Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)C.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17].C[O-].[Na+]>CN(C)C=O.C(#N)C>[C:16]([C:18]1[C:19](=[O:20])[NH:21][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[CH:4]=1)#[N:17]
Reactant: CN(C)C=C1C(=O)CCc2ccccc21
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1cc2c([nH]c1=O)CCc1ccccc1-2

Procedure:
Heat 11.4 g of 1-dimethylaminomethylene-2-tetralone, 4.46 gm of cyanoacetamide and 6.6 gm of sodium methoxide in 100 ml of dimethylformamide for 8 hours at 80°. Cool and dilute the reaction mixture with 150 ml of acetonitrile. Remove the tan solid by filtration. Dissolve the solid in hot water and filter the mixture. Acidify this aqueous solution with concentrated hydrochloric acid to give a tan precipitate. Filter and wash the tan solid with chloroform to give the title compound, m.p. 301°-3°. Concentrate the remaining dimethylformamide:acetonitrile solution in vacuo to give a green-black residue and chromatograph on 800 ml of silica gel using cloroform:methanol 98:2 as eluant to give an additional amount the title compound.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2.C(OCC)(=O)C>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: BrBr
Reactant: Oc1ccc2cnccc2c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Oc1ccc2cnccc2c1Br
Yield: 88.4 %

Procedure:
7.9 mL (19.18 g, 120 mmol) of bromine were added dropwise to a suspension of 17.42 g (120 mmol) of compound 7 in 250 mL of chloroform at room temperature. After stirring for 2 h ethyl acetate was added. The precipitate was filtered, washed with ethyl acetate and dried. Aqueous NaHCO3 solution was added carefully. The precipitate was filtered and washed with NaHCO3 solution until the filtrate had a pH of 8. Drying gave 23.78 g (88%) of compound 9 as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Brc1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A solution of 4-bromoaniline (1.76 g, 10 mmol) and benzaldehyde (1.06 g, 10 mmol) in dichloroethane (15 mL) was treated with NaBH(OAc)3 (2.32 g, 11 mmol) and glacial acetic acid (1 mL), stirred overnight at room temperature, quenched with 1N NaOH, and extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with water and brine, dried, (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5:1 hexanes/ethyl acetate to provide 2.21 g (84%) of the desired product. MS (ESI) m/e 261.9 (M+H)+, 263.9 (M+H)+.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1CCC(N=C=NC2CCCCC2)CC1>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21]([C@@H:22]([O:6][C:5](=[O:7])[CH2:4][CH:3]=[C:2]([CH3:1])[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: CC1=C(CC/C(C)=C/CC(=O)O)C(C)(C)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](OC(=O)CC=C(C)CCC1=C(C)CCCC1(C)C)c1ccccc1
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of 10.0 g (40 mmol) (E)-4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid [H. S. Corey, J. R. D. Cormick, W. E. Swensen, J. Am. Chem. Soc. 1964, 86, 1884], isomeric purity of 95%, in 100 ml MTBE were added at r.t. 6.64 g (40 mmol) (S)-(+)-mandelic acid methyl ester [α]D=+144.9 (c=1.04, MeOH) and 1.0 g DMAP. Then a solution of 8.24 g (40 mmol) DCC in 100 ml MTBE was added and the reaction mixture stirred for 2 h. After addition of 1 ml MeOH and 1 ml HTDNF the mixture was stirred for 30 min, filtered and the residue washed with MTBE. The combined organic phases were concentrated in vacuo and the residue (18.0 g) was purified by flash chromatography (silicagel, hexane/MTBE 9:1) affording 14.0 g (88%) 4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid (S)-methoxycarbonyl-phenyl-methyl ester (11) in form of a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:20](=[O:22])[CH3:21])=[CH:4][C:5]2[CH:11]([CH3:12])[CH2:10][N:9]([C:13](=[O:18])C(F)(F)F)[CH2:8][CH2:7][C:6]=2[CH:19]=1.[OH-:23].[Na+]>CO>[C:20]([C:3]1[C:2]([OH:1])=[CH:19][C:6]2[CH2:7][CH2:8][N:9]([C:13]([O:23][C:3]([CH3:20])([CH3:4])[CH3:2])=[O:18])[CH2:10][CH:11]([CH3:12])[C:5]=2[CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc2c(cc1O)CCN(C(=O)C(F)(F)F)CC2C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc2c(cc1O)CCN(C(=O)OC(C)(C)C)CC2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5.13 g of 1-[8-hydroxy-5-methyl-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl]ethanone in 50 ml of MeOH was added 50 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to a half of the amount, and to the residue were added 50 ml of dioxane and 4.27 g of di-t-butyl dicarbonate, followed by stirring at room temperature for 30 minutes. The reaction mixture was neutralized by the addition of 1 M hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 4.385 g of t-butyl 8-acetyl-7-hydroxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a yellow viscous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:9]=[N:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 60 %

Procedure:
As described for example 67, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (78 mg, 0.24 mmol), was converted, using cyclopropylmethylamine instead of isopropylamine, to the title compound (54 mg, 60%) which was obtained as a white gum. MS: m/e=382.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.CCN(CC)CC.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][C:30](Cl)=[O:31]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:30](=[O:31])[CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:8]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCN(C(=O)Cc1cccs1)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 60 mg (0.27 mmol) of the free base of N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1) and 0.11 mL Et3N (0.79 mmol) in 5 mL dry CHCl3 was cooled in an ice bath. After adding 0.05 ml (0.41 mmol) 2-thienylacetic acid chloride (A3-1: W=Cl, Cy=2-thienyl) to the mixture the ice bath was removed and the reaction was stirred for 2 hrs at room temperature. In a second step further 0.05 mL (0.41 mmol) of 2-thienylacetic acid chloride (A3-1) were added and the reaction stirred for 20 hrs. The mixture was washed with a saturated solution of aqueous NaHCO3 for several times and finally extracted with CH2Cl2. The organic layers were dried over MgSO4 and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 40/1 gave the product N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide.
Reaction SMILES: [CH:1]12[O:10][CH:2]1[CH2:3][C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:11]>>[NH2:11][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10]
Reactant: c1ccc2c(c1)CC1OC21
Reactant: N
Product: N[C@@H]1c2ccccc2C[C@H]1O

Procedure:
The trans amide can be made from the epoxide either (1) by treating the indene oxide with ammonia or a primary amine to produce a trans-1-amino-2-indanol and reacting the trans-1-amino-2-indanol with an acylating agent, or (2) by treating the epoxide with an amide anion to produce the trans hydroxy amide directly. In one embodiment the indene is oxidized with aqueous hypochlorite in the presence of a chiral salen catalyst to produce a partially resolved epoxide, which is converted to the partially resolved trans-1-amino-2-indanol by treating with ammonia or a primary amine followed by acylating with benzoyl chloride or acetic anhydride. The resulting benzamide or acetamide is recrystallized to yield substantially optically pure trans-1-benzamido-2-indanol or trans-1-acetamido-2-indanol. In two preferred embodiments, the cis-1-amino-2-indanols are (1S,2R)-1-amino-2-indanol and (1R,2S)-1-amino-2-indanol, produced by oxidation of indene in the presence of an R,R or S,S-salen catalyst respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][C:11](=[CH2:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]([CH3:13])([CH3:12])[CH3:10])=[CH:5][CH:4]=1
Reactant: C=C(C)C
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(C)(C)C)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a 300 cc stainless steel stirred autoclave may be added 124 g (1.0 mol) 4-methoxyphenol and 10 g of XN-1010, a cation exchange resin bearing sulfonic acid groups supplied by Rohm and Haas Co. The system may be charged with 56 g (1.0 mol) isobutylene and the mixture stirred 5 hours at 20° C. Resin may be removed by filtration and unreacted phenol may be removed by washing the filtrate with an aqueous solution of 10% sodium hydroxide. The organic material may be washed with water to remove caustic and dried with magnesium sulfate to afford t-butyl 4-methoxyphenyl ether in a yield of about 70%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:19]1[C:27]2[O:26][CH:25]=[CH:24][C:23]=2[CH:22]=[C:21]([CH3:28])[CH:20]=1.COCCOC>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.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[C:27]3[O:26][CH:25]=[CH:24][C:23]=3[CH:22]=[C:21]([CH3:28])[CH:20]=2)=[CH:5][CH:4]=1
Reactant: Cc1cc(Br)c2occc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: COc1ccc(-c2cc(C)cc3ccoc23)cc1
Yield: 90.4 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (4.76 g, 31.3 mmol), Na2CO3 (32.6 2 N aqueous, 65.2 mmol), Pd(PPh3)4 (1.5 g, 1.3 mmol), 7-bromo-5-methylbenzofuran (5.5 g, 26.1 mmol), and ethylene glycol dimethyl ether (275 ml) was heated to reflux for 12 h. The reaction was cooled, ether (500 ml) was added and the layers separated. The aqueous was further extracted with ether and the organic layers were dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 7.16 g brown oil. Further purification by column chromatography (10% EtOAc/hexanes) afforded 5.62 g (91%) product as a clear oil: 1H NMR (300 MHz, DMSO-d6): δ 3.44 (3H, s), 3.82 (3H, s), 6.94 (1H, d, J=2.2 Hz), 7.108 (2H, d, J=8.8 Hz), 7.30 (1H, s), 7.38 (1H, s), 7.81 (2H, d, J=8.8 Hz), 8.00 (1H, d, J=2.2 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][C:17]([F:16])([F:26])[F:27])=[CH:20][CH:21]=2)[CH:7]=1
Reactant: Fc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Fc1ccc(-c2nc(Cl)cc(Nc3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A mixture of compound 4,6-dichloro-2-(4-fluoro-phenyl)-pyrimidine (1 g, 4.10 mmol), 4-trifluoromethoxy aniline (0.8 g, 4.5 mmol) and triethyl amine (0.83 g, 8.20 mmol) in n-butanol (10 mL) was refluxed for 12 hours under nitrogen. The reaction mixture was then cooled to room temperature and concentrated under vacuum, the crude compound was passed through the silicagel by using 5-6% ethylacetate—petroleum ether to afford the compound [6-chloro-2-(4-fluoro-phenyl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine (0.75 g, 50%) as light brown solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN1[C:42](=[O:43])CCC1=O>CO.C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:20])=[C:15]([CH3:18])[C@@H:16]([O:43][CH3:42])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1S[C@@H]2[C@@H](NC(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of diphenylmethyl 7α-phenylacetamido-3-methyl-3-cephem-4-carboxylate (2.88 g, 5.8 mmole) in 40 ml of methanol and 60 ml of methylene chloride, was added N-chlorosuccinimide (882 mg, 6.6 mmol) and the mixture was stirred for 90 minutes at room temperature. The reaction solution was then washed with brine (2×) and dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resultant yellow foam (2.84 g) was chromatographed over 100 grams of silica gel employing 10-15% of ethyl acetate in toluene as the eluting solvent. The first fraction to elute from the column was the desired 2α-methoxy cephem compound which was subsequently recrystallized from a mixture of ethyl acetate and cyclohexane to give pure diphenylmethyl 7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate. (638 mg, 21% yield) (mp 144°-145° C.) i.r. (CHCl3) 1780, 1725 and 1680 cm-1 ; n.m.r. (CDCl3) δ1.95 (s, 3, CH3) 3.35 (s, 3, OCH3), 3.45 (s, 2, CH2Ph), 4.60 (s, 1, C2 --H), 4.70 (d, J=2 and 8 Hz, 1, C7 --H), 4.85 (d, J=2 Hz, 1, C6 --H), 6.95 (s, 1, CH2Ph), 7.3 (m, 16, aromatic H and N--H); u.v. (CHCl3) λmax 264 nm (ε=9726).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[CH:13]=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.CCCCCC.CN(C)[CH:32]=[O:33]>O1CCCC1>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:32]=[O:33])=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)ncn2C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=O)n2C)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
In 16 ml of dry tetrahydrofuran was dissolved 800 mg (3.1 mmol) of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole (X=Y=Me) (10). This solution was cooled to -78° C. and 2.2 ml of n-butyllithium-n-hexane (1.66 molar) was added dropwise under nitrogen. After 5 minutes, 680 mg (9.3 mmol) of dry N,N-dimethylformamide was added and the reaction was further conducted at the same temperature for 15 minutes. This reaction mixture was poured in ice-water and extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:5) to provide 644 mg (yield 73%) of Compound I-6. mp 93 to 94° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: COc1nc2c(N)nc(OC3CCC3)nc2n1CCCCCl
Product: Nc1nc(OC2CCC2)nc2c1[nH]c(=O)n2CCCCN1CCCCC1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-2-(cyclobutyloxy)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[OH:16]S(O)(=O)=O.[N+]([O-])(O)=O>O>[Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(Br)C12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C(O)C(Br)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 28 °C

Procedure:
α-Bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then reacted with H2SO4 and HNO3 to produce α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q). More specifically, α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q) is prepared from α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) by first charging an Erlen-Meyer flask with H2SO4. The flask is then cooled in an ice bath and 50% HNO3 is added to the flask. The solid α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then added to the mixture in portions which maintain the temperature under 28° C. The reaction is then heated to 60° C. with stirring until a clear solution is obtained. When the reaction is complete, it is cooled to and maintained at room temperature. Water is then added to quench the reaction. The resulting slurry is cooled in an ice bath and then filtered to obtain α-bromo-3-hydroxytricyclo [3.3.1.13,7]decane-1-acetic acid (Formula Q). See also Example 18 herein.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[N:26]1([C:31](N)=[NH:32])C=CC=C1.CCN(C(C)C)C(C)C>C1COCC1>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9]([NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][C:31]([NH2:32])=[NH:26])[N:4]=2)=[O:10])=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: N=C(N)n1cccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2nc(CNC(=N)N)cs2)c(C(=O)C2CCCC2)c1
Temperature: 60 °C
Yield: 87.9 %

Procedure:
To a solution of 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methylphenyl)-urea (90 mg, 0.25 mmol) in THF (10 mL) was added pyrrole-1-carboxamidine (54 mg, 0.50 mmol) and DIEA (90 μL). The reaction mixture was heated 60° C. for 3 h and concentrated. The crude product was purified by flash chromatography [silica, DCM:ethyl acetate (50:50 to 10:90)] to yield 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-(4-guanidinomethyl-thiazol-2-yl)-urea (88 mg, 88%).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[S:4][N:3]=1.[O:17]([CH3:19])[Na]>CO>[F:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[C:5]1[S:4][N:3]=[C:2]([O:17][CH3:19])[C:6]=1[C:7]#[N:8]
Reactant: Cc1ccc(-c2snc(Cl)c2C#N)c(F)c1
Reactant: CO[Na]
Solvent: CO
Product: COc1nsc(-c2ccc(C)cc2F)c1C#N
Temperature: 75 °C
Reaction time: 3 h

Procedure:
Into a 250-mL round-bottom flask, was placed 3-chloro-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carbonitrile (2.0 g, 7.91 mmol, 1.00 equiv), methanol (100 mL), NaOCH3 (2.1 g, 38.87 mmol, 4.91 equiv). The resulting solution was stirred for 3 h at 75° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 1.5 g (76%) of 5-(2-fluoro-4-methylphenyl)-3-methoxy-1,2-thiazole-4-carbonitrile as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[Na]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[OH:9])[CH:7]=1
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: OC(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 100.8 %

Procedure:
To the solution of (5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanone 15e (5.0 g, 13.0 mmol) in a dry tetrahydrofuran/methanol mixture (v/v=1/1, 20 mL) was added sodium brohydride (0.98 g, 26.0 mmol) in portions at 0° C. After the addition, the mixture was stirred at 0° C. for 40 min. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (50 mL). The water layer was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 15f as pale yellow oil (5.0 g, 99.5%). This material was not further purified.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([F:20])=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.CN(C)CCCN=C=NCC.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([F:20])=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
5-Chloro-4-(5-chloro-6-fluoropyridin-3-yloxy)-2-fluorobenzoic acid (Preparation 162, 6.100 g, 19.60 mmol), 4-dimethylaminopyridine (2.330 g, 19.06 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (5.480 g, 28.59 mmol) and methanesulfonamide (2.720 g, 28.59 mmol) were suspended in DCM (20 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with aqueous 1M HCl and extracted with EtOAc. Combined organics were concentrated in vacuo. The resulting residue was purified by reverse phase chromatography to afford the title compound as a white solid (4.50 g):