Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22]C)=[O:21])[CH:18]=3)[C:13]([S:24][CH3:25])=[CH:12]2)=[N:9][CH:10]=1>C1COCC1.O>[Br:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=3)[C:13]([S:24][CH3:25])=[CH:12]2)=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (1.63 g, 39.78 mmol) was added to an ice-cooled suspension of 51b) (5 g, 13.26 mmol) in THF/water (1:1, 50 mL) and the resulting mixture was stirred at room temperature for 16 h. The solvents were removed under reduced pressure and the residue was dissolved in water (20 mL). The aqueous solution was washed with ethyl acetate (2×20 mL), acidified with sodium hydrogen sulfate and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate and evaporated. White solid. Yield: 4 g (83% of theory)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1)[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC.[F:34][C:35]([F:42])([F:41])[C:36](OCC)=[O:37]>CO>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:4]([C:5]#[C:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:3][NH:2][C:36](=[O:37])[C:35]([F:42])([F:41])[F:34])[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(C(C#Cc2ccccc2)CN)cc1OC1CCCC1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#Cc2ccccc2)CNC(=O)C(F)(F)F)cc1OC1CCCC1

Procedure:
A solution of (+/-)-4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)-1-phenyl-1-butyne hydrochloride (50 mg, 0.14 mmol) and Et3N (40 mg) in a mixture of MeOH (1 ml) and ethyl trifluoroacetate (0.5 ml) was refluxed overnight. The solvents were evaporated, the residue taken up in Et2O, washed with H2O, 0.01N HCl, dried, and the solvent evaporated. The residue was crystallized from a mixture of cyclohexane and Et2O, and gave the titled compound, 32 mg (55%). mp 143-145°. 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.32 (m, 3 H), 6.94 (m, 2 H), 6.84 (d, 1 H), 6.54 (broad s, 1 H), 4.78 (m, 1 H), 4.08 (t, 1 H), 3.82 (s, 3 H), 3.78 (m, 1 H), 3.58 (m, 1 H), 1.76-1.92 (m, 6 H), 1.60 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.F[C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:16][C:15]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:21])=[O:22])=[CH:16][C:15]=2[C:29]([F:32])([F:31])[F:30])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(C(F)(F)F)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=C(C2N(CC)N=NN=2)C(OCC)=O)=CC=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)=[C:37]([C:43]2[N:44]=[N:45][N:46]([CH2:48][CH3:49])[N:47]=2)[C:38](OCC)=[O:39])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([C:50]2[CH:51]=[CH:52][C:53]([F:56])=[CH:54][CH:55]=2)=[C:37]([C:43]2[N:44]=[N:45][N:46]([CH2:48][CH3:49])[N:47]=2)[CH2:38][OH:39])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(CC)n1
Agent: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1CC
Product: CCn1nnc(C(CO)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 101.1 %

Procedure:
The general procedure of Example 46 was repeated, except that the ethyl 3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenoate utilized therein was replaced with 1.0 g of ethyl 3,3-bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenoate and there was thereby produced 0.9 g of the title compound; m.p.=82°-84° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[N:8][N:7]4[C:2]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:20][CH2:19]1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CC3)n2)cc1
Reactant: C1COCCN1
Product: COc1ccc(-c2nn3c(N4CCOCC4)cccc3c2-c2ccnc(NC3CC3)n2)cc1
Temperature: 140 °C
Yield: 93.2 %

Procedure:
A mixture of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine (75 mg, 0.19 mmol) and morpholine (2 mL, 23 mmol) was heated in a sealed tube at 140° C. for 4 hours. After cooling to room temperature, the mixture was concentrated. Flash chromatography (1:1 to 1:3 hexanes-ethyl acetate) provided N-cyclopropyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (78.4 mg, 92%) as an off-white solid. 1H NMR (CDCl3): δ 8.29 (d, 1 H), 8.08 (d, 1 H), 7.61 (d, 2 H), 7.31 (t, 1 H), 6.98 (d, 2 H), 6.45 (d, 1 H), 6.33 (d, 1 H), 5.40 (broad, 1 H), 4.00 (m, 4 H), 3.89 (d, 3 H), 3.51 (m, 4 H), 2.88 (m, 1 H), 0.89 (m, 2 H), 0.65 (m, 2 H); MS m/z 443 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28]O)=[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:42]C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(F)(=O)=O.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:42])=[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCO)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 37.4 %

Procedure:
To a stirred solution of 64 mg (0.11 mmol) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[3-tert-butoxy-4-(2-hydroxyethoxy)benzyl]-L-glutamate in 0.5 ml THF was added 102.7 mg (0.34 mmol) nonafluoro 1-butanesulphonic acid fluoride, 54.8 mg (0.34 mmol) triethylamine trihydrofluoride and 102 mg (1.01 mmol) triethyl amine. The reaction mixture is stirred for 3 days. Further 34 mg (0.11 mmol) nonafluoro 1-butanesulphonic acid fluoride, 18 mg (0.11 mmol) triethylamine trihydrofluoride and 34 mg (0.33 mmol) triethyl amine were added. The reaction mixture is stirred for 3 hours and is concentrated in vacuo. The crude product is purified by column chromatography (silica gel, hexane/ethylacetate gradient: 12:1→1:1). The desired product was obtained in 37.4% yield (64.2 mg, 0.04 mmol).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[F:6][C:7]1[C:8](/[C:17](/I)=[CH:18]/[C:19](=O)[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2>C1COCC1.[Cu]I>[CH:1]([C:17]1[CH:18]=[C:19]([C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)[C:10]2[C:11](=[O:16])[NH:12][C:13]3[C:9]=2[C:8]=1[C:7]([F:6])=[CH:15][CH:14]=3)([CH2:3][CH3:4])[CH3:2]
Reactant: [Li]C(C)CC
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC(C)c1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of copper(I) iodide (Aldrich, 190 mg, 1.0 mmol) in dry THF (2 mL) was added sec-butyllithium (Aldrich, 1.3 M solution in ether, 1.53 mL, 2.0 mmol), under argon, at 0° C. and the reaction mixture was stirred for 30 minutes. To the resulting brown solution obtained was added dropwise a solution of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (39.6 mg, 0.1 mmol) in THF (2 mL). After stirring at 0° C. for 45 minutes, the reaction mixture was stirred at room temperature for another 2 hours, then quenched with a saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product which was further purified by preparative TLC (silica gel, 20% ethyl acetate in hexanes) to afford (rac)-5-sec-butyl-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 3.6 mg, 11.7%).
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Ce+3].[Cl-].[Cl-]>C(O)C>[NH:13]([C:7]1[C:6](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:10]=2[C:9](=[O:11])[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: O=C1C=CC(=O)c2ncccc21
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCO
Product: O=C1C(Nc2ccccc2)=CC(=O)c2ncccc21
Temperature: 25 °C

Procedure:
Twenty and one-half grams of quinoline-5,8-quinone were dissolved in 500 ml of absolute ethanol, then 13 g of aniline were added, followed by the addition of 32 g of cerium chloride. This reaction mixture was refluxed overnight. The resulting mixture had a brown-blue color and was stirred and then left to cool to room temperature for about 26 hours.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][NH:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)N
Reactant: COc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Agent: Cl
Product: CCOC(=O)C(C)(C)NCc1ccc(OC)c(O[Si](C)(C)C(C)(C)C)c1
Yield: 94 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)-4-methoxybenzaldehyde (Example 12-2c) and ethyl 2-amino-2-methylpropanoate hydrochloride. Yield 94%, colorless liquid. MS 382 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[F:14].C([Li])CCC.[CH:20](N1CCOCC1)=[O:21].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:14][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[C:10]([O:12][CH3:13])=[CH:11][C:2]=1[CH:20]=[O:21]
Reactant: O=CN1CCOCC1
Reactant: COc1cc(Br)c(F)c2c1OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(F)c2c1OCCO2
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
To a solution of 549 mg of 6-bromo-5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxine in 15 ml of THF there was added dropwise 0.86 ml of n-butyllithium (2.55 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −72° C. for 30 minutes, 0.3 ml of N-formylmorpholine was added and the temperature was raised from −78° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (247 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C@:15]3([CH3:27])[C:21]([F:23])([F:22])[C:20]([CH3:25])([CH3:24])[O:19][CH2:18][C:17](=O)[NH:16]3)[CH:9]=2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C@:15]3([CH3:27])[C:21]([F:23])([F:22])[C:20]([CH3:25])([CH3:24])[O:19][CH2:18][C:17](=[S:38])[NH:16]3)[CH:9]=2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cc(F)cc(Cl)c3)ccc2F)C1(F)F
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cc(F)cc(Cl)c3)ccc2F)C1(F)F
Yield: 96.9 %

Procedure:
The reaction of (R)-5-(5′-chloro-4,3′-difluoro-biphenyl-3-yl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (130 mg, 313 μmol) with Lawesson's reagent (130 mg, 313 μmol) in 1,4-dioxane (5 ml) yielded the (R)-5-(5′-chloro-4,3′-difluoro-biphenyl-3-yl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (131 mg, 97%) as a white foam. MS (ISP): m/z=432.2 [M+H]+ and 434.2 [M+2+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:12]Cl>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:12]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClI
Solvent: CC(=O)O
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
Methyl 4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of acetic acid, and the stirred mixture was warmed to 65° C. A solution of ICl (37.8 g, 0.233 mol) in 50 mL of AcOH was added dropwise over 40 min. The mixture was stirred at 65° C. for 5 h and then stirred an additional 16 h at room temperature. The precipitated product was isolated via filtration, washed with water and dried under vacuum to give 27.5 g (99% pure by LCMS and HNMR)) of desired product. The mother liquors were evaporated and the resulting residue was washed with water and dried under vacuum to give another 31 g (95% pure by LCMS and NMR) of desired product. The combined yield of methyl 4-hydroxy-3-iodobenzoate was 58.5 g (90.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13]COC)=[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7]([CH2:23][CH2:24][CH3:25])=[CH:6]2.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:7]([CH2:23][CH2:24][CH3:25])=[CH:6]2
Reactant: CCCc1cc2cc(OC)ccc2c(OCOC)c1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Yield: 96.2 %

Procedure:
6-(Methyloxy)-1-{[(methyloxy)methyl]oxy}-2-phenyl-3-propylnaphthalene (96) (0.65 g, 1.92 mmol) was treated with 4 M HCl in dioxane at room temperature to give 0.54 g (97%) of compound 97 as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.79 (t, J=7.3 Hz, 3H), 1.40-1.55 (m, 2H), 2.45 (t, J=7.7 Hz, 2H), 3.92 (s, 3H), 5.15 (s, 1H), 7.05-7.10 (m, 2H), 7.22 (s, 1H), 7.35 (d, J=7.3 Hz, 2H), 7.42-7.48 (m, 1H), 7.49-7.56 (m, 2H), 8.08 (d, J=9.5 Hz, 1H). LCMS (ESI): m/z 293 (M+H)+, m/z 291 (M−H)−.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(=[O:4])=[O:3].[H-].[Na+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C=O)C>[CH:29]1([CH2:28][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH2:31][CH2:30]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a 100 mL round-bottomed flask was added tert-butyl 4-{2-[(methylsulfonyl)amino]phenyl}piperidine-carboxylate (Example 1 Step d) (1.9 grams, 5.4 mmol) and DMF (Aldrich) (30 mL). The solution was magnetically stirred vigorously at 25° C. under N2 atmosphere and treated in portions with NaH as a 60% dispersion in mineral oil (Aldrich) (150 mg, 6.4 mmol). After gas evolution ceased, (bromomethyl)cyclopropane (Aldrich) (675 μL, 940 mg, 7.0 mmol) was introduced via syringe. The reaction mixture was stirred at 25° C. for 15 h. The reaction was quenched by careful addition of satd NH4Cl (150 mL) and extracted with EtOAc (400 mL). The organic layer was washed with H2O (150 mL), satd NaCl (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a yellow foam (2.2 g). MS (ESI, pos. ion) m/z: 409 (M+1); (ESI, neg. ion) m/z: 407 (M−1). Calc'd for C21H32N2O4S: 408.56.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:22])[C:15](=[O:23])[C:14]2([CH3:25])[CH3:24])[CH:11]=[N:10][CH:9]=1)(C)(C)C.Cl.O1CCOCC1>CO.C([O-])(O)=O.[Na+]>[Cl:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[CH:13]([N:12]1[C:8]([CH2:7][OH:6])=[CH:9][N:10]=[CH:11]1)[C:14]([CH3:25])([CH3:24])[C:15]2=[O:23]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncn1C1c2c(Cl)cccc2C(=O)C1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)C(=O)c2cccc(Cl)c2C1n1cncc1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-4-chloro-2,2-dimethyl-indan-1-one (2.4 g, 5.9 mmol) in methanol (40 mL) is added a 4N solution of HCl in 1,4-dioxane (9 mL, 36 mmol). The reaction is permitted to stir for 30 minutes, at which time the reaction is cooled to 0° C. and diluted with saturated aqueous NaHCO3. The reaction mixture is then concentrated in vacuo to ca. one fourth of the original volume and diluted with ethyl acetate. The layers are separated and the aqueous layer is extracted two times with ethyl acetate. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:19) to furnish 4-chloro-3-(5-hydroxymethyl-imidazol-1-yl)-2,2-dimethyl-indan-1-one; HRMS: (ESI) m/z 291.0909 [(M+H)+: Calcd for C15H16N2O2Cl: 291.0909]; 1H NMR (400 MHz, CD3OD) δ ppm 0.91 (s, 3 H), 1.40 (s, 3 H), 4.80 (d, J=4.29 Hz, 2 H), 5.88 (s, 1 H), 6.89 (s, 1 H), 6.97 (s, 1 H), 7.69 (t, J=7.71 Hz, 1 H), 7.79-7.87 (m, 2 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C:13]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[CH:2]1.Br[C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.CCN(C(C)C)C(C)C>C(O)C.CN(C1C=CN=CC=1)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C:13]3([CH2:21][CH2:20][N:19]([C:24]4[S:25][C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=4)[CH2:18][CH2:17]3)[C:12]2=[O:22])=[CH:2]1
Reactant: Brc1nc2ccccc2s1
Reactant: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCNCC2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCN(c1nc3ccccc3s1)CC2
Temperature: 160 °C
Yield: 59.2 %

Procedure:
To the solution of 2-((1H-indol-3-yl)methyl)-2,9-diazaspiro[5.5]undecan-1-one (60 mg, 0.20 mmol) and 2-bromobenzo[d]thiazole [2516-40-7] (56 mg, 0.26 mmol) in ethanol (0.7 ml) was added DIPEA (176 μl, 1.0 mmol) and DMAP (1.2 mg, 0.01 mmol). The mixture was heated at 160° C. for 1.25 h under microwave conditions. The solvent was evaporated and the residue was purified by flash chromatography (EtOAc/hexane 2:3) to yield 51 mg (56%) of the title compound as a pale yellow solid. [1H NMR (600 MHz, DMSO-d6) ♀ ppm 10.96 (br. s., 1H), 7.76 (d, J=7.9 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22-7.32 (m, 2H), 7.01-7.11 (m, 2H), 6.96 (t, J=7.3 Hz, 1H), 4.63 (s, 2H), 3.82-3.96 (m, 2H), 3.38-3.49 (m, 2H), 3.17 (t, J=5.9 Hz, 2H), 2.06-2.18 (m, 2H), 1.74-1.84 (m, 2H), 1.61-1.74 (m, 2H), 1.53 (d, J=13.7 Hz, 2H); LCMS RtC=2.37 min, [M+H]+=431.2].
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:25]2[NH:26][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[N:17]=[C:16]([CH:18]=[C:19]5[N:23]=[C:22]([CH:24]=2)[C:21]([CH3:27])=[C:20]5[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[C:15]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])=[C:14]4[CH3:40])=[C:9]([CH3:41])[C:8]=3[CH2:42][CH3:43])[C:4]=1[CH3:44]>[OH-].[NH4+]>[CH3:1][CH2:2][C:3]1[C:25]2[NH:26][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[N:17]=[C:16]([CH:18]=[C:19]5[N:23]=[C:22]([CH:24]=2)[C:21]([CH3:27])=[C:20]5[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:15]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:14]4[CH3:40])=[C:9]([CH3:41])[C:8]=3[CH2:42][CH3:43])[C:4]=1[CH3:44]
Reactant: CCc1c(C)c2cc3[nH]c(cc4nc(cc5nc(cc1[nH]2)C(C)=C5CCC(=O)OC)C(CCC(=O)OC)=C4C)c(C)c3CC
Agent: [NH4+]
Agent: [OH-]
Product: CCc1c(C)c2cc3[nH]c(cc4nc(cc5nc(cc1[nH]2)C(C)=C5CCC(=O)O)C(CCC(=O)O)=C4C)c(C)c3CC

Procedure:
In some aspects, a method of synthesizing a metal mesoporphyrin compound comprises forming a protoporphyrin methyl ester from hemin and converting the protoporphyrin methyl ester intermediate to a metal mesoporphyrin compound through metal insertion and hydrogenation. In some embodiments, metal insertion yields a metal protoporphyrin dimethyl ester intermediate. In further embodiments, the metal protoporphyrin dimethyl ester is hydrogenated in dichloromethane over palladium catalyst to form a metal mesoporphyrin dimethyl ester. In embodiments, the metal mesoporphyrin dimethyl ester is heated in dilute ammonium hydroxide to form the metal mesoporphyrin compound. In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like. In some embodiments, tin is the inserted metal. In embodiments, tin is inserted into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]#[C:12][I:13])[C:3]1[S:4][CH:5]=[C:6]([CH:8]=O)[N:7]=1.CO.Cl.[NH2:17][OH:18]>C(N(CC)CC)C>[CH3:1][N:2]([CH2:10][C:11]#[C:12][I:13])[C:3]1[S:4][CH:5]=[C:6]([CH:8]=[N:17][OH:18])[N:7]=1
Reactant: CN(CC#CI)c1nc(C=O)cs1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CC#CI)c1nc(C=NO)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2-(N-methyl-3-iodo-2-propynylamino)-4-formylthiazole (No. 21) (72 mg) were added methanol (5 ml), triethylamine (0.2 ml) and hydroxylamine hydrochloride (24 mg) and the mixture was stirred at room temperature for 4 hours and evaporated to remove the solvent. After addition of a 5% aqueous solution of potassium carbonate, the residue was extracted with chloroform. The extract was washed with water, dried and evaporated to remove the solvent. The crystalline residue was treated with acetone to give 2-(N-methyl-3-iodo-2-propynylamino)-4-hydroxyiminomethylthiazole (No. 22) melting at 155°-156° C. (decomp.).