Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15](Cl)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].Cl.[NH2:32][C:33]1[C:38]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[C:35]([NH:45][CH2:46][CH2:47][NH2:48])[N:34]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:48][CH2:47][CH2:46][NH:45][C:35]4[CH:36]=[CH:37][C:38]([C:39](=[O:44])[C:40]([F:42])([F:43])[F:41])=[C:33]([NH2:32])[N:34]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
120 mg (0.23 mmol) of ethyl{4-[5-chlor-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]piperidin-1-yl}acetate (Example 55A), 78.7 mg (0.28 mmol) of 1-{2-amino-6-[(2-aminoethyl)-amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.24 ml (1.38 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 141 mg (90% of theory) of the product as a solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:25])([O:23][CH3:24])[CH3:22])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:62][CH:63](Br)[CH3:64])(=[O:61])[CH3:60].Cl>O.CN(C)C=O>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:22])([O:23][CH3:24])[CH3:25])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([O:13][CH:63]([O:62][C:59](=[O:61])[CH3:60])[CH3:64])=[O:12])=[N+:2]=[N-:3]
Reactant: CC(=O)OC(C)Br
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A mixture of 739 mg of 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid, 76 mg of potassium carbonate and 3 ml of dimethylformamide was stirred at 20° C. for 10 minutes and after cooling the mixture to 0° to 50° C., 0.6 g of 1-bromoethyl acetate was slowly added thereto. The mixture was stirred for 20 minutes at 0° to 5° C. and for one hour at 20° C. and then a mixture of 40 ml of iced water and 1.5 ml of N hydrochloric acid were added thereto. The mixture was vacuum filtered and the product was rinsed with water and dried to obtain 761 mg of the syn isomer of 1-acetoxyethyl 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10])[C:5](=[O:14])[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:4][C:5](=[O:14])[N:6]([C@H:8]([C:9]([NH2:11])=[O:10])[CH2:12][CH3:13])[CH2:7]1)(=[O:25])=[O:24]
Reactant: CC[C@@H](C(N)=O)N1CC(CO)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C(N)=O)N1CC(COS(C)(=O)=O)CC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 4 l three necked flask fitted with mechanical stirrer, dropping funnel and reflux condenser under inert atmosphere, 114 g (569 mmoles, 1 eq) of (2S)-2-[4-hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 are dissolved in 2 l of CH2Cl2 and cooled down to 0° C. 158.5 ml (115 g, 2 eq) of dry triethylamine are added in one portion, followed by dropwise addition of a solution of 66.3 ml (96.2 g, 1.5 eq) of methanesulfonyl chloride in 190 ml of CH2Cl2 over 1 hour, all the while maintaining the temperature below 4° C. After 4 hours, 7.5 ml of methanesulfonyl chloride and 15 ml of triethylamine are added and the mixture is kept overnight in the refrigerator. The mixture is filtered, the residue washed with CH2Cl2 and the combined organic phases concentrated to dryness to give 216 g of crude 37. It is purified by Prep LC in several batches (1 kg SiO2, CH2Cl2/EtOH, 100:0->96:4) to give 109 g of pure 37, 69%.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[NH:13][CH:12]1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])=O)C1C=CC=CC=1>C(O)C.[Pd]>[O:16]=[C:14]1[CH2:15][NH:11][CH:12]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[NH:13]1
Reactant: CC(C)COC(=O)/C=C/C1NC(=O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)COC(=O)CCC1NCC(=O)N1
Yield: 86.2 %

Procedure:
To a solution of isobutyl (E)-1-benzyloxycarbonyl-4-oxo-2-imidazolidineacrylate (7.7 g, 22.2 mmol) in 96% ethanol (200 ml), 5% palladium on charcoal (0.5 g) was added and hydrogen was bubbled at 20° C. and at atmospheric pressure for 2 hours. Removal of the catalyst and evaporation of the solvent gave a residue which was triturated with diisopropyl ether to give 4.1 g (86%) of the title compound, m.p. 50°-52° C. NMR (CDCl3): deltaH =4.45 (t, J=6 Hz, 1H, N--CH--N), 3.10 (s, 2 H, N--CH2 --CO). MS (E.I., 70 eV, 1.5 mA) m/z=214 (M+), 157 (M--C4H9 +, 85 (M--C7H13O2 +.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[CH2:30]([N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.6 %

Procedure:
A mixture of 9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 8.3 g of potassium carbonate, 20 g of benzyl bromide and 200 ml of acetone is stirred at room temperature for 3 days. Then, the reaction mixture is treated in the same manner as described in Example 1-(2). 9.3 g of tert.-butyl (4S)-1-benzyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless syrup. Yield: 75.6%
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C([N:14]1[CH2:28][CH:17]2[C:18]3[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[CH:22][C:23]=3[C:24](=O)[CH:16]2[CH2:15]1)C1C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:27][O:26][C:20]1[CH:21]=[CH:22][C:23]2[CH:24]([CH3:1])[CH:16]3[CH2:15][NH:14][CH2:28][CH:17]3[C:18]=2[CH:19]=1
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccc2c(c1)C1CNCC1C2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (18.1 g, 50.7 mmol) and potassium tert-butoxide (5.7 g, 50.7) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.9 g, 33.8 mmol) in anhydrous ether (68 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (200 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 8.1 g (82%—two steps) of the subtitle compound. MS calculated for C20H21NO+H: 292, observed: 292.
Reaction SMILES: [Na+:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[K+].Br[CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(O)C>[OH:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:10])=[O:11])=[CH:5][CH:4]=1.[Na+:1]
Reactant: CCCCCC(O)Br
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(OCCCCCCO)cc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
Into a three-necked round-bottom flask equipped with a magnetic stirring bar and a reflux condenser were added 4-hydroxybenzenesulfonicacid sodium salt (30.0 grams (g), 0.13 mol), potassium hydroxide (9.0 g, 0.16 mol) and distilled water (60 milliliter (ml)). 1-Bromohexanol (23.16 g, 0.13 mol) dissolved in ethanol (50 ml) was added drop wise into the reaction mixture at room temperature. The reaction mixture was refluxed for 24 hours and then cooled to room temperature. The precipitated product was filtered and washed with chloroform to remove excess of 1-bromohexanol. The product was dried under vacuum at 70° C. for 12 hours to provide 38.06 g of sodium 4-(6-hydroxyhexyl)oxybenzenesulfonate (92% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][OH:18])[S:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9]
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Product: O=S(=O)(c1cncc(Br)c1)N(CCO)CCO
Yield: 41.5 %

Procedure:
Prepared by general procedure III from 5-bromo-pyridine-3-sulfonyl chloride (Example B.2 step 2) (500 mg, 2 mmol) and diethanolamine (1.03 g, 10 mmol) to give the title compound as an off-white solid (270 mg, 42%). MS (ISP) 325.1 [(M+H)+], 327.1 [(M+2+H)+].
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:2]=[CH2:3].[NH2:22][C:23]([NH2:25])=[S:24].C(O)C.[ClH:29]>O>[ClH:29].[Si:15]([O:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:1][CH2:2][CH2:3][NH:25][C:23](=[NH:22])[SH:24])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1c(CCCNC(=N)S)ccc2ccccc12
Yield: 86 %

Procedure:
A mixture of the product of Example 122 Part C (1.55 g, 0.004 mole), thiourea (0.31 g, 0.004 mole), and absolute ethanol (8.0 mL) was heated at reflux for 7 hours. The cooled solution was treated with water (5.0 mL), cooled to 0°, and treated with concentrated hydrochloric acid (5.0 mL). The precipitated solid was isolated by filtration, rinsed with water and air-dried to provide the title compound (1.45 g, 86%) as a white powder, mp 190°-194°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[NH2-].[Na+].ClC(S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O)(Cl)Cl.O>O1CCCC1>[F:35][C:34]([F:37])([F:36])[CH2:33][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)CN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1

Procedure:
To 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.69 g) in anhydrous tetrahydrofuran was added sodium amide (0.20 g) at room temperature, and the resulting mixture was heated under reflux for 1.5 hours. After cooling, 2,2,2-trifluoroethyl trichloromethylsulfonate (0.666 g) in annydrous tetrahydrofuran was added to the mixture under ice-cooling, and then the mixture was heated under reflux for 11.5 hours. After cooling, water (0.2 g) was added thereto and inorganic materials were eliminated by filtration. The filtrate was evaporated and chromatographed to afford 5-[4-(2,2,2-trifluoroethyl)morpholin-2-yl]methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 174° - 177° C (hydrochloride).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[CH:8](OC)(OC)[O:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:8][O:9][CH:10]1[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: COC(OC)OC
Reactant: OCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC1OCC(CO)CO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.1 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (1.7 g, 16 mmol), trimethyl orthoformate (7 ml, 64.1 mmol), and p-toluenesulfonic acid monohydrate (275 mg, 1.6 mmol) was stirred at room temperature for 22 hours. To the reaction mixture, triethylamine (447 μl) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (1.4 g, 59.1% yield), which is a cis and trans (1:1) mixture, as a light yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][CH3:11].CO[C:14]1[C:15](=O)[C:16](=[O:20])[C:17]=1[O:18]C>CO>[CH3:8][CH:4]1[N:3]([CH2:9][CH2:10][CH3:11])[CH:2]([CH3:1])[CH2:7][N:6]([C:14]2[C:17](=[O:18])[C:16](=[O:20])[C:15]=2[N:6]2[CH2:5][CH:4]([CH3:8])[N:3]([CH2:9][CH2:10][CH3:11])[CH:2]([CH3:1])[CH2:7]2)[CH2:5]1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CCCN1C(C)CNCC1C
Solvent: CO
Product: CCCN1C(C)CN(c2c(N3CC(C)N(CCC)C(C)C3)c(=O)c2=O)CC1C

Procedure:
A solution of 1.5 grams of 2,6-dimethyl-1-propylpiperazine in 10 ml. of methanol is mixed with a solution of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 25 ml. of methanol and refluxed for 5 hours. The solvent is then evaporated by heating on a steam bath and the resulting red semi-crystalline residue is triturated with anhydrous ethyl ether and filtered and the filter cake is washed with 5 ml. of anhydrous ethyl ether to remove the colored by-products and leave 3,4-bis(3,5-dimethyl-4-propyl-1-piperazinyl)-3-cyclobutene-1,2-dione as a grey-white crystalline solid melting at about 145°-147° C.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:4]=[C:5]2C(=O)[O:9][C:7](=[O:8])[C:6]2=[CH:12][C:13]=1[F:14]>C(COC)OC>[F:2][C:3]1[CH:4]=[C:5]([NH2:1])[C:6](=[CH:12][C:13]=1[F:14])[C:7]([OH:9])=[O:8]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Reactant: N
Solvent: COCCOC
Product: Nc1cc(F)c(F)cc1C(=O)O
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
Dimethoxyethane (43 parts) was charged to a reactor and ammonia was bubbled in to form a saturated solution. The ammonia addition was continued while a solution of 1.84 parts of 4,5-difluorophthalic anhydride in 13 parts of dimethoxyethane was added slowly over a period of 0.5 hours. The reaction mixture was stirred for an additional 5 minute period and the dimethoxyethane was removed by vacuum distillation. The remaining white solid (the ammonium salt of 4,5-difluorophthalamic acid) was dissolved in 20 parts of aqueous sodium hydroxide (40% NaOH) and the solution was de-gassed under moderately reduced pressure to remove any remaining ammonia; then heated at atmospheric pressure, to 50° C. and maintained at that temperature while 14.1 parts of a 5.78% aqueous sodium hypochlorite solution was added. The solution was then heated to 60°-65° C. and maintained at that temperature, with stirring for about 30 minutes; then cooled to about 20°-25° C. and acidified to a pH of 4-6, by addition of concentrated hydrochloric acid. A precipitate formed and the mixture was extracted with chloroform. The acidification procedure was repeated until no additional precipitate formed. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the chloroform removed by vacuum distillation to yield 1.34 parts of solid 4,5-difluoroanthranilic acid having a melting point of 180°-181° C. The chemical structure of the product was confirmed by infra-red analysis.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28](OCC)=[O:29])=[C:26]([CH:33]=O)[N:25]=[C:24]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41].Cl.[NH2:43][NH2:44]>C(O)C>[ClH:41].[O:38]1[CH2:37][CH2:36][N:35]([C:24]2[N:23]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:16][CH:17]=3)[C:27]3[C:28](=[O:29])[NH:44][N:43]=[CH:33][C:26]=3[N:25]=2)[CH2:40][CH2:39]1
Reactant: CCOC(=O)c1c(C=O)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: O=c1[nH]ncc2nc(N3CCOCC3)nc(Nc3ccc(CN4CCNCC4)cc3)c12
Yield: 59.3 %

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-morpholinopyrimidine-5-carboxylate (100 mg, 0.18 mmol) was dissolved in ethanol, hydrazine dihydrochloride (28 mg, 26 mmol) was added and the mixture was refluxed for 3 hours. The solid precipitated was filtered and dried in vacuum to give the desired product (49 mg).
Reaction SMILES: C([CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]1=[O:10])(OC(C)(C)C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O1CCOCC1>[Cl:26][CH:15]1[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8]1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)C1CCCCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C1CC(Cl)CCCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 129.7 %

Procedure:
Example 228 B) To a solution of 1 g (0.0047 mol) of this Boc-caprolactam product of Example 228 A in 10 mL of anhydrous THF at -78° C. was added 0.005 mol of LiHMDS. After stirring for 30 minutes, 1.2 g (0.005 mol) of hexachloroethane in 5 ml of anhydrous THF was added. The mixture was allowed to warm to 0° C. and was quenched with dilute HCl. The mixture was extracted with EtOAc and the organic layer was washed with 5% HCl, dried (MgSO4), filtered and concentrated to afford a yellow oil. The residue oil was dissolved in 40 mL of 1,4-dioxane (satd. with anhydrous HCl), stirred for 40 minutes, concentrated to afford 0.9 g of 3-chlorocaprolactam as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.O[C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9]/[CH2:10][O:11][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The above allyl alcohol (0.889 g, 3.0 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.770 g, 3.9 mmol; see below) and triphenylphosphine (1.30 g, 5 mmol) were dissolved in a mixture of anhydrous toluene (12 mL) and tetrahydrofuran (4 mL). The mixture was cooled to 0° C., kept under nitrogen and diisopropyl azodicarboxylate (0.85 g, 4.2 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 3 h and then at 25° C. for 16 h. The solvents were evaporated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 98:2-90:10) affording methyl (E)-[4-[3-(4-bromophenyl)-3-phenylallyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>C(Cl)Cl>[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:10]([C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)N1CCNCC1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Reaction time: 15 h
Yield: 81.9 %

Procedure:
To a stirring anhydrous DCM (3.5 mL) solution of trans-2-phenyl-1-cyclopropanecarbonyl chloride (0.096 ml, 0.56 mmol), which is commercially available from, for example, Sigma-Aldrich Corporation (P.O. Box 14508, St. Louis, Mo. 63178), under an argon (g) atmosphere was added the 1-isopropylpiperazine (0.167 ml, 1. 17 mmol), which is commercially available from, for example, Sigma-Aldrich, in one portion at ambient temperature, wherein the reaction was allowed to stir for ca. 15 h before being washed with dilute aq. K2CO3 (1×2 mL), H2O (2×2 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting gum was subjected to flash chromatography (basic alumina-24 g; gradient elution: 30-10% EtOAc/Hexane over 14 min at 30 mL/min) to give 125 mg title compound as a colorless tacky solid (82% yield). m/z (ES+) M+1=273.2; HPLC tR=1.44 min. 1H NMR (500 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.20-7.16 (m, 1H), 7. 10 (d, J=7.0 Hz, 2H), 3.68-3.55 (m, 4H), 2.70 (ddd, J=12.9, 6.7, 6.6 Hz, 1H), 2.54-2.43 (m, 5H), 1.96 (ddd, J=8.4, 5.3, 4.3 Hz, 1H), 1.65 (ddd, J=9.2, 5.3, 4.3 Hz, 1H), 1.25 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 1.03 (d, J=6.7 Hz, 6H).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13]Cl)[CH:7]=1)[C:3]([OH:5])=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>CO>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][N:15]=[N+:16]=[N-:17])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCc1cc(C(N)C(=O)O)ccc1O
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid (252 mg, 1 mmole) in 4 ml of methyl alcohol is added sodium azide (156 mg, 2.4 mmole). The mixture is stirred at about 40° C. for 15 minutes. After about 10 minutes the title compound begins to precipitate. The mixture is cooled, filtered and the product is washed with a small amount of methyl alcohol and acetone. The title compound is collected (210 mg, 95% yield). M.P. >300°; [α]D18 =-73.03° (c 1.7, water), NMR (DMSO-D6) ppm (δ) 4.22 (s,1), 4.35 (s,2), 6.7-7.5 (superimposed q and s,3).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[F:14][C:15]([F:20])([F:19])[C@H:16]([OH:18])[CH3:17]>>[CH:8]1([C:7]2[C:2]([O:18][C@H:16]([CH3:17])[C:15]([F:20])([F:19])[F:14])=[CH:3][C:4]([C:11]([OH:13])=[O:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: O=C(O)c1cc(Cl)c(C2CC2)cn1
Reactant: C[C@@H](O)C(F)(F)F
Product: C[C@@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 68a, using 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48b) and (R)-1,1,1-trifluoropropan-2-ol (CAN 17628-73-8) as starting materials and isolated (231 mg, 41%) as light brown solid; MS (ESI, m/z): 276.5 (M+H+).