Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1([CH3:16])[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH2:9][CH2:8][CH:7]1I)=[O:4].[O-2].[Mg+2].[H][H]>[Pd].CO>[CH3:1][NH:2][C:3]([NH:5][C:6]1([CH3:16])[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: [H][H]
Reactant: CNC(=O)NC1(C)c2ccsc2CCC1I
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CO
Product: CNC(=O)NC1(C)CCCc2sccc21

Procedure:
Deiodination of 1-methyl-3-(5-iodo-4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea is accomplished by treating a methanol mixture of this compound with palladium on carbon and magnesium oxide in a Paar hydrogenator at 50 psig. After uptake of the hydrogen is completed, the mixture is filtered through diatomaceous earth and filtrate is evaporated to dryness to afford 1-methyl-3-(4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 135° C. to 145° C.
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.[NH2:7][C:8]1[CH:12]=[CH:11][NH:10][N:9]=1>C(O)(=O)C>[Br:1][C:2]1[CH:5]=[C:12]2[CH:11]=[N:10][NH:9][C:8]2=[N:7][CH:3]=1
Reactant: Nc1cc[nH]n1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Product: Brc1cnc2[nH]ncc2c1
Yield: 11.2 %

Procedure:
Dissolve 2-bromomalonaldehyde (Aldrich; 2.5 g, 16.5 mmol) and 3-aminopyrazole (Aldrich; 1.38 g, 16.5 mmol) in glacial acetic acid (25 mL) and reflux under nitrogen for 2 h. Concentrate under reduced pressure and dissolve the residue in absolute methanol (150 mL), vacuum filter through a pad of diatomaceous earth and concentrate under reduced pressure. Purify via chromatography (silica gel, hexane to 50% ethyl acetate/50% hexane) to obtain 365 mg (11%) of the title compound as a light yellow solid. TOF MS ES+ exact mass calculated for C6H5N3Br (p+H): m/z=197.9667, Found: 197.9674.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[C:4]([OH:17])[CH:3]=1.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22]CC)=[O:21].C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[Cl:1])[O:17][C:18](=[O:25])[C:19]([C:20]([OH:22])=[O:21])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(c1ccccc1)c1cc(Cl)c(Cl)cc1O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1c(-c2ccccc2)c2cc(Cl)c(Cl)cc2oc1=O
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A mixture of (4,5-dichloro-2-hydroxyphenyl) (phenyl)methanone (1.5 g), diethyl malonate (1.28 ml) and DBU (0.25 ml) was stirred at 170° C. for 30 minutes. The reaction mixture was dissolved in ethyl acetate (50 ml), and washed with water followed by a 1 N solution of hydrochloric acid and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced presurre, and the residue was purified by a column chromatography (packing: silica gel, eluent: ethyl acetate-hexane=1:9). The resultant crude product of ethyl 6,7-dichloro-2-oxo-4-phenyl-2H-chromene-3-carboxylate was dissolved in acetic acid (10 ml) and concentrated hydrochloric acid (5 ml), and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the resultant residue was dissolved in a solvent mixture of THF (10 ml) and ethyl acetate (50 ml), and then washed with water followed by a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by recrystallization from ethyl acetate to obtain the title compound (0.65 g, yield: 34%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:28])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)=[CH:23][CH:22]=2)[O:17]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: BrCc1ccc2ccccc2c1
Product: CC1(C)OB(c2ccc(OCc3ccc4ccccc4c3)cc2)OC1(C)C
Yield: 85 %

Procedure:
Alkylation of 2-Bromomethyl-naphthalene with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A in Example 2A to give 4,4,5,5-Tetramethyl-2-[4-(naphthalen-2-ylmethoxy)-phenyl]-[1,3,2]dioxaborolane in 85% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 2 H) 7.5 (dd, J=8.3, 1.8 Hz, 1 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (m, 4 H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=3[N:14]=2)[CH:7]=[CH:6][C:5]=1[OH:19])[CH2:2][CH3:3].[CH3:20][O:21][C:22](=[O:38])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH2:34][CH2:35][CH2:36]Br)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:20][O:21][C:22](=[O:38])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH2:34][CH2:35][CH2:36][O:19][C:5]3[CH:6]=[CH:7][C:8]([C:10]4[S:11][C:12]5[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=5[N:14]=4)=[CH:9][C:4]=3[CH2:1][CH2:2][CH3:3])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1O
Reactant: COC(=O)Cn1ccc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.1 %

Procedure:
2-Propyl-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenol (Example 36, 0.75 g, 2.76 mmol) was combined with [5-(3-bromo-propoxy)-indol-1-yl]-acetic acid methyl ester (Example 47, 0.75 g, 2.30 mmol) in 12 mL DMF (containing 1 v/v % of water). To this mixture was added Cs2CO3 (1.50 g, 4.60 mmol), and the resulting mixture was allowed to stir at rt for 14 h. At this time, the reaction mixture was diluted with EtOAc (50 mL) and then washed three times with water (75 mL total). The water layers were extracted with EtOAc (25 mL) and the combined organic extracts were dried over MgSO4, filtered, and then concentrated under reduced pressure. Purification via flash silica gel chromatography (1:1 hexane/EtOAc) gave the title compound (800 mg, 64%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.75-7.70 (m, 2H), 7.18-7.10 (m, 2H), 7.05 (d, 1H), 6.92-6.85 (m, 2H), 6.48 (d, 1H), 4.84 (s, 2H), 4.30-4.20 (m, 4H), 3.75 (s, 3H), 2.90-2.75 (m, 4H) 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H), 1.95-1.85 (m, 4H), 1.70-1.58 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1.O.[OH-].[Li+].O.Cl>C1COCC1>[CH:27]1([CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:5]([CH2:4][C:3]([OH:30])=[O:2])[CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N:13]([CH3:15])[CH3:14])=[CH:11][CH:12]=3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)[CH2:29][CH2:28]1
Reactant: COC(=O)CN(Cc1ccc(N(C)C)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc(OCC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 74.6 g (172.4 mmol) of the compound of Stage 1.4 in 800 ml of THF, 14.5 g (345.6 mmol) of lithium hydroxide monohydrate and 400 ml of H2O are successively added at 0–5° C. After stirring for 4 h at r.t., the mixture is neutralized with aqueous 2 mol HCl at 0–5° C. and extracted with CH2Cl2 several times. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)[CH:18]([CH3:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])(C)C)=[O:29])=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH2:12]([N:5]1[C:4](=[O:15])[C:3]2[N:16]=[C:17]([CH:18]([CH3:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:34])=[O:29])=[CH:22][CH:21]=3)[NH:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(OCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Solvent: c1ccccc1
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Temperature: 80 °C
Yield: 80.7 %

Procedure:
Dissolve the ethyl enolate of (-)-2-[[4-[3-[(6-amino-1-propyl-1,2,3,4-tetrahydro-3-propyl-2,4-dioxo-5-pyrimidinyl)amino]-2-methyl-3-oxopropyl]phenyl]oxy]-acetic acid, 1,1-dimethylethyl ester (1.01 g, 1.9 mmol) in anhydrous benzene (200 mL) and heat at 80° C. for 24 hours. Evaporate the solvent in vacuo and purify the residue by radial chromatography (40→50% ethyl acetate/hexane) to give (-)-2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8- yl)propyl]phenoxy]acetic acid, ethyl ester (0.7 g, 81%); [α]d 20 =-54.3° (C=0.856, CHCl3).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O)(=O)=[O:10].[C:14]1([S:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[NH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO.I([O-])(=O)(=O)=O.[Na+]>O>[C:14]1([S:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[NH:21])=[O:10])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Reactant: N=S(c1ccccc1)c1cccs1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: N=S(=O)(c1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 g. Phenyl-(2-thienyl)-sulphimide mesitylene-sulphonate are dissolved in 200 ml. methanol. A solution of 7 g. sodium periodate in 150 ml. water are added dropwise thereto, whereafter the reaction mixture is stirred for 24 hours at ambient temperature. The reaction mixture is then rendered alkaline and evaporated on a rotary evaporator. The residue obtained is partitioned between water and dichloromethane and the organic phase is evaporated. There are obtained 3.7 g. phenyl-(2-thienyl)-sulphoximide which, after recrystallisation from ethyl acetate/isopropanol, melts at 133° C.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16][NH2:17])=[O:15])[CH:8]=[CH:9][CH:10]=1.[C:24](=S)=[S:25]>CO>[F:3][C:4]([F:22])([F:23])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]2[O:15][C:24](=[S:25])[NH:17][N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2ccccc2-c2n[nH]c(=S)o2)c1
Yield: 68.8 %

Procedure:
Potassium hydroxide (123.0 mg, 1.87 mmol) is added to a 020 C. solution of 2-[(3-trifluoromethylphenyl)amino]-benzoic acid, hydrazide (515.8 mg, 1.75 mmol) and carbon disulfide (250 μl, 3.96 mmol) in 15 ml of methanol. The mixture is heated at reflux overnight. The solution is concentrated in vacuo and the residue dissolved in water. The resulting aqueous solution is acidified with 1N hydrochloric acid and the resulting solids extracted into a 1:1 mixture of ether and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is chromatographed, eluting with hexane:ethyl acetate (1:1), providing a white solid. Drying in vacuo at 65° C. overnight gives 406.4 mg (69%) of product, mp 211°-213° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:16][CH:17]2[CH2:19][CH2:18]2)C(=O)OC(C)(C)C)[N:5]2[N:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:4]2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:77][C:78]1[CH:79]=[C:80]([CH:82]=[CH:83][C:84]=1[F:85])[NH2:81]>O1CCOCC1.O>[Cl:77][C:78]1[CH:79]=[C:80]([NH:81][C:2]2[CH:7]=[C:6]([NH:8][CH2:16][CH:17]3[CH2:18][CH2:19]3)[N:5]3[N:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:4]3[N:3]=2)[CH:82]=[CH:83][C:84]=1[F:85]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)c1cc(Cl)nc2c(C=O)cnn12
Reactant: Nc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cnn2c(NCC3CC3)cc(Nc3ccc(F)c(Cl)c3)nc12
Temperature: 110 °C

Procedure:
To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropylmethyl)carbamate (50 mg, 0.14 mmol) in 1 mL of 1,4 dioxane was added cesium carbonate (65 mg, 0.2 mmol), Pd (OAc)2 (4 mg, 0.006 mmol), (+)-BINAP (5 mg, 0.009 mmol), 3-chloro-4-fluoroaniline (31 mg, 0.21 mmol). The reaction mixture was heated in microwave at 110° C. for 20 minutes. The mixture was then cooled to room temperature, water was added, and the product was extracted with ether. The organic layer was then concentrated under reduced pressure and the crude product was dissolved in 1:1 mixture of dichloromethane and trifluoroacetic acid at room temperature for 1 hour. The reaction mixture was concentrated with 10 mL of dichloromethane. To the reaction mixture, ether/hexanes (1:1) was added and the flask was sonicated for 10 minutes then filtered to obtain the yellow precipitate. The precipitate was washed with hexane to yield 5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=460)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([O:32][C:2]2[CH:3]=[C:4]([N:9]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:30][CH:31]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(I)c1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(Oc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound was prepared following Example 342 using N-(3-iodo-4-methylphenyl)-N-(ethanesulfonyl)pyrid-3-ylmethylamine and 4-tert-butylphenol and purifying via radial chromatography eluting with 50:50 to 53:47 THF/hexanes gave the title compound. 1H NMR (400 MHz) 1.32 (9H, s), 1.39 (3H, t, J=7.8 Hz), 2.19 (3H, s), 3.07 (2H, q, J=7.8 Hz), 4.79 (2H, s), 6.70 (3H, m), 6.92 (1H, dd, J=2.0, 7.8 Hz), 7.16 (1H, d, J=7.8 Hz), 7.20-7.31 (3H, m), 7.67 (1H, d, J=8.3 Hz), 8.31 (1H, bs), 8.50 (1H, bs). HRMS calculated 439.2055 [M+H]+ Found 439.2073.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccncc1F
Reactant: COc1ccc(N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2cnccc2C(=O)O)cc1
Temperature: -78 °C
Yield: 12.7 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and p-anisidine (44 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative RP chromatography to give 11 mg (45 μmol, 13% yield) of pure desired product. LC-MS (method V): rt=1.82 min; m/z [M+H]+ 245.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C(=O)N([Br:25])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][Br:25])=[CH:13][N:12]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2ccc(C)cn2)CCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(c2ccc(CBr)cn2)CCCC1
Temperature: 0 °C

Procedure:
A mixture containing the product of Step 2, above (44) (1 equiv.), n-bromosuccinimide (1.1 equiv.), CCl4 and a catalytic amount of azobisisobutyronitrile was heated at reflux for 4 hours, cooled to 0° C. and filtered through celite. The residue was washed well with CCl4 and the filtrate was concentrated and chromatographed on silica gel to yield the title compound (45).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:10][C:9]2[NH:8][N:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:6]1[C:5]2[CH2:4][CH2:3][C:2]([CH3:11])([CH3:1])[CH2:10][C:9]=2[NH:8][N:7]=1
Reactant: II
Reactant: CC1(C)CCc2cn[nH]c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(C)CCc2c(I)n[nH]c2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
To a solution of 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (0.50 g, 3.33 mmol) in DMF (8 mL) at room temperature was added powdered potassium hydroxide (560 mg, 10.0 mmol) and iodine (1.69 g, 6.66 mmol). The maroon reaction mixture was stirred at room temperature for 45 min then quenched with 10% aqueous Na2S2O3, diluted with water and extracted with EtOAc (2×). The combined organics were washed with water (3×), dried over MgSO4 and concentrated to afford 920 mg (99%) of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole as a light yellow waxy solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 2.44 (s, 2H), 2.35 (t, J=6.4 Hz, 2H), 1.55 (t, J=6.4 Hz, 2H), 1.01 (s, 6H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:21]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([C:14]#[CH:21])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OC)c(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A mixture of 3-(1-admantanyl)-4-methoxybenzaldehyde (0.12 g, 0.42 mmol), dimethyl(1-diazo-2-oxopropyl)phosphonate (0.097 g, 0.51 mmol) and K2CO3 (0.069 g, 0.5 mmol) in anhydrous MeOH (5 ml) was stirred overnight at 80° C. The solvent was evaporated and the residue was diluted to 50 ml with EtOAc, washed with H2O, dried over MgSO4 and filtered. The filtrate was passed through SiO2 bead and the filtrate was evaporated to dryness to give the title product (0.05 g; 42%), which was used for the next step without purification. 1H-NMR (CDCl3) 1.75 (s, 3H); 2.05 (broad s, 9H); 2.96 (s, 1H); 3.82 (s, 3H); 6.77 (d, 1H, J=8.31 Hz); 7.29-7.34 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH:12]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[CH:16]=1)([CH3:14])[CH3:13].CCN(CC)CC>O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:20]2[C:15]([CH:12]([CH3:13])[CH3:14])=[CH:16][C:17]([CH:24]([CH3:26])[CH3:25])=[CH:18][C:19]=2[CH:21]([CH3:23])[CH3:22])=[CH:5][CH:4]=1
Reactant: CC(C)c1cc(C(C)C)cc(C(C)C)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)cc1
Yield: 88.3 %

Procedure:
4-Methoxyphenylboronic acid (152 mg, 1.00 mmol), and Pd(dtbpf)Cl2 (6 mg, 0.01 mmol) were added to a reaction tube equipped with a magnetic stir bar. Under a positive flow of argon while stirring, surfactant solution (1.0 mL, 2 wt % TPGS-M-PEG-750 in water), 2,4,6-triisopropylbenzene (126 μL, 0.50 mmol), and Et3N (0.21 mL, 1.5 mmol) were added by syringe and stirred vigorously for 24 h. The reaction mixture was then diluted with brine and extracted with EtOAc. The solution obtained was dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by flash column chromatography eluting with 5% CH2Cl2/hexanes to afford the product (137 mg, 88%) as a white solid.
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4](Br)[C:5](Br)=[C:6]([CH3:9])[C:7]=1[CH3:8].[I-].[K+].[CH3:15][O:16][C:17]1[C:18](=[O:24])[CH:19]=[CH:20][C:21](=[O:23])[CH:22]=1.[Br-]>CN(C)C=O.O>[CH3:15][O:16][C:17]1[C:18](=[O:24])[C:19]2[C:20]([C:21](=[O:23])[CH:22]=1)=[CH:8][C:7]1[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:9]=2
Reactant: COC1=CC(=O)C=CC1=O
Reactant: Cc1c(C)c(Br)c(Br)c(Br)c1Br
Agent: [Br-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1=CC(=O)c2cc3ccccc3cc2C1=O

Procedure:
16 g of, α, α, α', α', -tetrabromo-o-xylene, 44 g of potassium iodide and 10 g crude 2-methoxy-1,4-benzoquinone were stirred in 160 ml of N,N-dimethylformamide at 70° C. overnight. After the reaction was complete, no bromide was left as determined by thin layer chromotography and the reaction mixture was poured into 1200 ml of H2O. 10%aq Na2S2O5 solution was added to decolorize the solution. The precipitate formed in the aqueous solution was collected and dried. Continuous extraction of the dark precipitate using benzene as a solvent yielded a dark colored solution. The solution was then washed with 2.5% NaOH, H2O, dried and concentrated. 7 g of crude product was obtained. Recrystallization from methanol yielded 5 g of pure yellow powder of MAQ.
Reaction SMILES: Cl[Sn]Cl.Cl.[CH2:5]([O:7][P:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][C:16]=1[N+:23]([O-])=O)([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]>CO>[CH2:11]([O:10][P:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][C:16]=1[NH2:23])([O:7][CH2:5][CH3:6])=[O:9])[CH3:12]
Reactant: C=Cc1ccc(OCP(=O)(OCC)OCC)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: C=Cc1ccc(OCP(=O)(OCC)OCC)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of SnCl2 (4 mmole) in freshly prepared methonolic HCl (10 mL) was added to a cold (0° C.) solution of 2-diethylphosphonomethyloxy-5-vinylnitrobenzene (1 mmole) in MeOH (5 mL). The mixture was warmed to room temperature and stirred for 3 h. Evaporation, extraction and chromatography provided 2-diethylphosphonomethyloxy-5-vinylaniline.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.[NH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][N:29]([CH3:35])[CH2:30]2>CN(C=O)C>[CH3:35][N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[CH:34][C:25]=2[NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[C:3]([CH3:13])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:30]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(C)c(Br)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C)c(Br)cc1C(=O)Nc1cccc2c1CCN(C)C2
Temperature: 25 °C
Yield: 53.9 %

Procedure:
5-Bromo-2-methoxy-4-methylbenzoic acid (0.245 g, 1 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (0.200 g, 1 mmol) and 1-hydroxy-benzotriazole (0.155 g, 1 mmol) were dissolved in dry DMF (10 ml) and stirred at room temperature under argon for 25 mins before 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.163 g, 1 mmol) was added. The mixture was then stirred for 24 under argon at room temperature. The DMF was removed in vacuo and the residue suspended in ethyl acethate and washed with water. The insoluble white precipithate was filtered off, washed with water then dried to afford the title compound (210 mg).