Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[C:1]([N:31]=[N+:32]=[N-:33])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
There are added to a suspension of 12.3 g of nicotinic acid in 100 ml of dimethylformamide 14.2 ml of triethylamine and then, after cooling to 0° C., 22 ml of diphenylphosphoryl azide in 50 ml of dimethylformamide. After stirring for 2 hours, the reaction mixture is poured onto ice. After extraction with ether, the organic phase is washed with a NaHCO3 solution, dried, and then concentrated to yield 9.68 g of the expected product.
Reaction SMILES: [CH2:1]1[O:4][C@H:2]1[CH3:3].[SH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1>>[OH:4][C@@H:2]([CH3:3])[CH2:1][S:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: C[C@H]1CO1
Product: COC(=O)c1ccc(SC[C@H](C)O)cc1

Procedure:
150 mg of (S)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (S)-methyl 4-(2-hydroxypropylthio)benzoate. 650 mg of (S)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 350 mg of (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (S)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:35][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
Lithium hydroxide monohydrate (0.015 g, 0.35 mmol) was added to a stirred solution of {6-chloro-4-[4-(4-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.043 g, 0.086 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(4-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.039 g, 93%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s., 1 H) 8.15 (d, J=7.82 Hz, 2 H) 8.10 (d, J=7.82 Hz, 2 H) 7.97 (d, J=8.80 Hz, 1 H) 7.91 (s, 1 H) 7.77 (d, J=7.82 Hz, 2 H) 7.54 (d, J=7.82 Hz, 2 H) 7.48 (d, J=8.80 Hz, 1 H) 6.95 (s, 1 H) 3.84 (s, 2 H) 2.01 (s, 3 H) MS calcd. for C25H17Cl2O4S [(M−H)−] 483, obsd. 482.8.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:14][CH2:15][CH2:16][SiH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>CCOCC>[C:1]([C:5]1[CH:11]=[C:10]([O:12][CH2:14][CH2:15][CH2:16][SiH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=C[SiH2]CCCCl
Reactant: CC(C)(C)c1cc(O)ccc1O
Solvent: CCOCC
Product: CC(C)=C[SiH2]CCCOc1ccc(O)c(C(C)(C)C)c1

Procedure:
In the first reaction shown, t-butylhydroquinone is reacted with chloropropyldimethylvinylsilane in a conventional Williamson ether synthesis to form 2-t-butyl-4-(3'-dimethylvinylsilylpropoxy)phenol (I).
Reaction SMILES: [Na].[O-]CC.[Na+].O=[C:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9][CH:8]1[C:15]([O:17]CC)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36](=[NH:38])[NH2:37])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>O.C(O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]3[NH:38][C:15](=[O:17])[C:8]4[CH2:9][C:10]5([CH2:11][CH2:12]5)[CH2:13][CH2:14][C:7]=4[N:37]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1CC2(CCC1=O)CC2
Reactant: N=C(N)CCCN1CCN(c2ccc(Cl)cc2)CC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(CCCN2CCN(c3ccc(Cl)cc3)CC2)nc2c1CC1(CC2)CC1
Temperature: 25 °C
Yield: 5.9 %

Procedure:
Sodium (0.094 g, 4.08 mmol) was added to ethanol (15 ml) under stirring condition at room temperature. The resulting mixture was stirred for 30 min. To this freshly prepared clear solution of sodium ethoxide, were added ethyl 6-oxospiro[2.5]octane-5-carboxylate (0.4 g, 2.03 mmol) and 4-(4-(4-chlorophenyl) piperazin-1-yl)butanimidamide (0.343 g, 1.223 mmol) and the reaction mixture was heated at 85° C. for 18 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain crude residue which was dissolved with water (15 ml). Aqueous layer was extracted with ethylacetate (2×30 ml). The combined organic layer was dried over sodium sulphate, filtered and solvent was removed under reduced pressure to obtain a crude product which was purified by flash chromatography over silica gel (100-200 mesh) using 3-4% methanol in dichloromethane as eluent to obtain title compound (0.030 g, 4% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:19][NH:20][C:21](=[O:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1(O)C=CC=CC=1>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:25]3[CH2:26][CH2:27][CH:22]([C:21]([NH:20][CH3:19])=[O:28])[CH2:23][CH2:24]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: CNC(=O)C1CCNCC1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Solvent: O
Solvent: Oc1ccccc1
Product: CNC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1
Temperature: 160 °C
Yield: 57.7 %

Procedure:
A mixture of 5.1 g (21 mmole) of 4-chloro-2-(4-chlorophenyl)quinoline, prepared as in Example 1(a), 6.2 g (42 mmole) of N-methylisonipecotamide, and 10 g of phenol was stirred and heated in an oil bath at 160° C. for 3.5 hr. It was then cooled and diluted with 100 ml of water. Crystallization was induced by scratching, warming and the addition of a small amount of ethanol. The solid was collected and washed with ether to give 7.0 g of crude product. Recrystallization from 150 ml of butanol gave 4.6 g of product, mp 251°-255° dec.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:28]Br.CCOC(C)=O>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:28])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1nsc2nc(CC(C)C)n(Cc3ccccc3)c(=O)c12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nsc2nc(C(Br)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of 5-benzyl-6-isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 27) (5.81 g, 18.5 mmol) and sodium acetate (10 g) in acetic acid (100 ml) at 100° C., a solution of the bromine (6 g, 38 mmol) in acetic acid (60 ml) was added dropwise over a period of 20 minutes. The reaction mixture was stirred at that temperature for 30 min and cooled and the TLC (eluent 10% EtOAc in hexanes) and MS showed the complete disappearance of the SM and only the product. The reaction mixture was poured into ice water and extracted with EtOAc (3×60 ml) and the organic layers were combined and washed with 2% sodium thiosulfate solution (60 ml), water (100 ml), brine (100 ml) and dried over Na2SO4. Concentration of the organic layer provided 5-benzyl-6-(1-bromo-2-methyl-propyl)-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (7.27 g, 99%) as white crystalline solid. 1H NMR (300 MHz) δ 0.54 (d, 3H), 1.11 (d, 3H), 2.62-2.76 (m, 1H), 2.83 (s, 3H), 4.42 (d, 1H), 4.80 (d, 1H), 6.22 (d, 1H), 7.12-7.42 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>C(#N)C>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Nitro-1H-pyrazole (565 mg, 5 mmol) was stirred in acetonitrile (15 mL) with potassium carbonate (829 mg, 6 mmol) for 5 minutes and then 4-methoxybenzyl chloride (861 mg, 0.746 mL, 5.5 mmol) was added. The reaction was stirred at ambient temperature for 18 hours, and then partitioned between ethyl acetate and an aqueous 2M hydrochloric acid solution. The organic layer was separated and the aqueous was extracted with a further portion of ethyl acetate. The combined ethyl acetate layers were dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with 20% ethyl acetate/hexane and then 50% ethyl acetate/dichloromethane to afford the desired title compound as an oil, 1.08 g, 93%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([O:15]C)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].[OH-].[Na+]>O.CO>[CH3:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12]
Reactant: COC(=O)c1ccc2c(c1C)SCCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)ccc2c1SCCC2=O

Procedure:
41.1 g (0.17 mol) of methyl 8-methylthiochroman-4-one-7-carboxylate are hydrolyzed under reflux with 10.3 g (0.26 mol) of NaOH in a mixture of 400 ml of water and methanol. The methanol is then distilled off and the residue is diluted with water and acidifed with 2N hydrochloric acid. The useful product precipitates out and is filtered off with suction, washed with water and dried.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38](C(OC(C)(C)C)=O)[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:51])([F:50])[F:49])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:50])([F:51])[F:49])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)(=[O:5])[O:3][CH2:1][CH3:2])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCNCC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 246A, 180 mg, 0.25 mmol) was added methylene chloride (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 hour, after which, the reaction mixture was concentrated and purified by MDP. 1H NMR (400 MHz, methanol-d4) δ=1.27 (t, J=6.9 Hz, 6H), 2.77-2.85 (m, 2H), 3.19 (s, 3H), 3.29 (d, J=21.5 Hz, 2H), 3.50 (t, J=6.1 Hz, 2H), 3.88-3.94 (m, 2H), 4.01-4.17 (m, 4H), 4.59 (s, 2H), 6.02 (dt, J=3.3, 1.7 Hz, 1H), 7.35 (dd, J=8.5, 2.4 Hz, 2H), 7.50 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 8.35-8.43 (m, 1H), 8.72 (br. s., 1H). MS (ES+): m/z 631.23 (100) [MH+]; HPLC: tR=0.68 min (UPLC, purity).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH:11]=O)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[NH:29][C:30](=[O:33])[CH2:31][OH:32])[NH:25][C:24](=[O:34])[CH2:23]2>>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[NH:29][C:30](=[O:33])[CH2:31][OH:32])[NH:25][C:24](=[O:34])[C:23]2=[CH:11][C:9]1[NH:10][C:6]2[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=2[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Product: O=C(CO)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1-c1ccccc1)C(=O)NCC3)C(=O)N2
Yield: 92 %

Procedure:
The title compound was prepared under the same conditions as described in Example 41 with 4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide as starting materials to give N-[5-fluoro-2-oxo-3-(4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene)-2,3-dihydro-1H-indol-6-yl]-2-hydroxy-acetamide (39 mg, 92%) as a red solid.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[C:48]([CH3:49])=[N:47][CH:46]=[C:45]2[NH:50][CH:51]=[CH:52][C:44]=12>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:40][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:43]4[C:48]([CH3:49])=[N:47][CH:46]=[C:45]5[NH:50][CH:51]=[CH:52][C:44]=45)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: Cc1ncc2[nH]ccc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1ncc2[nH]ccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Temperature: 150 °C
Yield: 44.9 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (72 mg, 0.10 mmol), 4-bromo-5-methyl-1H-pyrrolo[2,3-c]pyridine (22 mg, 0.10 mmol), Pd(PPh3)4 (12 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (4 mg, 20 mol %) in dioxane (1 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-20% MeOH in DCM) to give 153 as a pale yellow solid (24 mg, 43%). LCMS (Method E): RT=4.19 min, [M+H]+ 535.2. 1H NMR (400 MHz, CHCl3-d): δ 9.14 (s, 1 H), 8.73 (s, 1 H), 7.34-7.32 (m, 2 H), 7.11 (d, J=5.3 Hz, 1 H), 6.67-6.65 (m, 1H), 5.30 (d, J=4.7 Hz, 1 H), 4.04 (t, J=4.7 Hz, 4 H), 3.87 (d, J=4.7 Hz, 4 H), 3.85 (s, 2H), 2.76 (s, 3 H), 2.61 (m, 8 H), 1.28-1.22 (m, 6 H)
Reaction SMILES: [I-:1].[I-].[I-].CO[CH2:6][CH2:7][N:8]([CH2:26][CH2:27]OC)[C:9]1[CH:10]=[C:11]([CH3:25])[C:12]2[C:21]([CH:22]=1)=[S+:20][C:19]1[C:14](=[C:15]([CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1)[N:13]=2.[CH3:30][O:31][CH2:32][CH2:33][N:34](C1C=C(C)C2C(C=1)=[S+]C1C(=C(CC)C=CC=1)N=2)[CH2:35][CH2:36]OC.COC[CH2:59][N:60](C1C=C(C)C2C(C=1)=[S+]C1C(=C(CC)C=CC=1)N=2)CCOC.CN1CCNCC1.[CH3:89][OH:90]>>[I-:1].[CH3:89][O:90][CH2:36][CH2:35][N:34]([CH2:33][CH2:32][O:31][CH3:30])[C:17]1[CH:16]=[C:15]([CH2:23][CH3:24])[C:14]2[C:19]([CH:18]=1)=[S+:20][C:21]1[C:12](=[C:11]([CH3:25])[CH:10]=[C:9]([N:8]3[CH2:7][CH2:6][N:60]([CH3:59])[CH2:27][CH2:26]3)[CH:22]=1)[N:13]=2
Reactant: CCc1cccc2[s+]c3cc(N(CCOC)CCOC)cc(C)c3nc12
Reactant: CO
Agent: CN1CCNCC1
Agent: [I-]
Product: CCc1cc(N(CCOC)CCOC)cc2[s+]c3cc(N4CCN(C)CC4)cc(C)c3nc12

Procedure:
A solution of 3-(bis(2-methoxyethyl)amino)-9-ethyl-1-methylphenothiazin-5-ium triiodide (150 mg, 0.2 mmol) in methanol (10 mL) and 1-methylpiperazine (30 mg, 0.3 mmol) was stirred for 2 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[N+:27]([O-])([O-:29])=[O:28].[K+]>S(=O)(=O)(O)O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccccc3)cc2c1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2c1O
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
200 mg of 1-Chloro-4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester, Example D-10a, was dissolved in 3 ml of concentrated sulfuric acid. The reaction mixture was cooled to −20° C. and 60 mg of potassium nitrate was added slowly to the stirring solution. The reaction was kept between −10 to −20° C. while stirring for 15 min, and poured into ice-water. The aqueous mixture was extracted twice with ethyl acetate. The organic fractions were washed successively with saturated bicarbonate and brine solutions, dried over anhydrous magnesium sulfate, and concentrated to a residue under reduced pressure. The resultant solid was triturated with ethyl acetate followed by methanol to produce 103 mg of white solid; MS (+): m/z 417.07 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:13][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-bromo-pyridine-2-carbaldehyde (1.06 g, 5.73 mmol) in dry CH2Cl2 (30 mL) was added isopropylamine (0.51 mL, 6.02 mmol). The mixture was stirred at RT and under N2 for 30 min followed by the addition of NaBH(OAc)3 (2.42 g, 11.46 mmol) and HOAC (1.3 mL, 22.92 mmol). The resulting cloudy light-yellow solution was stirred at RT and under N2 for 15 h. A 10% solution of Na2CO3 (50 mL) was added to the mixture and stirred for 30 min. The organic phase was separated, washed with H2O, brine, dried over MgSO4 and concentrated to afford a light yellow-oil without further purification. MS m/z: 229.1 (M+H). Calc'd for C9H13BrN2: 228.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9](=O)[CH2:10][CH:11](O)[C:12](OCC)=[O:13])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9]2[CH:10]=[CH:11][C:12](=[O:13])[NH:27][N:28]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)CC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: O=c1ccc(C(c2ccc(F)cc2)c2ccc(F)cc2)n[nH]1
Temperature: 130 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
To a solution of ethyl 5,5-bis(4-fluorophenyl)-2-hydroxy-4-oxopentanoate (796 mg) in 1-butanol (4 mL) was added hydrazine hydrate (137 mg) at ambient temperature. The reaction mixture was stirred at 130° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was evaporated in vacuo. The resulting residue was stirred at 160° C. for 3 hours. After cooling, the reaction mixture was purified by silica gel column chromatography (EtOAc:n-hexane=2:1) and crystallized from solvent (EtOAc:n-hexane=1:2) to give 6-[bis(4-fluorophenyl)methyl]pyridazin-3(2H)-one (344 mg) as a pale brown solid.
Reaction SMILES: N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[C:44]([CH2:45]O)=[C:43]([F:47])[CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2.[C:48]1(=[O:58])[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:50](=[O:57])[NH:49]1>C1COCC1>[F:34][C:35]1[C:44]([CH2:45][N:49]2[C:50](=[O:57])[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:48]2=[O:58])=[C:43]([F:47])[CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1c(F)cc2ncccc2c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1c(F)cc2ncccc2c1F
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
A mixture of (E)-diisopropyl diazene-1,2-dicarboxylate (4.72 g, 23.36 mmol) and triphenylphosphine (6.13 g, 23.36 mmol) in THF (100 mL) was stirred for 15 min, and a solution of (5,7-difluoroquinolin-6-yl)methanol (3.80 g, 19.47 mmol) and isoindoline-1,3-dione (3.15 g, 21.42 mmol) in THF (200 mL) was added dropwise. The reaction mixture was heated at 40° C. for 24 h. After cooling and evaporating, the residue was purified by silica gel with hexane:EtOAc to provide 2-(5,7-difluoroquinolin-6-ylmethyl)isoindoline-1,3-dione (5.10 g, 81%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.93 (m, 1H), 8.39 (m, 1H), 7.85 (m, 2H), 7.72 (m, 2H), 7.59 (d, 1H), 7.43 (m, 1H), 5.15 (s, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH2:22][C:23]([OH:25])=[O:24])=[O:34])(=[O:11])=[O:12]
Reactant: O=C(O)CSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(O)CS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a solution of ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)acetic acid (44 mg, 0.11 mmol) in CH2Cl2 (2 ml) and acetonitrile (2 ml) was added mCPBA (27 mg, ˜0.11 mmol). The reaction was stirred at room temperature for 4 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane, then 20-30% MeOH in EtOAc) followed by PTLC (25% MeOH in EtOAc) to yield the title compound (34 mg, 74%).