]=4)=[O:31])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ncc(-c2ccc(F)cc2)cn1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ncc(-c4ccc(F)cc4)cn3)cn12

Procedure:
2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 5-(4-fluorophenyl)-2-pyrimidinecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1ccc(F)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 62.1 %

Procedure:
A mixture of (3-chloro-4-fluorophenyl) boronic acid (300 mg, 1.72 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (331 mg, 1.89 mmol), K2CO3 (474 mg, 3.44 mmol) and Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) in THF (2 mL) and H2O (1 mL) was heated at 80° C. in a sealed tube for 3 h. The mixture was cooled to rt and partitioned between EA (20 mL) and H2O (20 mL). The aqueous layer was extracted with EA (20 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel elute with PE to give 2-chloro-1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (240 mg, 62.3% yield) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH2:22][CH2:23][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CCCC2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using pyrrolidine in Step 2. LC-MS Method 2 tR=1.225 min, m/z=491.1; 1H NMR (CD3OD) 1.62 (d, 3H), 2.01 (m, 2H), 2.14 (m, 2H), 2.22-2.49 (m, 4H), 2.56 (m, 1H), 2.92-3.13 (m, 3H), 3.19 (m, 1H), 3.41 (m, 1H), 3.69 (m, 2H), 5.64 (m, 1H), 7.12 (d, 2H), 7.21 (m, 3H), 7.43 (m, 4H), 7.57 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[C:4]([OH:12])[CH:3]=1.[H-].[Na+].[C:15]([CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O)([F:18])([F:17])[F:16].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH2:19][C:15]([F:18])([F:17])[F:16])[N:5]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: CC(C)(C)c1cc(Br)cc(O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)cc(OCC(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-6-(tert-butyl)pyridin-2-ol (5.00 g, 21.8 mmol) in dry DMF (50 mL) was added NaH (1.75 g, 43.7 mmol) at 0° C. under N2 and the mixture was stirred at 0° C. for 30 min. Then CF3CH2OTs (11.1 g, 43.7 mmol) was added and the solution was stirred at 70° C. overnight. Water was added and the mixture was extracted with EA twice. The combined organic layers were washed with water (3×) and brine twice, concentrated and purified by CC (PE/EA=30/1) to give compound P2a (1.13 g, 17%) as a white oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)(O)=[O:2].C(Cl)(=O)C([Cl:49])=O.CN(C)C=O>ClCCl>[Cl:49][C:1]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)O)c2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)Cl)c2)cc1
Reaction time: 1 h

Procedure:
The solution of 0.474 g of tert-butyl 3-(3-carboxy-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 12 ml of dichloromethane is admixed at 0° C. successively with 0.132 ml of oxalyl chloride and 0.005 ml of N,N-dimethylformamide. The reaction mixture is stirred over 1 hour and then concentrated by evaporation. The residue is dissolved once more in 20 ml of dichloromethane and concentrated by evaporation. This gives the crude title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[CH2:21][OH:22].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][OH:22])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: OCC1CCCCN1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCCCC1CO
Temperature: 25 °C
Yield: 28 %

Procedure:
3-(Trifluoromethyl)benzenesulfonic acid chloride (1 eq), dissolved in methylene chloride (65 ml), was added dropwise to a cooled solution (0° C.) of 2-piperidinemethanol (40 mmol, 1.1 eq) in methylene chloride (160 ml) and triethylamine (2.5 eq). When the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature until, according to thin layer chromatography control, the reaction was complete (90 min). Hydrogen chloride solution (0.5 mol/l, 75 ml) was added, the mixture was stirred for 15 min, the phases were separated and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. Yield: 28%
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][CH:35]=1)[CH2:13][NH:14][C:15](=[O:32])[CH2:16][O:17][CH2:18][C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])=[O:20]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:22]([NH:21][C:19](=[O:20])[CH2:18][O:17][CH2:16][C:15](=[O:32])[NH:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:35]=[C:34]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:33]=2)=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25]
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(Br)c1
Reactant: OB(O)c1cccs1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(-c2cccs2)c1

Procedure:
Using the same method as in Example 19-(ii), 2-thiopheneboronic acid was reacted with the 2-[((2-[(3-bromobenzyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 72-(i) to give 5-chloro-2-([(2-oxo-2-([3-(thiophen-2-yl)benzyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:17])C(=O)[NH:7]2.[OH-:18].[Na+].OO.Cl>C(O)(=O)C>[NH2:7][C:8]1[C:4]([C:5]([OH:17])=[O:18])=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cc2c(c(OC)c1OC)C(=O)C(=O)N2
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(N)c(C(=O)O)c(OC)c1OC
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
A solution of 4,5,6-tris(methyloxy)-1H-indole-2,3-dione (10 g, 42.2 mmol) in 33% aqueous NaOH (70.5 ml, 582 mmol) at 100° C. was treated with 30% aqueous hydrogen peroxide (12.9 ml, 126 mmol) dropwise over 30 min, at a rate to prevent the foaming mixture from overflowing the flask. After addition was complete, the mixture was stirred for 10 minutes before being cooled and diluted by the addition of ice. The mixture was adjusted to pH 8 by addition of concentrated HCl (70 mL) and then acidified to pH 3 with the addition of glacial acetic acid. The solid that formed was collected by filtration, washed with water, and dried under vacuum to give 6-amino-2,3,4-tris(methyloxy)benzoic acid (2.7 g, 28%) as a tan solid. MS (m/z) 228.0 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]([C:19]1[CH:20]=[C:21]([N:25]2[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:30](O)=[O:31])[CH:28]=[N:27][NH:26]2)[CH:22]=[CH:23][CH:24]=1)#[CH:18]>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:30]([C:29]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:25]([C:21]4[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[CH:18])[CH:20]=4)[NH:26][N:27]=[CH:28]3)=[O:31])[C:7]=2[CH:8]=1)#[N:13]
Reactant: C#Cc1cccc(N2NN=CC2(C(=O)O)c2ccccc2)c1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CO
Product: C#Cc1cccc(N2NN=CC2(C(=O)N[C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)c2ccccc2)c1

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 1-(3-ethynylphenyl)-5-phenyl-1,2,3-triazole-5-carboylic acid by the same method as described for the title compound of Example 2 to afford a white solid, m.p. 115°-125° C. (softens at 81° C.). [α]D =-110.1° (c=0.69, MeOH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]1[N:13]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-])=O)=[CH:18][C:19]=3[C:6]1=[N:5]2.[H][H].C(Cl)Cl>CC(N(C)C)=O.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]2[N:13]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:7]3[C:6]([C:19]=2[CH:18]=1)=[N:5][C:4]1[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[CH:3]=1)[N:8]=3
Reactant: [H][H]
Reactant: Cc1cc2nc3c4cc([N+](=O)[O-])ccc4n(CCN(C)C)c3nc2cc1C
Agent: [Pd]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1cc2nc3c4cc(N)ccc4n(CCN(C)C)c3nc2cc1C
Yield: 84 %

Procedure:
A suspension of 3.63 g (10 mmol) of (2d) and 0.36 g 10% Pd/C in 160 ml DMA was left under 2.7 atm hydrogen pressure for 24 h. The product was soluble in DMA. Pd/C was filtered away with celite. The filtrate was poured onto ice-water and pH was increased to basic with 20% KOH, which resulted in a brown precipitate. The precipitate was chromatographied in 20% MeoH/CH2Cl2, which resulted in 2.80 g of the product (3d).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[OH:42][C:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O)([CH3:45])[CH3:44]>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>[OH:42][C:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)([CH3:45])[CH3:44]
Reactant: CC(C)(O)c1ccccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)c1ccccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Yield: 40 %

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 50 mg, 0.112 mmol), potassium carbonate (77 mg, 0.561 mmol) and Pd(Ph3P)4 (12.96 mg, 0.011 mmol) was added dioxane (561 μl), (2-(2-hydroxypropan-2-yl)phenyl)boronic acid (20.18 mg, 0.112 mmol) and Water (187 μl) and irradiated at 100° C. for 30 min affording conversion to desired product (˜40%) with starting material remaining. To the mixture was added additional boronate (50 ul) and Pd(Ph3P)4 (12.96 mg, 0.011 mmol) and irradiated another 30 min at 100° C. affording consumption of starting material and product as the primary species. The organic layer was decanted and the aqueous rinsed once with EtOAc and the organics combined and dried under reduced pressure. To the resulting oil was added DCM (2 ml) and TFA (0.6 ml) and the resulting solution stirred at room temperature. The mixture was dried under reduced pressure and purified with a 25 g HP spherical silica gel (15 μm spherical, Interchim) ramping DCM:MeOH (90:10) in DCM (0-100%) affording product as a yellow film which was lyophilized from MeOH/H2O affording a fluffy yellow solid 1-(2-(2-hydroxypropan-2-yl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate (39 mg, 0.072 mmol, 64.5% yield). 1H NMR (400 MHz, DMSO-d6) δ=12.92 (br. s., 1H), 8.67-8.55 (m, 2H), 8.27 (br. s., 1H), 7.94 (d, J=8.3 Hz, 1H), 7.77-7.65 (m, 2H), 7.56 (t, J=7.1 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 7.29 (d, J=4.6 Hz, 1H), 7.21 (d, J=7.3 Hz, 1H), 6.89 (d, J=4.6 Hz, 1H), 1.37 (s, 3H), 1.24 (s, 4H). m/z (ESI) 426.0 (M+H)+
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH3:20][NH:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[OH:24][CH2:23][CH2:22][N:21]([CH3:20])[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(CCO)CC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 15.5 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), 2-(methylamino)ethanol (0.045 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided N2-(2-hydroxyethyl)-N2-methyl-N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylglycinamide (0.022 g) as its trifluroacetic acid salt after reverse-phase HPLC purification. MS (ESI) m/z 317 ([M+H]+); MS (ESI) m/z 315 ([M−H]−).
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:8]=2[N:7]=1)([OH:5])[CH3:4].[CH3:18][CH:19]([CH3:22])[CH2:20][SH:21].C[O-].[Na+]>CO>[Cl:16][C:14]1[C:13]([Cl:17])=[CH:12][C:9]2[N:10]([CH3:11])[C:6]([C:3]([OH:5])([CH3:4])[CH2:2][S:21][CH2:20][CH:19]([CH3:22])[CH3:18])=[N:7][C:8]=2[CH:15]=1
Reactant: Cn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Reactant: CC(C)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CSCC(C)(O)c1nc2cc(Cl)c(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol (408 mg) in methanol (10 mL) at room temperature was added a solution of 2-methyl-1-propanethiol (150 mg) and sodium methoxide (0.381 mls of 25 wt % in MeOH). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated. The crude product was purified by flash chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a light orange solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[N:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[CH3:19])=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.CN(C)C=O>[CH3:19][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]2[C:9]=1[C:7]1[O:8][CH2:2][C:3](=[O:4])[NH:5][N:6]=1
Reactant: Cc1ccc2nc(C)c(C(=O)NNC(=O)CCl)n2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(C)c(C3=NNC(=O)CO3)n2c1
Yield: 16.4 %

Procedure:
A mixture of 21 g of N'-chloroacetyl-2,6-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide and 30 g of potassium carbonate in 200 ml of methyl ethyl ketone and 100 ml of dimethylformamide is stirred with refluxing for 5 hours. After insoluble substances are filtered off, the solvent is distilled off and water is added to the resultant residue. The precipitated crystals are collected by filtration and recrystallized from methanol to give 3 g of 2-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-4,6-dihydro-1,3,4-oxadiazin-5-one as white crystals, melting at 313° C. with decomposition.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18]4[CH:19]=[N:20][CH:21]=[N:22][CH:23]=4)=[CH:11][CH:12]=3)[C:7]([CH:25]=[CH2:26])(O)[C:6]=2[CH:5]=1.[NH2:27][C:28]([NH2:30])=[S:29]>CC(O)=O>[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18]4[CH:23]=[N:22][CH:21]=[N:20][CH:19]=4)=[CH:11][CH:12]=3)[C:7]3([CH2:25][CH2:26][S:29][C:28]([NH2:30])=[N:27]3)[C:6]=2[CH:5]=1
Reactant: C=CC1(O)c2cc(OC)ccc2Oc2ccc(-c3cncnc3)cc21
Reactant: NC(N)=S
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C1(CCSC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 N HCl (3 mL) was added to solution of 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol (50 mg, 0.150 mmol) and thiourea (9.25 pt, 0.171 mmol) in HOAc (5 mL). The reaction mixture was allowed to stir overnight at rt and concentrated under reduced pressure. The residue was treated with of TFA (4 mL). The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated under reduced pressure and the residue was treated with aqueous, half-saturated sodium bicarbonate, extracted with EtOAc, and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH 20:1 to 5:1) to give 2′-methoxy-7′-(pyrimidin-5-yl)-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[F:18][C:19]1[C:24]([NH:25][NH2:26])=[C:23]([F:27])[C:22]([F:28])=[C:21]([F:29])[C:20]=1[F:30]>C(O)C>[F:18][C:19]1[C:24]([NH:25][N:26]=[CH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]([CH3:8])=[C:4]2[CH3:9])=[C:23]([F:27])[C:22]([F:28])=[C:21]([F:29])[C:20]=1[F:30]
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Reactant: NNc1c(F)c(F)c(F)c(F)c1F
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2C=NNc2c(F)c(F)c(F)c(F)c2F)C(C)=C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (10.0 mmol) in ethanol (60.0 mL) was added dropwise pentafluorophenylhydrazine (11.0 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hrs. The solvent was distilled off under reduced pressure and the residue was recrystallized from hexane to give 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde pentafluorophenylhydrazone (4.00 g, yield 97.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[OH:8][NH2:9].Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5](=[NH:6])[NH:9][OH:8]
Reactant: NO
Reactant: COC(=O)CC#N
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CC(=N)NO
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-Cyano-acetic acid methyl ester (990 mg, 10 mmol) was dissolved in THF (30 mL). Hydroxy amine (690 mg, HCl salt, 10 mmol) was added thereto, and the mixture was stirred for 2 h at 80° C. After completion of the reaction, 1N HCl was added. The reaction mixture was extracted with EtOAc, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH2:26]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:12]([NH:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:9])=[N:13][CH:14]=[CH:15][N:16]=2)=[CH:23][CH:22]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: c1ccc(CNc2ccccn2)cc1
Product: O=S(=O)(Nc1nccnc1-c1ccc(CN(Cc2ccccc2)c2ccccn2)cc1)c1ccccc1Cl
Yield: 35 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro) benzenesulfonamide (Intermediate 8), and 2-benzylaminopyridine, the title compound was isolated as a yellow solid in 35% yield (94% purity by HPLC).