Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CN(C=O)C.S(Cl)([Cl:22])=O>ClC1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([Cl:22])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: O=S(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2cc1O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 723 %

Procedure:
99.0 g (0.52 mol) of 3-hydroxy-2-naphthoic acid and 1 ml of N,N'-dimethylformamide are initially introduced into 600 ml of chlorobenzene and 68.5 g=42 ml (0.58 mol) of thionyl chloride are added at 40° C. The mixture is subsequently stirred at 40° C. for 1.5 h and excess thionyl chloride is then distilled off in vacuo. 776.8 g of 3-hydroxy-2-naphthoyl chloride are obtained as a clear solution in chlorobenzene.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[CH2:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:8]2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[OH:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C=CCc1c(O)ccc2cc(C(=O)OCC)[nH]c12
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc2cc(C(=O)OCC)[nH]c12

Procedure:
The product of step b) was dissolved in dry ethanol (350 ml), treated with 10% Pd/C (0.3 g) and hydrogenated at 35 psi at room temperature until H2 uptake ceased (1.5 hours). The catalyst was filtered off and the filtrate evaporated to dryness.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2].[H][H]>[OH-].[Na+].[Pd]>[CH2:7]([CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: CCC(=Cc1ccccc1)C(=O)O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: CCC(Cc1ccccc1)C(=O)O
Yield: 100 %

Procedure:
A solution of 35.2 gm (0.2 mol) of α-ethyl cinnamic acid in 450 ml of 3% sodium hydroxide was reduced in a hydrogen atmosphere at 60 psi using 4 gm of 5% palladium on charcoal. After hydrogen uptake had ceased, the reaction mixture was filtered, acidified with hydrochloric acid and extracted with ether. Evaporation gave 36 gm (0.2 mol) of 2-benzyl butanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[F:30][C:31]1([F:38])[CH2:37][CH2:36][CH2:35][CH2:34][NH2+:33][CH2:32]1>>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C:31]([F:38])([F:30])[CH2:32]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Reactant: FC1(F)CCCC[NH2+]C1
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)N4CCCCC(F)(F)C4)C3)c2CC1

Procedure:
Prepared according to example 38c starting from 300 mg (0.58 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) and 120 mg (0.70 mmol) of 3,3-Difluoro-perhydro-azepinium chloride.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].CI>C1COCC1>[CH3:9][C:10]([CH3:2])([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(C)Cc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of LDA (2.9 mL of 2 M) in THF (30 mL) at −78° C. add ethyl 2-methyl-3-[4-(trifluoromethyl)phenyl]propanoate (1 g, 3.85 mmol). Stir for 10 min, then add methyl iodide (1.48 g, 10.4 mmol) and stir for an additional 15 min Quench the reaction with 10 mL of 1 N HCl and allow to warm to ambient temperature. Extract with EtOAc (50 mL). Wash extract with brine, dry over sodium sulfate, filter, and concentrate. Purify the residue by flash chromatography (5% EtOAc in petroleum ether) to give the title compound (475 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]([F:16])([F:15])[F:14])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:6]2)#[N:2].[OH-].[Li+].Cl.C(OCC)C>CO.O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]([F:15])([F:16])[F:14])[C:7]([C:17]([OH:19])=[O:18])=[CH:6]2)#[N:2]
Reactant: CCOC(=O)C1=Cc2cc(C#N)ccc2NC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)N2
Temperature: 25 °C

Procedure:
To a suspension of ethyl 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (140 mg, 0.45 mmol) in methanol-tetrahydrofuran-water (10 mL, 7:2:1) was added lithium hydroxide (76 mg, 0.91 mmol) and the mixture gently heated to reflux for two hours. The contents were cooled to room temperature and 1 N aqueous hydrochloric acid added until pH=1. The organic solvent was removed in vacuo to afford a suspension of crude yellow solid. Diethyl ether (20 mL) was added, and the solution was washed with water (2×20 mL), saturated ammonium sulfate (2×20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid as a yellow solid, (116 mg, 95%): mp 238–240° C. 1H NMR (CD3OD/300 MHz) 7.75 (s, 1H), 7.56 (m, 1H), 7.43 (m, 1H), 6.79 (d, 1H, J=8.5 Hz) 5.19 (q, 1H, J=7.1 Hz). EIHRMS m/z 267.0405 (M−H, Calc'd 267.0381). Anal. Calc'd for C14H11F3N2O2: C, 53.74; H, 2.63; N, 10.45. Found: C, 53.99; H, 2.89; N, 10.19.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH:13]=[C:14](Cl)C=O)([O-:5])=[O:4].S(=O)(=O)(O)O>O1CCOCC1>[C:13]([C:12]1[CH:11]=[C:10]([CH:20]=[CH:19][CH:18]=1)[O:9][C:8]1[CH:21]=[CH:22][C:23]([N+:24]([O-:26])=[O:25])=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)#[CH:14]
Reactant: O=CC(Cl)=Cc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C#Cc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1

Procedure:
To 50 ml of refluxing 1N sodium hydroxide solution, under a nitrogen atmosphere, was added a solution containing 10 g (0.028 mole) of m-(3,4-dinitrophenoxy)-α-chlorocinnamaldehyde dissolved in 50 ml of 1,4-dioxane. The dark mixture was refluxed for one-half hour at which time the solution was cooled and acidified with 10% sulfuric acid. The reaction mixture was extracted with several 50 ml portions of ether, and the combined extracts evaporated to dryness. The residue was chromatographed on a 1 × 12 inch dry column of silica gel. Elution of the column using 3/1 hexane/methylene chloride produced a first band of sideproduct. Further elution using 1/1 hexane/methylene chloride yielded a second band which contained the desired product. Evaporation of the eluate to dryness in vacuo afforded 2 g (25%) of 4-(3-ethynylphenoxy)-o-dinitrobenzene as light yellow crystals, m.p. 68°-69°C.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([C:32]#[C:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:41])C.[OH-].[Na+].Cl>C(O)C>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:33]#[C:32][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:42])=[O:3])=[C:8]([CH3:41])[CH:9]=3)[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[CH:17]=2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(F)cc3)cc(OCc3ccc(S(C)(=O)=O)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(F)cc3)cc(OCc3ccc(S(C)(=O)=O)cc3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 113 mg (85%). HPLC-MS: m/z: 599.4 (M+Na); Rt: 2.50 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:26])[C:16]2[N:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:2].[OH-].[Na+]>C(O)C>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:13]2[NH:14][C:15](=[O:26])[C:16]3[N:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=3[N:18]=2)[CH:6]=1
Reactant: CCCc1ccnc2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1ccnc2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Yield: 71.5 %

Procedure:
Stannous chloride dihydrate (2.48 g, 0.011 mol) was added to a stirred solution of 2-(2-ethoxy-5-nitro-phenyl)-8-n-propylprido [3,2-d]pyrimidin-4(3H)-one (Example 10; 0.78 g, 0.0022 mol) in ethanol (10 ml) and the mixture was heated under reflux for 2 hours, allowed to cool, basified to pH 11 by the addition of 10% aqueous sodium hydroxide solution, and then extracted with methanol:dichloromethane (1:9, 3×50 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum, then the residue was chromatographed on silica gel (12 g) using a methanol in dichloromethane elution gradient (0-2% methanol). Trituration of the product with hexane:ethyl acetate gave the title compound as a colourless solid (0.51 g, 71%), m.p. 156°-158° C. Found: C,66.61; H,6.20; N,17.14. C18H20N4O2 requires C,66.65; H,6.22; N,17.27%.
Reaction SMILES: C(O[C:4](=[O:25])[NH:5][S:6]([C:9]1[CH:24]=[CH:23][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][C:11]=2[CH:10]=1)(=[O:8])=[O:7])C.[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:33][C:4]([NH:5][S:6]([C:9]2[CH:24]=[CH:23][C:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:20])[CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)(=[O:8])=[O:7])=[O:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCCCC1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N(C)C)CC2
Product: CN(C)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCCC3)cc2CC1

Procedure:
By the reaction of [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1-H-3-benzazepin-7-yl)sulfonyl]carbamic acid ethyl ester with cycloheptylamine in a manner analogous to that described in Example 12, there is obtained 1-cycloheptyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[CH:28][C:29]([C:30]3[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=3)=[C:23]2[N:22]=1)([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.O.[NH:50]([C:52](=[S:54])[NH2:53])[NH2:51].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[CH:28][C:29]([C:30]3[CH:31]=[CH:32][C:33]([C:34]([NH:51][NH:50][C:52](=[S:54])[NH2:53])=[O:35])=[CH:37][CH:38]=3)=[C:23]2[N:22]=1)([CH3:13])[CH3:14]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)O)cc3)c2n1
Reactant: NNC(N)=S
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NNC(N)=S)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.8 %

Procedure:
EDCI (157 mg, 0.819 mmol) was added to a mixture of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid (Example 9, Step 1; 50 mg, 0.136 mmol) and HOBT-H2O (62.7 mg, 0.409 mmol) in DMF (2 mL) at ambient temperature, and the reaction mixture was stirred for 20 minutes at ambient temperature. 1.0 mL of hydrazinecarbothioamide (12.4 mg, 0.136 mmol) in DMF and triethylamine (95 μL, 0.682 mmol) were added. The resulting mixture was stirred for 1 hour at ambient temperature. The reaction mixture was diluted with EtOAc, washed with aqueous NH4Cl, NaHCO3, and brine, dried over MgSO4, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (0-5% MeOH in dichloromethane) to afford 20.2 mg (21%) of (S)-2-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoyl)hydrazinecarbothioamide. LCMS (APCI−) m/z 438.4 [M−H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: CCO
Reactant: COc1ccc(C(=O)O)cc1N
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(OC)c(N)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
3-Amino-4-methoxybenzoic acid (3.34 g) was dissolved in ethanol (100 ml). Concentrated sulfuric acid (3 ml) was added to the solution, and the mixture was stirred at 65° C. overnight. The solvent was removed from the reaction solution by distillation under the reduced pressure, and the residue was adjusted to pH 7 by the addition of a saturated aqueous sodium carbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 3.50 g (89.4%) of ethyl 3-amino-4-methoxybenzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.C([Sn](CCCC)(CCCC)[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:37]2)[CH:33]=[N:32][CH:31]=1)CCC.N#N.O>CN(C=O)C.[Cu]I.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:37]2)[CH:33]=[N:32][CH:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCCC(NC(=O)OC(C)(C)C)C2)n1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (400 mg, 0.91 mmol) and tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (520 mg, 0.91 mmol) in DMF (9.1 mL) was purged with N2 for 15 min and added CuI (225 mg, 1.18 mmol) and Pd(PPh3)4 (105 mg, 0.09 mmol). The reaction mixture was heated at 80° C. for 2 h and cooled to RT. To the reaction mixture was added water and precipitate was formed. The precipitate was collected by filtration, washed with water and dried overnight to give crude product. The crude was purified by chromatography (eluting with 0-10% MeOH and DCM) to obtain the title compound (350 mg, 66% yield). MS (ESI, pos. ion) m/z: 591 (M+1).
Reaction SMILES: [S:1](Cl)(Cl)=O.[NH2:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].Cl>N1C=CC=CC=1>[CH3:13][C:7]1[C:6]2[C:11](=[N:12][S:1][N:5]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(N)c1N
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc2nsnc12
Temperature: 25 °C

Procedure:
Thionyl chloride (166 g, 1.4 mol) was added to a solution of 2,3-diaminotoluene (71 g, 0.58 mol) in pyridine (430 mL) dropwise at a temperature below 45° C. Concentrated HCl (300 mL) was then added dropwise while care was taken to ensure that the reaction temperature did not exceed 65° C. After cooling to room temperature, the reaction mixture was subjected to a steam distillation. The light-yellow oil suspension in the water layer was extracted with diethyl ether. The combined extracts were washed with brine and dried over Na2SO4. After removal of the solvent by rotary evaporation, 4-methyl-2,1,3-benzothiadiazole was obtained as a light-yellow liquid in 92% (80.6 g) of yield. Rf=0.62 (hexane/ethyl acetate=3:1); 1H NMR (200 MHz, CDCl3) δ2.74 (s, 3H), 7.34 (m, 1H), 7.48 (d,J1=8.7 Hz, J2=6.7 Hz, 1H), 7.83 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8](C3C=CC=CC=3)=[C:9]3[N:32]=[C:12]([C:13](Br)=[C:14]4[NH:30][C:17](=[C:18](C5C=CC=CC=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:3]12[CH:2]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:17]3[NH:30][C:14]([CH:15]=[CH:16]3)=[CH:13][C:12]3=[N:32][C:9]([CH:10]=[CH:11]3)=[CH:8][C:6]([NH:7]1)=[CH:5][CH:4]=2
Reactant: Brc1c2nc(c(-c3ccccc3)c3ccc([nH]3)c(Br)c3nc(c(-c4ccccc4)c4ccc1[nH]4)C=C3)C=C2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The general procedure was used to couple 5,15-dibromo-10,20-diphenylporphyrin (31.0 mg, 0.05 mmol) with (+)-dihydrocholesterol (77.8 mg, 0.2 mmol), using Pd2(dba)3 (4.6 mg, 0.005 mmol) and DPEphos (10.7 mg, 0.02 mmol) in the presence of Cs2CO3 (65.2 mg, 0.2 mmol). The reaction was conducted in toluene at 100° C. for 17 h. The title compound was isolated by flash chromatography (silica gel, methylene chloride: hexanes (v/v)=8:2) as a purple solid (27.5 mg, 45%). 1H NMR (300 MHz, CDCl3): δ 9.43 (d, J=4.8 Hz, 4H), 8.78 (d, J=4.8 Hz, 4H), 8.18 (m, 4H), 7.74 (m, 6H), 4.95 (s, 2H), 0.62-2.3 (m, 92H), −2.59 (s, 2H). UV-vis (CH2Cl2, λmax, nm): 418, 520, 557, 602, 660. HRMS-MALDI ([M+H]+): calcd for C86H115N4O2, 1235.9015, found 1235.90110 with an isotope distribution pattern that is the same as calculated one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.I[CH3:21].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:21])[C:10]([CH3:15])=[C:9]2[C:16]([O:18][CH3:19])=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(F)cc1
Temperature: 0 °C

Procedure:
The product from Example 2, Step 1 (1.5 g, 5.70 mmol, 1 equiv) and iodomethane (809 mg, 5.70 mmol, 1 equiv) were dissolved in DMF (20 mL) and cooled to 0° C. To this was added portionwise sodium hydride 60% in mineral oil (228 mg, 5.70 mmol, 1 equiv) and warmed to room temperature over 1 h. The reaction was quenched with water, and extracted with EtOAc. The organic phase was concentrated in vacuo. The product was obtained as a light yellow oil (1.58 g, quant.). MS (ES+) m/e 278 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.CCN(CC)CC.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[C:3]=1[CH2:34][C:33]1[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=1[C:31]([F:30])([F:41])[F:42]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Cc1ccccc1C(F)(F)F

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran -2-one (0.300 g, 1.02 mmol), Et3N (0.15 mL, 1.1 mmol), 2-trifluoromethylbenzoyl chloride (0.21 mL, 1.02 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.04 mL, 0.47 mmol), Et3N (0.29 mL, 2.1 mmol), glacial acetic acid (3.0 mL), sodium cyanoborohydride (0.20 g, 3.1 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 1% MeOH in CH2Cl2) to provide an oil (0.102 g). 1H NMR (400 MHz, DMSO-d6) δ 11.21 (bs, 1 H), 7.584 (d, 1 H, J=8 Hz), 7.457-7.030 (m, 12 H), 6.179 (d, 1 H, J=7.5 Hz), 3.594 (s, 2 H), 3.362 (d, 1 H, J=17 Hz), 3.249 (d, 1 H, J=17 Hz), 2.686-2.603 (m, 1 H), 2.374-2.182 (m, 3 H).
Reaction SMILES: B.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].Cl>O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH2:8][OH:9])[CH:11]=1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)cc1CO
Temperature: 0 °C
Yield: 91.1 %

Procedure:
A solution of borane:tetrahydrofuran complex (25.8 g, 0.3 mole) in tetrahydrofuran (THF) (300 mL) was added dropwise to a stirred solution of 5-chloro-2-nitrobenzoic acid (50.0 g, 0.24 mole) in dry THF (400 mL) maintained at 0° C. under an atmosphere of nitrogen. After completion of the addition, the mixture was heated at 50° C. for 96 hours before being cooled in an ice bath. Hydrochloric acid (10% solution) was added dropwise and the mixture refluxed for 30 minutes. The THF was removed in vacuo and the residue extracted with dichloromethane (3×350 mL). Combined extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and the solvent evaporated to give a solid (45 g, 100%), crystallization from chloroform-hexane gave 5-chloro-2-nitro-benzenemethanol (41.0 g, 91%) mp 79°-81° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[C:13]([F:14])=[C:12]([O:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[Se:29][C:28]([CH:30]=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.O.Cl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:7][C:8]1[C:13]([F:14])=[C:12]([O:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[Se:29][C:28]([CH:30]=[CH2:1])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)[O-]
Reactant: CCCOc1ccc(-c2ccc(-c3ccc(C=O)[se]3)cc2)c(F)c1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2ccc(-c3ccc(OCCC)c(F)c3F)cc2)[se]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.50 g (12.6 mmol) of methyltriphenylphosphonium bromide are initially introduced in 50 ml of THF at 0° C., and 1.40 g (12.5 mmol) of potassium tert-butoxide dissolved in 30 ml of THF are added. After 1 h, 4.1 g (10.1 mmol) of 5-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)selenophene-2-carbaldehyde in 100 ml of THF are added, and the batch is stirred at RT for 17 h. Water and 2 N hydrochloric acid are added to the mixture, and the batch is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). 2-(2′,3′-Difluoro-4′-propoxy-biphenyl-4-yl)-5-vinylselenophene is obtained as an orange solid.