Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]([O:19]C)=[O:18])[C:11]2[N:21]([CH3:30])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:10]1=2.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]([OH:19])=[O:18])[C:11]2[N:21]([CH3:30])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:10]1=2
Reactant: COC(=O)CN1CCSC(c2ccc(Cl)cc2Cl)c2c(-c3ccccn3)nn(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccn2)c2c1N(CC(=O)O)CCSC2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A mixture of methyl 2-[4-(2,4-dichlorophenyl)-1-methyl-3-(2-pyridyl)-6,7-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetate (0.300 g, 0.64 mmol) and lithium hydroxide (0.062 g, 2.6 mmol) in THF (10 mL) and water (5 mL) was stirred at rt for about 2 h. Then 1 M aqueous HCl (15 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Table 2, Method a) to give 2-[4-(2,4-dichlorophenyl)-1-methyl-3-(2-pyridyl)-6,7-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetic acid (0.160 g, 0.36 mmol, 56%) as a white solid: LC-MS (Table 1, Method b) Rt=6.57 min; m/z 449 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.73-2.91 (2 H, m) 3.40-3.63 (2 H, m) 3.92 (3 H, s) 4.12 (1 H, d, J=18.4 Hz) 4.21 (1 H, d, J=18.4 Hz) 5.95 (1 H, br s) 6.46 (1 H, s) 6.94 (1 H, d, J=8.4 Hz) 7.00-7.07 (2H, m) 7.40 (1H, d, J=2.1Hz) 7.58 (1H, td, J=7.5, 1.8 Hz) 7.72 (1H, d, J=7.9 Hz) 8.40 (1H, d, J=5.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][CH3:19].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.O>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:6]=[C:5]3[NH:18][CH3:19])=[CH:24][CH:23]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(Br)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OC)nc3)cc12
Temperature: 90 °C
Yield: 50.1 %

Procedure:
To a 1 dram reaction vial was added 6-bromo-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine (35 mg, 0.111 mmol), 6-methoxypyridin-3-ylboronic acid (20.4 mg, 0.133 mmol), Pd(APhos)2Cl2 (3.2 mg, 0.0041 mmol) and potassium phosphate monohydrate (77 mg, 0.33 mmol) in a mixture of dioxane-water (9:1, 2 mL). The reaction mixture was heated to 90° C. for 14 h after which it was cooled to room temperature and diluted with water (5 mL). The resultant precipitate was collected by filtration and recrystallized from methanol to give 6-(6-methoxypyridin-3-yl)-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine as a pale yellow solid (19.1 mg, 51%). LCMS m/z=344 (M+1) (Method C) (retention time=2.01 min) 1H NMR (300 MHz, DMSO) δ 9.64 (d, J=1.3 Hz, 1H), 8.84-8.74 (m, 1H), 8.68 (dd, J=6.2, 1.7 Hz, 2H), 8.57 (d, J=1.6 Hz, 2H), 8.16 (ddd, J=14.4, 8.7, 2.2 Hz, 2H), 7.85 (d, J=8.7 Hz, 1H), 7.54 (dd, J=7.9, 4.8 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 3.18 (d, J=4.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].[K+].C(O[C:15]([S-:17])=[S:16])C.Cl>CN(C=O)C>[SH:17][C:15]1[S:16][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(Cl)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(S)nc2c1
Temperature: 115 °C
Yield: 49.4 %

Procedure:
To a solution of 3-amino-4-chloro-benzonitrile (Example 251, 9.0 g, 59 mmol) in 90 mL of DMF was added O-ethylxanthic acid potassium salt (Aldrich, 21.23 g, 133 mmol). The mixture was heated to 115° C. for 4 h. After cooled to room temperature, the mixture was diluted with ice/water and was acidified to pH 2 with 2N HCl. Filtration followed by washing with water gave a crude product, which was recrystallized from EtOH/water to give 5.6 g (49%) of product. 1H NMR (400 MHz, DMSO-d6) δ 14.10 (br s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.69 (dd, J=8.3, 1.1 Hz, 1H), 7.60 (s, 1H). MS (EI): m/z 191 (M−H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]([OH:36])=[O:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]([OH:36])=[O:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cc(C(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-carboxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:5][CH:6]=1.Cl.Cl.[OH-].[Na+]>O>[CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Reaction time: 5 h
Yield: 115.3 %

Procedure:
To a warmed solution, 40° C., of 24.08 g of tetramisole hydrochloride (0.1 mol) in 113 ml. water adjusted to pH 4 with hydrochloric acid was added dropwise during a period of 50 minutes a suspension containing 15.85 g of L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (0.05 mol) and 2 g of sodium hydroxide (0.05 mol) in 85 ml of water. The mixture was cooled to 15°-20° C. and additionally stirred during 5 hours. The precipitate was filtered off, washed with water and dried under vacuo at 50° C., yielding 23.55 g of levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield=90.3%); αD20 =-63° (c5, 1N HCl); mp. 127.4°-128.1° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH:31][C:2]1[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=1)=[CH:26][CH:25]=2)=[O:21])[CH3:18]
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 2-ethoxycarbony-5-aminoindole gave N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.95 (d, 1H), 7.84 (d, 1H, J=3.9 Hz), 7.34 (s, 1H), 7.33 (d, 1H, J=1.8 Hz), 7.22-7.19 (m, 2H), 7.11-7.05 (m, 2H), 6.55 (m, 1H), 4.62 (s, 2H), 4.38 (q, 1H, J=6.9 Hz), 1.40 9t, 3H, J=7.5 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1([O:24][C:25](=O)[NH:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=CC=CC=1>O1CCOCC1>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:25]([NH:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:24])[CH2:8][CH2:7]1
Reactant: O=C(NCCCc1ccccc1)Oc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)NCCCc2ccccc2)CC1
Yield: 7 %

Procedure:
The diastereoisomer mixture of (4-aminomethyl-1-phenyl-cyclohexyl)-dimethylamine (465.8 mg, 2.0 mmole) was added to a solution of (3-phenylpropyl)carbamic acid phenyl ester (510.6 mg, 2.0 mmole) in dioxane (15 ml). The batch was then refluxed for 12 h. Working up was performed by removing dioxane by distillation in a rotary evaporator and combining the residue with water (10 ml). The batch was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The combined EE extracts were washed with 1M NaOH (1×5 ml) and dried with Na2SO4. The solvent was removed by distillation under a vacuum. The residue was the diastereoisomer mixture of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-(3-phenyl-propyl)-urea, which was separated and purified by flash chromatography on silica gel (60 g). Ethanol/EE (1:1, 1100 ml) was used as eluent. The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-(3-phenyl-propyl)-urea (310 mg, yellow oil, 39%) and the more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-(3-phenyl-propyl)-urea (55 mg, m.p. 159-165° C., 32%) were isolated in this manner.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[C:15](=[C:23]([OH:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[CH:25]=2)[C:14]1=[O:32])(=[O:12])[CH3:11].C(N(C(C)C)C(C)C)C>ClCCl>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[C:15](=[C:23]([O:31][CH3:6])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[CH:25]=2)[C:14]1=[O:32])(=[O:12])[CH3:11]
Reactant: CC(=O)N1C(=O)C(=C(O)c2cccc(I)c2)c2ccc(Cl)cc21
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.36 g of trimethyloxonium tetrafluoroborate are added batchwise to a solution of 3.52 g of 1-acetyl-3-[1-hydroxy-1-(3-iodo-phenyl)-methylene]-6-chloro-2-indolinone (educt VII) and 2.72 ml of ethyldiisopropylamine in 80 ml dichloromethane and the mixture is stirred for one hour at ambient temperature. Then another 1.4 ml ethyldiisopropylamine and 1.2 g trimethyloxonium tetrafluoroborate are added and the mixture is stirred for a further two hours at ambient temperature. Then it is extracted with water, the organic phase is dried over magnesium sulphate and evaporated to dryness. The residue is recrystallised from ether and dried in vacuo at 80° C.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH:2]([CH3:4])[CH3:3].[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53]([C:59]([OH:61])=O)[CH2:54][CH2:55][C:56]([OH:58])=[O:57])(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[CH3:42][C:43]1[CH:44]=[CH:45][C:46]([S:49]([NH:52][C@H:53]([C:59]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:1][CH:2]([CH3:4])[CH3:3])[C:29]([OH:31])=[O:30])=[O:61])[CH2:54][CH2:55][C:56]([OH:58])=[O:57])(=[O:50])=[O:51])=[CH:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(4-methylbenzenesulfonyl)-L-glutamic acid (360 mg, 1.2 mmol) prepared in step A of this example. The final product was purified by preparative HPLC to yield 20 mg (25%) of the desired material.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:13][CH:14]([C:21]#[N:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:13])[C:21]#[N:22])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C#N)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C#N)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 24 h

Procedure:
This compound is synthesized according to Makosza, et al with some modifications (Makosza, M., et al, Tetrahedron (1974), 30: 3723). A solution of 4-chloronitrobenzene (31.5 g, 0.2 mol) in pyridine (100 mL) is added dropwise to a vigorously stirred suspension of KOH (fine powder 70.0 g) and α-methylbenzylcyanide (26.2 g, 0.2 mol) in pyridine (150 mL), with the reaction temperature being maintained at 10° C. The reaction mixture is stirred for 24 hours at 25° C., and poured onto an excess of HCl-ice mixture. The acidic aqueous mixture is extracted with benzene, the organic phase washed with brine, dried (Na), and the benzene evaporated under vacuum. A crude product 42.5 g (84 wt %) results and is recrystallized from isopropanolpetroleum ether to give Compound 7 as white crystals,
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][NH:12]2.[CH2:20](Br)[CH3:21]>CC(C)=O>[CH2:20]([N:12]1[C:13]2[C:9](=[C:8]([F:7])[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)[CH3:21]
Reactant: CCBr
Reactant: O=[N+]([O-])c1ccc2c(c1F)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCc2c1ccc([N+](=O)[O-])c2F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
Anhydrous potassium carbonate (0.83 g, 6 mmol) was added to a solution of 4-fluoro-5-nitro-indoline (0.54 g, 3 mmol) in acetone (20 mL). The mixture was stirred at 60° C. for 10 min and ethyl bromide (0.33 mL, 4.50 mmol) added dropwise and the mixture was refluxed for a further 12 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (5×10 mL). The combined organic layers were washed with water (3×10 mL), brine (3×10 mL) and then dried over anhydrous sodium sulphate. Concentration of the organic layer afforded the crude product which was purified by column chromatography over silica gel neutral alumina mesh using 5-8% ethyl acetate in hexane as eluent to afford 1-ethyl-4-fluoro-5-nitro-indoline (0.47 g, 75%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[IH:21].[NH2:22][NH:23][C:24]([NH:26][CH3:27])=[NH:25]>I.C(O)CC>[IH:21].[CH3:27][NH:26][C:24]([NH:23][N:22]=[C:10]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[NH:25]
Reactant: CNC(=N)NN
Reactant: O=C(C=Cc1ccc(Cl)cc1)C=Cc1ccc(Cl)cc1
Agent: I
Solvent: CCCO
Product: CNC(=N)NN=C(C=Cc1ccc(Cl)cc1)C=Cc1ccc(Cl)cc1
Yield: 53.3 %

Procedure:
A mixture consisting of 3.03 grams of 1,5-bis(p-chlorophenyl)-1,4-pentadien-3-one, 2.16 grams of 1-amino-3-methylguanidine hydroiodide, 3 drops of 57 percent hydroiodic acid, and 50 ml. of n-propanol is stirred and heated under refluxing conditions for two hours. Cooling failed to yield a product. After concentration to about 15 ml. of volume, and addition of 60 ml. of ether, a yellow product is obtained. Recrystallization from ethanol gives 2.67 grams of the subject compound melting 213°-214.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](I)[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[C-:25]#[N:26].[Na+]>C(#N)C.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.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:25]#[N:26])[C:8]2[C:7](=[O:12])[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: [C-]#N
Reactant: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc(Cl)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
A mixture of 5-chloro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.339 g, 0.73 mmol), Pd(PPh3)4 (0.084 g, 0.073 mmol), sodium cyanide (0.046 g, 0.95 mmol), and CuI (0.017 g, 0.073 mmol) in acetonitrile (5 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate afforded 6-chloro-3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.184 g, 69%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.31 (s, 2H), 4.81 (s, 2H), 7.20 (d, 2H), 7.37 (d, 2H), 7.62 (s, 1H), 7.76 (s, 1H). GC-MS: m/z 366 (M)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH:17]([C@H:19]1[CH2:23][CH2:22][C:21](=[O:24])[N:20]1[CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=O>COCCOC>[O:24]=[C:21]1[CH2:22][CH2:23][C@H:19](/[CH:17]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:20]1[CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCSCCN1C(=O)CC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of sodium hydride (95%, 14 mg, 0.58 mmol) in 3 mL of anhydrous 1,2-dimethoxyethane at 0° C. under an argon atmosphere was added dimethyl 2-oxoheptylphosphonate (ACROS, 0.13 mL, 0.61 mmol). The cooling bath was removed and the reaction was stirred for 2 hours. After this time period, the mixture was cooled to 0° C. and a solution of methyl 4-({2-[(2R)-2-formyl-5-oxopyrrolidin-1-yl]ethyl}thio)butanoate (0.55 mmol) in anhydrous 1,2-dimethoxyethane was added. The reaction was allowed to come to room temperature, stirred for 2 hours and then quenched with an aqueous solution of saturated ammonium chloride. Ethyl acetate (50 mL) was then added and the mixture was partitioned between the two phases. The organic solution was dried (brine, Na2SO4), evaporated via reduced pressure and purified with column chromatography (SiO2, EtOAc/Hexane-1/1) to yield methyl 4-[(2-{(5R)-2-oxo-5-[(1E)-3-oxooct-1-enyl]pyrrolidin-1-yl}ethyl)thio]-butanoate as an oil. This material was taken directly on to the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4]/[C:5](/[CH3:21])=[CH:6]/[CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[C:10]([CH3:18])[C:9]=1[O:19][CH3:20].[Na+].[I-:23].CC(C)=O>O>[I:23][CH2:2][CH2:3][CH2:4]/[C:5](/[CH3:21])=[CH:6]/[CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[C:10]([CH3:18])[C:9]=1[O:19][CH3:20]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCl)c1C
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCI)c1C
Temperature: 25 °C
Yield: 99 %

Procedure:
(E)-1-(6-chloro-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (725.8 mg, 2.334 mmol) and NaI (3.09 g, 20.61 mmol) were dissolved into acetone (10 mL) and heated to reflux for 18 h. The reaction mixture was cooled to room temperature and the cloudy solution added to H2O (50 mL) and of a 50% EtOAc/hexanes solution (50 mL), the layers separated and the aqueous phase extracted with hexanes (3×25 mL), then MTBE (2×25 mL). The organics were combined and washed with saturated NaCl solution (2×25 mL) and dried over anhydrous Na2SO4. Concentration yielded 930.0 mg (99.0%) of 1-((E)-6-iodo-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene as a pale yellow oil. 1H NMR (400 MHz, CDCl3) d 5.12 (t, J=6.4 Hz, 1H), 3.65 (s, 6H), 3.36 (d, J=6.0 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 2.18 (S 9H), 2.07 (t, J=7.2 Hz, 2H), 1.91 (t, J=7.2 HZ, 2H), 1.77 (s, 3H), 13C NMR (100 MHz, CDCl3) d 153.1, 152.6, 133.0, 131.3, 128.4, 127.9, 127.6, 124.7, 60.9, 60.1, 40.1, 31.7, 26.1, 16.1, 12.8, 12.7, 12.2.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][C:6]([CH3:16])=[C:7]([CH3:15])[N:8]=2)[N:3]=1.[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])([O:19][CH3:20])=[O:18].C(OC(C)C)(C)C>C(#N)C>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[N:5][C:6]([CH3:16])=[C:7]([CH3:15])[N:8]=2)[N:3]=[C:2]([NH:1][C:31]([NH:30][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:29])=[O:28])=[O:32])[N:11]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1nc2nc(N)nc(N(C)C)c2nc1C
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(N(C)C)c2nc(C)c(C)nc2n1
Yield: 80.8 %

Procedure:
A mixture of 1 g of 2-amino-4-dimethylamino-6,7-dimethylpteridine and 1.3 g of 2-carbomethoxyphenylsulfonyl isocyanate was stirred in 10 ml of acetonitrile for 30 minutes at room temperature and then the mixture was heated to reflux for 3 to 4 minutes. After cooling diisopropyl ether was added thereto and the mixture was vacuum filtered to obtain 1.7 g (81% of theory) of N-(4-dimethylamino-6,7-dimethylpteridin-2-yl)-N'-(2-carbomethoxyphenylsulfonyl)-urea melting at 196° C.
Reaction SMILES: [CH2:1]([CH:8]([C:12](O)=O)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NCC)C.C=O.Cl>O>[CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)C(=O)O
Agent: C=O
Agent: Cl
Solvent: CCNCC
Solvent: O
Product: C=C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a cooled (0° C.) mixture of benzyl malonic acid (3.37 g, 17.4 mmol) and diethylamine (1.34 g, 18.3 mmol) in water (10 ml) was added formaldehyde (37% solution in water, 2.1 g, 26.1 mmol) with stirring. The reaction was allowed to warm to room temperature and after 2 hours heated to reflux. After 16 hours, the reaction mixture was cooled to room temperature, then made acidic with hydrochloric acid. The mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined and dried over sodium sulfate, then the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography to yield 2.2 g (78%) of white solid. 1H NMR (CDCl3): δ 3.7 (s, 2H), 5.6 (s, 1H), 6.4 (s, 1H), 7.1-7.4 (m, 5H)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C@H:12]1([CH2:20][OH:21])[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CCN(CC)CC>C(Cl)Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([CH2:20][OH:21])[CH2:13][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](CO)CC2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4-Toluenesulfonyl chloride (742.5 g, 3.75 mol) was added to a solution of trans-cyclohexane-1,4-diyldimethanol (500 g, 4.17 mol) and Et3N (695 g, 5 mol) in DCM (6000 mL) at −20° C. The mixture was stirred at room temperature for 10 h and then quenched with water (10 L). The organic layer was separated, the aqueous layer was extracted with DCM (2×3 L), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give trans-4-(hydroxymethyl)cyclohexylmethyl 4-methylbenzenesulfonate as a yellow oil.