Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]1[CH:23]2[CH2:24][CH:25]([NH2:26])[CH:21]([CH2:22]2)[CH2:20]1>ClCCl>[CH:21]12[CH2:22][CH:23]([CH2:19][CH2:20]1)[CH2:24][CH:25]2[NH:26][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: NC1CC2CCC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc(C#N)c(NC2CC3CCC2C3)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a 0° C. solution of 10.0 g (53.9 mmol) of 4-chloro-2-(methylthio)-5-pyrimidinecarbonitrile in 100 mL of dichloromethane is added 9.0 mL (64.6 mmol) of triethylamine followed by dropwise addition of 7.0 mL (59.3 mmol) of exo-2-aminonorbornane. The reaction mixture is stirred at 0° C. for 2 hours. The resulting precipitate of triethylamine hydrochloride is filtered. The filtrate is washed three times with saturated aqueous solution of sodium bicarbonate. The aqueous phase is back extracted twice with dichloromethane. The combined organic phase is concentrated, and the residue is purified by filtering through a short column of silica gel eluted with dichloromethane to give 8.9 g (64%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:21][C:22]1([CH3:46])[CH2:31][CH2:30][C:29]2[N:28]=[CH:27][N:26]=[C:25]([N:32]3[CH2:38][C:37]4[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:36]=4[O:35][CH2:34][CH2:33]3)[C:24]=2[CH2:23]1>>[CH3:21][C:22]1([CH3:46])[CH2:31][CH2:30][C:29]2[N:28]=[CH:27][N:26]=[C:25]([N:32]3[CH2:38][C:37]4[CH:39]=[C:40]([C:2]5[CH:3]=[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]([NH:8][CH2:9][C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)=[N:6][CH:7]=5)[CH:41]=[CH:42][C:36]=4[O:35][CH2:34][CH2:33]3)[C:24]=2[CH2:23]1
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1NCc1ccccc1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(NCc6ccccc6)c(NS(C)(=O)=O)c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using N-{5-bromo-2-[(phenylmethyl)amino]pyridin-3-yl}methanesulfonamide (reagent preparation 39) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-D4): 8.26 (s, 1H), 8.06 (s, 1H), 7.64 (s, 1H), 7.37 to 7.08 (m, 7H), 6.94 (d, 1H), 4.59 (s, 2H), 4.57 (s, 2H), 4.20 (m, 2H), 3.85 (m, 2H), 2.91 (s, 3H), 2.67 (t, 2H), 2.36 (s, 1.59 (t, 2H), 1.21 (s, 6H), 0.82 (s, 6H); MS (EI) for C32H36N6O3S: 585 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[S:15]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21])([OH:18])(=[O:17])=[O:16].C(=O)(O)[O-].[Na+]>CC(C)=O.O>[S:15]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12)=[O:21])([OH:18])(=[O:17])=[O:16]
Reactant: O=C(Cl)C(c1ccccc1)S(=O)(=O)O
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(c3ccccc3)S(=O)(=O)O)C(=O)N12

Procedure:
The α-sulfo-acylamido-3-halo-cephem compounds of the Formula I wherein Q is a sulfo group (-SO3H) are prepared by following the acylation procedures employed for the preparation of α-sulfobenzylpenicillins described by U.S. Pat. No. 3,660,379 and in the J. Med. Chem., 15 (11), 11-5 (1972); ibid, p. 1108. For example, 7-amino-3-chloro-3-cephem-4-carboxylic acid is reacted with α-sulfophenylacetyl chloride in a mixture of acetone and water containing an excess of sodium bicarbonate to yield 7-(α-sulfophenylacetamido)-3-chloro-3-cephem-4-carboxylic acid. Examples of α-sulfoacylamido-3-halo-cephems of the present invention are,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)N)=[CH:4][CH:3]=1.CO[CH:20](OC)[CH2:21][CH2:22][CH2:23][NH:24][CH3:25]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:20]=[C:21]2[CH2:22][CH2:23][NH:24][CH3:25]
Reactant: CNCCCC(OC)OC
Reactant: NN(CCN1CCCCC1)c1ccc(Cl)cc1
Product: CNCCc1cn(CCN2CCCCC2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(4-chlorophenyl)-1-(2-(piperidin-1-yl)ethyl)hydrazine (Example 3) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([C:13]2([NH2:16])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:17][CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[C:7]1([C:13]2([NH:16][C:19](=[O:20])[CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[Br:17])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)C(Br)C(=O)Cl
Reactant: NC1(c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)C(Br)C(=O)NC1(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-phenylcyclopropylamine (8.9 g) and triethylamine (7.4 g), and α-bromo-tert-butylacetyl chloride (14.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. The benzene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 14.8 g of N-(1-phenylcyclopropyl)-α-bromo-tert-butylacetamide. M.P., 161°-162.5° C.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12]C=1.[C-:16]1([N:21]2[C:25](=[O:26])[NH:24][NH:23][C:22]2=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17]1.[CH-]1C=CC=C1.[Fe+2:33]>O1CCCC1>[C-:16]1([N:21]2[C:22](=[O:27])[N:23]=[N:24][C:25]2=[O:26])[CH:17]=[CH:18][CH:19]=[CH:20]1.[CH-:12]1[CH:13]=[CH:14][CH:15]=[CH:10]1.[Fe+2:33]
Reactant: O=c1[nH][nH]c(=O)n1-[c-]1cccc1
Reactant: Ic1ccccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1N=NC(=O)N1[c-]1cccc1

Procedure:
With reference to EXAMPLE 1-2, 4.5 mg (0.014 mmol) of iodobenzene diacetate was added to a mixture of 5 mg (0.017 mmol) of 4-ferrocenylurazole and 0.25 mL of tetrahydrofuran at room temperature, followed by stirring for an hour. Thus, the tetrahydrofuran solution of 4-ferrocenyl-1,2,4-triazoline-3,5-dione was obtained. A tetrahydrofuran (0.25 mL) solution of 1 mg (0.0025 mmol) of alfacalcidol prepared in accordance with the method described in Japanese Patent Publication (KOKAI) No. 48-62750, Tetrahedron Lett., 1973, 2339 and Tetrahedron, 30, 2701 (1974) was added to the solution obtained. The mixture was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:2) to give 1 mg (57%) of the titled alfacalcidol/4-ferrocenyl-1,2,4-triazoline-3,5-dione adduct (ALF-FTAD) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:31])[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:14][CH2:13][C:12]([F:31])([F:11])[CH2:17][CH2:16]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:28])([F:29])[F:30])=[N:23][CH:22]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=448.1, tR (minutes, Method F)=2.95. [α]D20==+28.00 (c=1.5 mg/mL,CHCl3)
Reaction SMILES: [CH2:1]([S:5][C:6]1[C:7]([C:12]2(O)[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:8][CH:9]=[CH:10][N:11]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:23][C:12]1([C:7]2[C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:11][CH:10]=[CH:9][N:8]=2)[CH:17]2[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]2)[CH2:13]1
Reactant: CCCCSc1nccnc1C1(O)CN2CCC1CC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCSc1nccnc1C1(Cl)CN2CCC1CC2
Temperature: 25 °C

Procedure:
A 1 g sample of 60% NaH dispersion in oil was triturated twice with hexane then suspended in 300 ml of THF. The mixture was treated with 5 ml of butanethiol and after 30 min the mixture was heated to reflux for 45 min. After cooling to ambient temperature, 1.5 g of (7), (0.0063 mol) was added and the reaction was heated to reflux for 1 h. The mixture was diluted with 100 ml of butanethiol and the reaction was heated to reflux overnight. The solvent was removed by distillation, the residue suspended in 50 ml of H2O, and the mixture extracted 3× with 25 ml of CHCl3, the extracts washed with brine, and the solvent evaporated. The brown solid residue was recrystallized from ether to give 1.25 g of 3-(3-butylthiopyrazinyl)-1- azabicyclo[2.2.2]octan-3-ol (29a). NMR ppm (CDCl3) 0.97 (3H, t), 1.19 (1H, t), 1.19 (1H, m), 1.35-1.57 (4H, m), 1.7 (2H, m), 2.21 (1H, m), 2.5-3.02 (6H, m), 3.2 (2H, m), 4.1 (1H, d), 4.5 (1H, m), 8.17 (1H, d), 8.25 (1H, d). A solution of 1.2 g of (29a) (0.0041 mol) in 100 ml of CH2Cl2 was cooled to 0° C. as 0.95 ml of thionyl chloride in 10 ml of CH2Cl2 was added dropwise. The cooling was removed and after 1 h the reaction was heated to reflux for 45 min. After cooling to ambient temperature, the reaction was treated with ice and the solution was made basic with 1 N NaOH. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated to give a brown liquid. The liquid was purified by radial chromatography eluting with 5% ethanol-0.5% NH4OH-CHCl3 and then 10% ethanol-1% NH4OH-CHCl3 to give 1 g of 3-chloro-3-(3-butylthiopyrazinyl)-1-azabicyclo[2.2.2]octane (29b). NMR ppm (CDCl3) 0.99 (3H, t), 1.5 (3H, m), 1.7 (4H, m), 2.38 (1H, m), 2.7 (2H, m), 2.98 (1H, m), 3.05-3.4 (4H, m), 3.76 (1H, d), 4.19 (1H, d), 8.18 (1H, d), 8.3 (1H, d). A mixture of 1 g of (29b) (0.0032 mol) and 0.4 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated for 1 h at 60 psi of H2. The catalyst was removed, the solvent was evaporated, the residue suspended in 5 ml of H2O, and the mixture made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol-0.5% NH4OH-CHCl3 and then 10% ethanol-1% NH4OH-CHCl3. The hydrochloride salt (29) crystallized from ethyl acetate to give 0.44 g of a floculant white solid, mp 193°-194° C. NMR ppm (CDCl3) 0.99 (3H, t), 1.5 (2H. m), 1.7 (4H, m), 2.15 (2H, m), 2.5 (1H, m), 3.23 (3H, m), 3.4 (3H, m), 3.64 (2H, m), 4.38 (1H, q), 8.21 (1H, d), 8.31 (1H, d). Anal. C15H23N3S-HCl requires C: 57.40; H: 7.71; N: 13.37%. Found C: 57.14; H: 7.92; N: 13.12%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>>[CH2:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH2:23][CH2:24][CH3:25]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCCCc1cc(C(=O)OCC)c(N)s1
Product: CCCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 15.8 %

Procedure:
From 6.2 g (0.040 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 9.0 g (0.040 mol) of 2-amino-5-butyl-3-thiophenecarboxylic acid, ethyl ester and heating in a wax bath at 180°-195° C. for one hundred forty-five minutes and then at 185°-200° C. for ninety minutes, following the procedure of Example 22 there is obtained 1.9 g of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 266°-267° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](N)=[O:4].[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:8]([O:14][C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCO
Reactant: CC(C)(O)C(N)=O
Product: CCCCCCOC(=O)C(C)(C)O
Yield: 51.8 %

Procedure:
A mixture of 20.6 g of α-hydroxy-isobutyramide and 204 g of n-hexyl alcohol was heated in the presence of 0.45 g of PbO for 6 hours at 200° C. in an autoclave. On working up by distillation, 19.5 g (= 51.8 percent of theory) of α-hydroxy-isobutyric acid-n-hexyl-ester were obtained. The amide conversion is 75 percent.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][C@H:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:8]2)[NH:4][C:3]1=[O:20].[NH2:21][OH:22]>C(O)C.O>[OH:22]/[N:21]=[C:16](\[NH2:17])/[C:15]1[CH:18]=[CH:19][C:12]([C@H:9]2[CH2:10][CH2:11][C:5]3([NH:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]3=[O:7])[CH2:8]2)=[CH:13][CH:14]=1
Reactant: CN1C(=O)NC2(CC[C@H](c3ccc(C#N)cc3)C2)C1=O
Reactant: NO
Solvent: O
Solvent: CCO
Product: CN1C(=O)NC2(CC[C@H](c3ccc(/C(N)=N/O)cc3)C2)C1=O
Temperature: 60 °C
Yield: 97.9 %

Procedure:
4-((7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)benzonitrile (0.88 g, 3.27 mmol) was suspended in ethanol (20 ml). To this was added hydroxylamine (0.240 ml, 3.59 mmol) as 50% weight solution in water, and the reaction was heated to 60° C. under an atmosphere of nitrogen for about 20 hours. The reaction mixture was left to cool down to ambient temperature. Solvent was partially removed. The resulting white precipitate was filtered, rinsed with cold ethanol and vacuum-dried to afford (Z)-N′-hydroxy-4-{(7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl}benzimidamide as light brown solid (1.12 g, 3.20 mmol).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:29]=[C:25]([C:24]([F:23])([F:34])[F:35])[N:26]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:27]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3nc(C(F)(F)F)cc3C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.9 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (50 mg, 0.19 mmol) was dissolved in DCM (5 mL) and cooled to 0° C. before thionyl chloride (110 mg, 0.93 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (3 mL) to this was added 3,5-bis(trifluoromethyl)-1H-pyrazole (38 mg 0.19 mmol) followed by potassium carbonate (51 mg, 0.37 mmol). The reaction mixture was heated to 60° C. for 2 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative acidic HPLC gave (R)—N-(5-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (1.7 mg, 3.7 μmol, 2.0%). MS (ESI): m/z [M+H]+ 456.1
Reaction SMILES: [CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([OH:26])[C:13]2[CH:14]([CH3:25])[C:15]3[CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]=3[O:21][C:22]=2[CH:23]=1)[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:26][C:12]1[C:13]2[CH:14]([CH3:25])[C:15]3[CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]=3[O:21][C:22]=2[CH:23]=[C:10]([CH:2]([CH3:1])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=1)(=[O:29])[CH3:28]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC1=C(CCC(C)C1)C2C
Reaction time: 24 h

Procedure:
To a solution of 1.2 g. of 3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydro-1-hydroxy-6,9-dimethylxanthene in 20 ml. of dry pyridine is added 8.0 g. of acetic anhydride. The solution is stirred at 25° for 24 hours, then concentrated in vacuo. The residue is dissolved in water and extracted with hexane. The extract is washed with water until neutral, then dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(F)cc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(c2ccc(C#N)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-cyanophenyl)amino]pyrimidine and 4-fluorobenzonitrile
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C(F)(F)F)C=1)CCC(O)=O.[C:33]([C@H:37]1[CH2:42][CH2:41][C@H:40]([O:43][C:44]2[CH:45]=[C:46]3[C:51](=[CH:52][CH:53]=2)[CH:50]=[C:49]([C:54]([N+:61]([O-])=O)([CH3:60])[CH2:55][CH2:56][C:57]([OH:59])=[O:58])[CH:48]=[CH:47]3)[CH2:39][CH2:38]1)([CH3:36])([CH3:35])[CH3:34]>>[NH2:61][C:54]([C:49]1[CH:48]=[CH:47][C:46]2[C:51](=[CH:52][CH:53]=[C:44]([O:43][C@H:40]3[CH2:41][CH2:42][C@H:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:38][CH2:39]3)[CH:45]=2)[CH:50]=1)([CH3:60])[CH2:55][CH2:56][C:57]([OH:59])=[O:58]
Reactant: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(N)CCC(=O)O)ccc3c2C(F)(F)F)CC1
Product: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
4-amino-4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl) pentanoic acid was synthesized as per 4-amino-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl) butanoic acid (Example 203) in 3% yield using 4-(6-(trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)-4-nitropentanoic acid as starting material. MS: m/z=381.53 [M-NH2]+. 1H NMR (MeOD) δ: 7.91 (d, J=8.7 Hz, 1H), 7.83-7.88 (m, 2H), to 7.55 (dd, J=8.7, 1.9 Hz, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.21 (dd, J=9.1, 2.3 Hz, 1H), 4.34-4.47 (m, 1H), 2.69 (s, 3H), 2.40-2.57 (m, 2H), 2.23-2.39 (m, 3H), 2.06-2.19 (m, 1H), 1.91-2.01 (m, 2H), 1.88 (s, 2H), 1.39-1.55 (m, 2H), 1.11-1.39 (m, 3H), 0.96 (s, 9H)
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C:33]1[CH:65]=[CH:64][C:36]([CH2:37][CH:38]2[S:42][C:41](=[O:43])[N:40]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]2=[O:63])=[CH:35][CH:34]=1.[C:66]([O:70][C:71]([NH:73][C@H:74]([CH3:77])[CH2:75]O)=[O:72])([CH3:69])([CH3:68])[CH3:67]>C1C=CC=CC=1>[C:66]([O:70][C:71]([NH:73][C@H:74]([CH3:77])[CH2:75][O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][CH:38]2[S:42][C:41](=[O:43])[N:40]([C:44]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:39]2=[O:63])=[CH:64][CH:65]=1)=[O:72])([CH3:69])([CH3:68])[CH3:67]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
13.2 g of diethyl azodicarboxylate were added dropwise to a solution of 20.7 g of triphenylphosphine in 300 ml of benzene, whilst ice-cooling. The mixture was then stirred at room temperature for 30 minutes, after which 35.0 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in Preparation 11] were added. The mixture was then stirred at room temperature for one hour, after which 13.2 g of (R)-2-t-butoxycarbonylamino-1-propanol were added to the mixture and the mixture was allowed to stand overnight at the same temperature. 40.9 g of triphenylphosphine, 23.68 ml of diethyl azodicarboxylate and 33 g of (R)-2-t-butoxycarbonylamino-1-propanol were then added, in turn and in 3 or 4 portions, to the mixture, and the mixture was stirred for 2 days. At the end of this time, the reaction mixture was freed from benzene by distillation under reduced pressure. The residue was then purified by column chromatography through silica gel, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 30.0 g of 5-{4-[2(R)-t-butoxycarbonylamino-1-propoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione, melting at between 153° C. and 157° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1H-indole-5-carboxylic acid (323 mg, 2.0 mmol) in 10 mL of DCM was added DIPEA (1.03 g, 8.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (400 mg, 2.1 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0° C. The resulting mixture was stirred at r.t. for 18 h. TLC indicated that the starting material was gone. The mixture was diluted with DCM (100 mL) and washed with water (30 mL). The organic layer was separated and dried over anhydrous Na2SO4. The solution was concentrated to give a crude product, which was then purified with silica gel column (Hexane/EtOAc=1/1) to give HJC-2-13 (605 mg, 92%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H), 7.73 (s, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.26-7.27 (m, 2H), 6.59 (s, 1H), 3.56-3.63 (m, 4H), 3.42-3.47 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [SH2]=N.C(O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([NH:16][C:17](=[O:19])[OH:18])[CH2:13][CH2:14][CH3:15].C1(O)C=CC=CC=1.[Na]>O>[CH2:12]([NH:16][C:17](=[O:18])[O:19][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)c1ccccc1
Reactant: CCCCNC(=O)O
Agent: N=[SH2]
Agent: [Na]
Solvent: Oc1ccccc1
Solvent: O
Product: CCCCNC(=O)Oc1ccccc1
Reaction time: 3 h

Procedure:
5 g. N-butyl-carbamic acid benzoic acid sulfimide are suspended in the mixture of 1.67 g. phenol and 50 ml water, then while stirring (5 hours) a solution of 0.71 g. sodium hydroxyd in 50 ml water is added. After stirring another 3 hours the mixture is extracted with 2×30 ml ether. The ethereal extracts dried with sodium sulfate, then the solvent evaporated in vacuum at a temperature not above 30° C. 2.15 g. phenyl N-butyl-carbamate are obtained, which can be distilled at 146°-148° C. at 2 mmHg.