Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[CH3:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1.[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:7]=[C:6]([N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1ncc[nH]1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1COCCO1
Product: Cc1nc(N2CCN(Cc3ccccc3)CC2)nc(-n2ccnc2C)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (175 mg, 0.84 mmol) in dioxane (5 mL) at 80° C. was added 2-methylimidazole (85 mg, 0.84 mmol) and 1-benzylpiperazine (148 μL, 0.84 mmol). The solution was stirred overnight at 80° C., cooled, and directly chromatographed (1/1 hexane diethyl ether) to yield the title compound (u).
Reaction SMILES: [Cl:1][N:2](Cl)C1C=CC=CC=1.ClC(C)(C[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[Cl:22])C=O>C(O)(=O)C>[ClH:1].[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[NH2:2]
Reactant: CC(Cl)(C=O)Cc1cccc(Cl)c1Cl
Reactant: ClN(Cl)c1ccccc1
Solvent: CC(=O)O
Product: Cl
Product: Nc1cccc(Cl)c1Cl
Reaction time: 10 h
Yield: 80 %

Procedure:
2,3-dichloroaniline hydrochloride is prepared by 162 g of dichloroaniline being added slowly and with vigorous agitation to a mixture of 280 ml of acetic acid and 280 ml of concentrated (9 N) HCl, diazotization being effected by the addition of 75 g of NaNO2 dissolved in 150 ml of water, the temperature being maintained between 0° and 5° C. A mixture of 5 g of CaO and 60 ml of methacrolein (dissolved in 120 ml of acetone) and a solution of 6 g of CuCl dissolved in 60 ml of HCl are introduced simultaneously into the filtered diazonium salt solution over a period of 30 minutes. After the addition of the reagents the mixture is left to react at from 0° to 5° C. for 2 hours, then at from 10°-12° C. for 10 hours. The α-chloro-α-methyl-β-(2,3-dichlorophenyl)propionaldehyde is isolated similarly to the products in the previous examples. 206 g, corresponding to an 80% yield, of an oil distilling between 118° and 120° C. at a pressure of 0.01 mm Hg are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.CC(=O)CCC(=[O:28])C.C[C:31]1[N:32]([C:37]2[C:38](OC)=[CH:39][C:40](C(C)C)=[C:41]([CH:51]=2)OC2C(N)=NC(N)=NC=2)C(C)=CC=1>>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([NH:1][C:31]([NH:32][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:51]=3)=[O:28])[CH:16]=2)=[CH:13][N:12]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-n1c(C)ccc1C
Reactant: CC(=O)CCC(C)=O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1NC(=O)Nc1ccccc1

Procedure:
Similarly prepared from 5-(5-amino-2-Isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.313 g, 1.1 mmol) and 2,5-hexanedione (0.14 ml, 1.2 mmol) was 5-[5-(2,5-Dimethyl-pyrrol-1-yl)-2-isopropyl-4-methoxy-phenoxy]-pyrimidine-2,4-diamine, (0.259 g, 64%). (M+H)=368.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:5][CH2:4][CH2:3]1.[H-].[Na+].[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30](F)[CH:29]=1>CN(C=O)C.O>[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([O:14][CH2:13][C:11]2[CH:10]=[CH:9][C:8]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[F:23])=[C:7]([C:6]3[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=3)[CH:12]=2)[CH:29]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Reactant: Fc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(COc3cc(Br)ccn3)cc2C2=CCCC2(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A dry round bottom flask containing 14.3 (0.0937 g, 0.287 mmol) in dry DMF (1 mL) was cooled in an ice bath. After 10 minutes, sodium hydride (60% wt. in oil) (15.4 mg, 0.385 mmol) was added carefully, and the mixture was stirred at 0° C. After 10 minutes, 4-bromo-2-fluoropyridine (commercially available from Synthonix Corporation) (0.0511 g, 0.290 mmol) was added. The reaction was allowed to stir overnight at room temperature. After 18 hours, the reaction was diluted with water and extracted five times with EtOAc. The combined organic layers were then washed one time with brine and dried over anhydrous magnesium sulfate. The solid was filtered off, and the solvent was concentrated. The residue was purified by silica gel flash chromatography (0-45% EtOAc/hexane) to afford 95.A (105.9 mg, 76% yield). 1H NMR (400 MHz) (CDCl3) δ ppm 8.02 (1H, d, J=4.7 Hz), 7.41 (1H, m), 7.35 (2H, m), 7.08 (2H, m), 7.00 (1H, m), 6.79 (2H, dt, J=5.1, 2.5 Hz), 5.52 (1H, s), 5.42 (2H, s), 3.76 (3H, s), 2.25 (2H, td, J=6.9, 2.5 Hz), 1.67 (2H, t, J=7.0 Hz), 0.87 (6H, s).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)[CH3:4].[O:19]=O.[NH4+].[Cl-]>CCOCC>[CH:6]1[C:7]2[CH2:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][C:5]=1[CH:3]([CH3:4])[CH2:2][OH:19]
Reactant: O=O
Reactant: CC(CBr)c1ccc2c(c1)Cc1ccccc1O2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2

Procedure:
3.03 g. of 2-(1-bromo-2-propyl)-xanthene is reacted with 0.26 g. of Mg filings in 100 ml. of ether. The mixture is cooled to -5°, oxygen is introduced for 4 hours, and the mixture is combined with aqueous NH4Cl solution. The usual working-up step yields 2-(2-xanthenyl)-propanol, m.p. 86°-89°.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([O:16]CC4C=CC=CC=4)=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C1CCCCC=1>[OH-].[Pd+2].[OH-]>[C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(COc2ccc3sc(-c4ccccc4)nc3c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Oc1ccc2sc(-c3ccccc3)nc2c1

Procedure:
Palladium hydroxide (100 mg) was added to a solution of 27 (260 mg, 0.8 mmol) of ethanol/cyclohexene (5 mL/2 mL) followed by warming for reflux for 16 h. The reaction mixture was cooled and the catalyst was removed by filtration (through Celite). The solvent was evaporated to provide compound 29 as a white solid. Synthesis of 5-(oxiran-2-ylmethoxy)-2-phenylbenzothiazole (59):
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[S:13])[NH:11][N:12]=2)[O:5][C:6]=1[CH3:7].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][NH+:19]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([S:13][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: Cc1cc(-c2n[nH]c(=S)[nH]2)oc1C
Reactant: BrCCc1cccc[nH+]1
Agent: [Br-]
Product: Cc1cc(-c2nc(SCCc3ccccn3)n[nH]2)oc1C
Yield: 55 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4,5-dimethylfuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 5a) and 2-(2-bromoethyl)pyridinium bromide (example 8a). Yield 55%. 1H NMR (500 MHz, CDCl3): δ 1.96 (s, 3H), 2.24 (s, 3H), 3.28 (t,2H), 3.49 (t, 2H), 6.77 (s, 1H), 7.13-7.23 (m, 2H), 7.65 (t, 1H) 8.58 (s, 1H). MS(M+H, 301).
Reaction SMILES: [NH2:1][C:2](=[N:21][C:22]1[CH:33]=[CH:32][C:25]([C:26]([O:28]CC=C)=[O:27])=[CH:24][CH:23]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([C:11]23[CH2:20]C4CC(CC(C4)[CH2:12]2)[CH2:18]3)[CH:4]=1>CO>[NH2:1][C:2](=[N:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:32][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([C:11]([CH3:20])([CH3:12])[CH3:18])[CH:4]=1
Reactant: C=CCOC(=O)c1ccc(N=C(N)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Solvent: CO
Product: COc1ccc(C(N)=Nc2ccc(C(=O)O)cc2)cc1C(C)(C)C
Yield: 78 %

Procedure:
In a round bottom flask, there are introduced 300 mg (0.82 mmole) of the derivative obtained above in (c), 180 mg (4.5 mmoles) of soda and 10 ml of methanol. After 24 hours of reaction at reflux of the methanol, the mixture is evaporated and the remainder is taken up in water. The reaction mixture is neutralized to pH 5-6 by acetic acid. The resulting precipitate is filtered, washed with demineralized water and then dried for 48 hours at 80° C. 210 mg (78%) of the expected acid whose melting point is 170°-172° C. are obtained
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH2:4].[Cl:5][C:6]([Cl:12])(Cl)[P:7]([Cl:10])([Cl:9])=[O:8].C(Cl)[Cl:14]>C1C(C(OOC(C)(C)C)=O)=CC=CC=1>[Cl:5][C:6]([Cl:12])([P:7]([Cl:10])([Cl:9])=[O:8])[CH2:4][CH:3]([Cl:14])[CH2:2][CH3:1]
Reactant: C=CCC
Reactant: O=P(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: ClCCl
Agent: CC(C)(C)OOC(=O)c1ccccc1
Product: CCC(Cl)CC(Cl)(Cl)P(=O)(Cl)Cl

Procedure:
5.6 g (0.1 mole)butene-1, 71 g (0.3 mole) trichloromethane phosphonic dichloride and 0.5 g tert. butyl perbenzoate were heated in 100 ml methylene chloride in a closed ampoule and in the absence of air, during 10 hours at 120°. After cooling, the ampoule was opened and its contents distilled. Unconverted trichloromethane phosphonic dichloride sublimed between 70° and 125° at 25 mm pressure. The continued distillation yielded 10.3 g 1.1,3-trichloropentane-1-phosponic dichloride, bp/0.05: 64°-66°. Found Cl: 61.3%. Calc. for C5H8Cl5OP: 61.0%.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([N:39]=[C:40]=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:40]([NH:39][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:41])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCN=C=O
Reactant: c1ccc(NCCCCCSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)N(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)c1ccccc1
Yield: 56 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]benzeneamine (0.41 g, 0.001 mol) in toluene (25 mL) was added n-octylisocyanate (0.23 g, 0.0015 mol). The reaction mixture was stirred at reflux for 18 hours and then the solvent was removed under vacuum. The residue (1.0 g) was chromatographed with 7:3 hexane-ethyl acetate. The resulting solid was triturated with hexane to give the title compound (0.32 g, 0.00056 mol) as a white solid, mp 74°-76°. 1H NMR (CDCl3) 11.8(s,1H), 7.75-7.1(m,15H), 4.3(t,1H,J=6.0Hz), 3.8(t,2H,J=7.0Hz), 3.0(quintet,4H,J=6.0Hz), 1.9-0.90(m,18H), 0.8(t,3H,J=7.0Hz).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1S(Cl)(=O)=O.CCN(CC)CC.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31].O>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:31][CH2:30][CH:29]([OH:32])[CH2:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1
Reactant: OCC(O)COc1ccccn1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(OCC(O)COc2ccccn2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
2-Mesitylenesulfonyl chloride (120.8 mg, 0.55 mmol), Bu2SnO (63.1 mg, 0.25 mmol), DMAP (61.9 mg, 0.51 mmol) and Et3N (1 mL) were added to a solution of 3-(pyridin-2-yloxy)propane-1,2-diol (83.7 mg, 0.50 mmol) in toluene (5 mL). The reaction mixture was stirred at room temperature for 2 h. Following the addition of water, the mixture was extracted with CH2Cl2. The organic layers were dried with Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography to give the title product (123.9 mg, 71%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32](C4CCCN4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:39][C:40]([CH3:42])=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=4[NH:31][C:32]([CH:40]4[CH2:42][CH2:5][N:9]([CH:8]([CH3:10])[CH3:7])[CH2:39]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCN4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCN(C(C)C)C4)ncn3)cccc2s1

Procedure:
The title compound was prepared by reacting N-(2-(6-(2-acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)pyrrolidine-2-carboxamide [Example 62(b)] with acetone under the conditions of Example 3(d). MS (ESI, pos. ion.) m/z: 585 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1.[CH2:23]1C[O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:25](=[O:26])[CH:24]=[CH2:23])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 1.00 g (3.20 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile in 2 ml hot DMF, added 12 ml THF and chilled to 0° C. under N2. Added 490 μl (3.52 mmol) triethyl amine and 295 μl (3.52 mmol) acryloyl chloride. Removed ice bath at 15 minutes, and at 1.5 hours stripped solvent. Slurried residue with a dilute sodium bicarbonate, collected solids, and washed with water. Recrystallized from ethyl acetate, giving 215 mg of yellow solid: mass spectrum (electrospray m/e): M+H=367.1, 369.1.
Reaction SMILES: C(C1C=CC(C(O)C[NH:12][C:13]([NH:27]S(C)(=O)=O)=[N:14][CH2:15][CH2:16][S:17][CH2:18][C:19]2[O:20][C:21]([CH2:24][NH:25][CH3:26])=[CH:22][CH:23]=2)=CC=1)(=O)N.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>C(O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH3:26][NH:25][CH2:24][C:21]1[O:20][C:19]([CH2:18][S:17][CH2:16][CH2:15][NH:14][C:13]([NH2:27])=[NH:12])=[CH:23][CH:22]=1
Reactant: CNCc1ccc(CSCCN=C(NCC(O)c2ccc(C(N)=O)cc2)NS(C)(=O)=O)o1
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CNCc1ccc(CSCCNC(=N)N)o1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In 1430 ml of 95% aqueous ethanol solution was dissolved 239 g of N-[2-(4-carbamoylphenyl)-2hydroxyethyl]-N'-methanesulfonyl-N"-[2-[[5-(methylamino)methyl-2-furyl]methylthio]ethyl]guanidine. Thereto was added a solution formed by dissolving 46.8 g of oxalic acid in 240 ml of 95% aqueous ethanol solution. Further, 2.5 g of a seed crystal was added thereto. The mixture was stirred at 40° C. for 3 hours and at room temperature for 3 hours and then allowed to stand overnight. The crystals deposited were collected by filtration to obtain 257 g (yield: 91%) of N-[2-(4-carbamoylphenyl)-2-hydroxyethyl]-N'-methanesulfonyl-N"[2-[[5-(methylamino)methyl-2-furyl]methylthio]ethyl]guanidine oxalate (1:1). Melting point: 142.5°-145.5° C. (recrystallized from 95% aqueous ethanol solution)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[CH:10]=2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:20][CH2:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cccc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of [4′-(trifluoromethyl)-3-biphenylyl]methanol (177 mg, 0.70 mmol) in dry DCM (10 mL) was cooled to 0° C. (ice/water bath) under nitrogen and treated with CBr4 (256 mg, 0.77 mmol) in one portion. PPh3 (202 mg, 0.77 mmol) was then added portion-wise and the resulting mixture stirred for 1 hour at this temperature and was then allowed to warm to rt. The resulting mixture was then reduced and the residue purified directly by SPE (silica, 10 g cartridge) eluting with cyclohexane:DCM afforded the title compound as a colourless oil (220 mg).
Reaction SMILES: C([O:8][C:9]1[CH:41]=[CH:40][CH:39]=[C:11]2[C:12]([N:14]([CH2:17][P:18]([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:20])[OH:19])[C:15](=[O:16])[C:10]=12)=[O:13])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:41]=[CH:40][CH:39]=[C:11]2[C:12]([N:14]([CH2:17][P:18]([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:19])[OH:20])[C:15](=[O:16])[C:10]=12)=[O:13]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)c2cccc(OCc3ccccc3)c2C1=O
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)c2cccc(O)c2C1=O
Reaction time: 4 h

Procedure:
0.2 g of [[3-(benzyloxy)phthalimido]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid was dissolved in 50 ml of methanol containing 0.1 g of 10% palladium-on-charcoal. The mixture was hydrogenated for 4 hours and then filtered. The filtrate was evaporated to give 0.16 g of [[(3-hydroxyphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of an off-white foam.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:17]=2)[C:3]1([CH3:31])[CH3:30].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:27][O:26][C:24](=[O:25])[C:23]([CH3:29])([O:22][C:18]1[CH:17]=[C:16]([CH:4]2[C:3]([CH3:31])([CH3:30])[CH2:2][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[NH:5]2)[CH:21]=[CH:20][CH:19]=1)[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)N2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)N2
Yield: 47 %

Procedure:
A mixture of methyl 4-hydroxy-2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dim ethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (510 mg, 1.19 mmol) and triethylsilane (400 mg, 3.44 mmol) in dichloromethane (6 mL) was stirred and cooled with a ice bath. A solution of trifluoroacetic acid (554 mg, 4.86 mmol) in dichloromethane (6 mL) was added slowly to the mixture. The reaction mixture was treated with sodium carbonate, and stirred for 30 min. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (silica gel, petroleum ether: ethyl acetate=15:1) to afford 230 mg of methyl 2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. (Yield: 47%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S:20][CH2:21][C@H:9]23)=[CH:4][CH:3]=1.[OH:22]OS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CO.O.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S@@:20](=[O:22])[CH2:21][C@H:9]23)=[CH:6][CH:7]=1
Reactant: Oc1ccc([C@@H]2Oc3ccc(O)cc3[C@@H]3CSC[C@@H]32)cc1
Reactant: O=S([O-])OO
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=[S@]1C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 81.8 %

Procedure:
To a solution of enantiomer A of 4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol 11d (20 mg, 0.066 mmol) in MeOH/H2O (1:1, 3 mL) add oxone (40 mg, 0.066 mmol). Stir the reaction at room temperature for 30 minutes. Add 1.0 M Na2SO3 and stir the reaction for 5 minutes. Dilute with EtOAc and wash with saturated sodium bicarbonate. Extract aqueous layer with EtOAc (2×). Combine organic extracts, dry (Na2SO4), filter and concentrate to afford 4-(4-hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ4-thia-cyclopenta[a]naphthalen-8-ol 13 (17 mg, 0.054 mmol, 85%). 1H NMR (δ, 400 MHz, MeOD) 7.44 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 6.75 (d, 1H, J=8.8 Hz), 6.70 (d, 1H, J=2.8 Hz), 6.61 (dd, 1H, J=8.8, 2.8 Hz), 5.19 (s, 1H), 4.19 (dd, 1H, J=6.2, 6.2 Hz), 3.76 (d, 1H, J=7.9 Hz), 3.06-2.94 (m, 1H), 2.84 (dd, 1H, J=14.1, 5.3 Hz), 2.62 (dd, 1H, J=13.0, 5.5 Hz), 2.29 (dt, 1H, J=5.2, 14.0 Hz). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 7.17 min). LRMS calcd for C17H15O4S: 315.1; found (ES−, M−H): 315.2.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>O>[NH2:12][C:4]1[N:3]=[C:2]([NH:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: CCCCN
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Solvent: O
Product: CCCCNc1nc(N)nc2c1CCCC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100 mg, 0.545 mmol) and butylamine (2 ml) was stirred for 4 hours at 90° C. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the solvent in the filtrate was removed in vacuo. The residue was purified by column chromatography (10% MeOH/CHCl3) to give the object compound (94.5 mg, 78.9%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([Br:13])[CH:9]=[CH:10][CH:11]=2)[C:6](C=O)=[CH:5]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([Br:13])[CH:9]=[CH:10][CH:11]=2)[C:6](=[O:24])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)n1cc(C=O)c2c(Br)cccc21
Solvent: ClCCl
Product: CC(=O)N1CC(=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
1-Acetyl-4-bromo-1H-indole-3-carbaldehyde (3.5 g, 13.2 mmol) was dissolved in CH2Cl2 (50 mL). 3-Chloroperbenzoic acid (3.9 g, 15.8 mmol) was added, and the reaction stirred 16 h at r.t. The solution was washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was stirred with K2CO3 (100 mg) in MeOH (50 mL) for 2 min. The solution was concentrated and purified by silica gel chromatography (100% CH2Cl2) to give 880 mg (26%) of the title compound as a faintly blue solid. MS (ES) [m+H] calc'd for C10H8BrNO2, 254, 256; found 254, 256.
Reaction SMILES: [Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1([C:9]([CH:11]2[CH2:13][CH2:12]2)=[NH:10])[CH2:8][CH2:7]1.[Cl-].[NH4+]>CS(C)=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[N+:10]12[CH2:13][CH2:12][CH2:11][C:9]=1[CH2:6][CH2:7][CH2:8]2
Reactant: N=C(C1CC1)C1CC1
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: C1CC2=[N+](C1)CCC2
Product: [O-][Cl+3]([O-])([O-])[O-]
Temperature: 100 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of dicyclopropylmethanimine perchlorate (0.200 g, 0.954 mmol) in 1.0 ml of dimethyl sulfoxide was added 0.0510 g (0.0954 mmol) of ammonium chloride. The mixture was heated with stirring at 100° C. for 3 hours. The solvent was distilled out in vacuo and isobutyl alcohol was added to the residue. Precipitated crystals was obtained and recrystallized from ethanol to afford 0.16 g (Yield: 82%) of the desired compound.