Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.S(C)C>C1COCC1>[NH2:11][CH2:10][CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:12]
Reactant: N#CCC(O)c1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CSC
Product: NCCC(O)c1cccc(Br)c1
Temperature: 0 °C

Procedure:
To a solution of nitrile 23 (22.4 g, 99 mmol) in anhydrous THF (200 mL) under nitrogen was added BH3.SMe2 (28.4 mL, 297 mmol) via addition funnel over a period of 1 h. The mixture was then refluxed for 14 h. After cooling to 0° C., the excess borane was quenched by slow addition of methanol. This was concentrated to dryness under reduced pressure. The process was repeated six times. This was followed by the dissolution of the crude product in 6N HCl and extraction with DCM. Aqueous layer was basified to pH 10 with conc. NH4OH and extracted with DCM. Combined organics were dried over Na2SO4. The solution was filtered and concentrated under reduced pressure to give 24 as clear oil. Yield (15.94 g, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.42 (bd, J=7.6 Hz, 1H), 7.22-7.34 (m, 2H), 4.69 (m, 1H), 2.67-2.74 (m, 2H), 1.65-1.77 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[O:2].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20].CCN(CC)CC>C1COCC1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][NH:17][C:16]2=[O:20])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: NCCN1CCNC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)NCCN2CCNC2=O)cc1
Reaction time: 4 h

Procedure:
A solution of the 4-formylbenzoyl chloride (16.5 g, 0.098 mol) in dry THF (100 ml) was added, over a period of minutes, to a suspension of 1-(2-amino-ethyl)imidazolidin-2-one (12.6 g, 0.098 mol) and Et3N (19.8 g, 0.195 mol) in dry THF (300 ml) at −35° C. During the addition, the temperature of the reaction medium was maintained between −35 and −38° C. The temperature of the reaction medium was then slowly brought back to ambient temperature over a period of 4 hours. The precipitate obtained (mainly the expected product as a mixture with triethylamine hydrochloride Et3N.HCl) was filtered off and washed with THF (twice with 20 ml). The reaction crude was solubilized in an aqueous solution of Na2CO3 (3.4 g, 0.032 mol in 40 ml of water). The expected compound was extracted several times with EtOAc (total volume: 3.5 l).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16]([NH:18]C)=[O:17])=[O:13])[C:5]([CH3:24])=[N:4][C:3]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].Cl.[CH3:36]NC(=O)CN>>[NH2:18][C:16]([C@@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Br:1])=[C:3]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[F:34])[N:4]=[C:5]2[CH3:24])[CH:10]=1)[CH3:36])=[O:17]
Reactant: CNC(=O)CN
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: Cl
Product: Cc1ccc(C(=O)N[C@@H](C)C(N)=O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 45 %

Procedure:
The title compound was prepared by employing a similar procedure as described for (±) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide, substituting S-alanineamide hydrochloride for N-methylglycineamide hydrochloride. Yield 45%: 1H NMR (CD3OD/400 MHz) δ 7.96 (m,1H), 7.73 (dd, 1H, J=2.0 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.56 (abq, 2H), 4.55 (abq, 1H), 2.18 (s, 3H), 2.14 (s, 3H), and 1.45 (d, 3H, J=7.2 Hz); ES-HRMS m/z 535.0757 (M+H calcd for C23H22N4O4F2 Br requires 535.0787). 19F NMR (CD3OD/400 MHz) −111.86 (m) and −115.90 (m).
Reaction SMILES: BrC1C=C([N:8]2[C:20]3[CH:19]=[C:18]4[C:21]([CH3:29])([CH3:28])[C:22]5[C:27]([C:17]4=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:26][CH:25]=[CH:24][CH:23]=5)C=C(Br)N=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:28][C:21]1([CH3:29])[C:18]2=[CH:19][C:20]3[N:8]([C:34]4[CH:35]=[C:36]([C:33]5[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=5)[N:31]=[C:32]([C:33]5[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=5)[CH:33]=4)[C:9]4[C:14]([C:15]=3[CH:16]=[C:17]2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cc(Br)nc(Br)c4)c3cc21
Reactant: OB(O)c1cccnc1
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: COCCOC
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cc(-c5cccnc5)nc(-c5cccnc5)c4)c3cc21

Procedure:
20 g (38.6 mmol) of 10-(2,6-dibromopyridin-4-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene and 10.4 g of 3-pyridineboronic acid (84.9 mmol) are suspended in 400 ml of ethylene glycol dimethyl ether. 85 ml of a 2 M Na2CO3 solution are added to the reaction mixture. 2.23 g (1.93 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 12 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. Yield: 12 g, 60% of theory.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=1.C([O-])(=O)C.[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:11]([CH3:17])[CH:10]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1c(C)cc(Br)cc1C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Ethyl bromoacetate (0.66 mL) was added to a mixture of 4-bromo-2,6-dimethylphenol (1.0 g) and potassium acetate (1.03 g) in N,N-dimethylformamide (10 mL), and stirred at 80° C. for 3 hrs. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elent:ethyl acetate/n-hexane=1/10) to afford the title compound (1.29 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH2:33][OH:34])[CH:24]=[C:25]([S:27]([F:32])([F:31])([F:30])([F:29])[F:28])[CH:26]=1)([O-])=O>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:18][C:21]2[CH:22]=[C:23]([CH2:33][OH:34])[CH:24]=[C:25]([S:27]([F:32])([F:28])([F:29])([F:30])[F:31])[CH:26]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(CO)cc(S(F)(F)(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: COc1cc(F)ccc1-c1nc(Nc2cc(CO)cc(S(F)(F)(F)(F)F)c2)ncc1F

Procedure:
Intermediate 60.4 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and [3-nitro-5-(pentafluoro-λ6-sulfanyl)phenyl]methanol. The batch was purified by chromatography (DCM/EtOH 9:1) to give the desired product.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:1]1([CH:7]2[CH2:8][C:9](=[O:14])[CH:10]([C:25](=[O:26])[NH:24][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:27])=[CH:16][CH:17]=3)(=[O:22])=[O:23])[C:11](=[O:13])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC(c3ccccc3)CC2=O)cc1

Procedure:
Reaction of equimolar amounts of 5-phenyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-PHENYL-2-[N-p-TOLUENESULFONYLCARBAMOYL]-1,3-CYCLOHEXANEDIONE, m.p. 163.5°-166° C. (corr.).
Reaction SMILES: C(OC([C:6]1[C:7](=[O:26])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C@@H:9]2[C@H:14]([C:15]=1[OH:16])[C@@H:13]1[CH2:17][C@H:10]2[CH2:11][CH2:12]1)=O)C.S(=O)(=O)(O)O>O1CCOCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:8]2[C:7](=[O:26])[CH:6]=[C:15]([OH:16])[C@H:14]3[C@@H:9]2[C@H:10]2[CH2:17][C@@H:13]3[CH2:12][CH2:11]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N(Cc2ccc(F)cc2)C1=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C1C=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 110 °C
Yield: 54 %

Procedure:
(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-ene-5-carboxylic acid ethyl ester was suspended in a 1/1 mixture of 1,4-dioxane and 1.0 M aqueous sulfuric acid solution (200 mL). The mixture was heated to 110° C. for 40 min, and then was allowed to cool to 25° C. The cooled mixture was poured into a separatory funnel and was extracted with ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo to afford a white solid. This material was triturated with hexanes and was collected by filtration, washed with hexanes (2×15 mL) and air-dried to afford the desired product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (2.24 g, 7.80 mmol, 54% over three steps), as a white solid. 1H NMR (major tautomer, 400 MHz, CDCl3) δ: 1.11-1.16 (1H, m), 1.20-1.39 (3H, m), 1.57-1.69 (2H, m), 2.53 (1H, d, J=8.4 Hz), 2.63 (1H, bs), 2.73 (1H, bs), 3.39 (1H, d, J=4.1 Hz), 3.51 (1H, d, J=9.5 Hz), 4.29 (1H, d, J=14.9 Hz), 5.20 (1H, d, J=14.9 Hz), 6.98-7.04 (2H, m), 7.19-7.24 (2H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]=O)=[N:4][N:5]([CH3:7])[CH:6]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[C:3](/[CH:8]=[CH:11]/[C:12]([OH:14])=[O:13])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cn1cc(Br)c(C=O)n1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cn1cc(Br)c(/C=C/C(=O)O)n1

Procedure:
A solution of 4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (1.00 g, 5.29 mmol), malonic acid (825 mg, 7.94 mmol) and piperidine (0.12 mL, 1.2 mmol) in pyridine (0.60 mL) was heated to reflux for 3 hours. The mixture was then poured into 10% HCl and extracted with ethyl acetate (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford (2E)-3-(4-bromo-1-methyl-1H-pyrazol-3-yl)prop-2-enoic acid as a colorless solid.
Reaction SMILES: I[C:2]([F:5])([F:4])[F:3].Br[C:7]1[C:12]([O:13][CH2:14][C:15]2[N:16]([CH3:20])[N:17]=[CH:18][N:19]=2)=[N:11][N:10]2[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:22][N:23]=[C:9]2[CH:8]=1>CN(C=O)C.ClCCl.[Cu]>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[N:10]2[N:11]=[C:12]([O:13][CH2:14][C:15]3[N:16]([CH3:20])[N:17]=[CH:18][N:19]=3)[C:7]([C:2]([F:5])([F:4])[F:3])=[CH:8][C:9]2=[N:23][N:22]=1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1Br
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 6.2 %

Procedure:
Iodotrifluoromethane (2.0 g, 10 mmol) was bubbled through a solution of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.10 g, 0.25 mmol) in dry DMF (2 ml) at room temperature until the required quantity of gas had dissolved. Copper powder (0.16 g, 2.5 mmol) was added and the mixture was stirred in a sealed tube at 80° C. for 18 h. The mixture was cooled, diluted with dichloromethane (50 ml) and filtered. The filtrate was washed with water (50 ml), then dried (Na2SO4), filtered and concentrated. Preparative thin layer chromatography, eluting with 3% methanol-dichloromethane, gave 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3 ylmethoxy)-7-trifluoromethyl-1,2,4-triazolo[4,3-b]pyridazine (0.0061 g, 6%) as a pale yellow solid; m.p. 123-126° C.; 1H NMR (360 MHz, CDCl3) δ3.92 (3H, s), 5.60 (2H, s), 7.31 (1H, dd, J=8 and 8 Hz), 7.40 (1H, dd, J=8 and 8 Hz), 7.56-7.64 (1H, m), 7.86-7.94 (2H, m), 8.50 (1H, s); MS (ES+) m/e 393 [mH]+.
Reaction SMILES: [IH:1].[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:9][C:10](=[NH:13])SC)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24]N.CS>ClC1C=CC=CC=1Cl.C(O)(C)C>[IH:1].[C:2]1([CH:8]([NH:9][C:10]2[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][N:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Reactant: NCCCCN
Agent: CS
Agent: I
Solvent: Clc1ccccc1Cl
Solvent: CC(C)O
Product: c1ccc(C(NC2=NCCCCN2)c2ccccc2)cc1

Procedure:
A suspension of 38.43 grams (0.1 mole) of 1-diphenylmethyl-2-methylthiopseudourea hydroiodide and 8.82 grams (0.1 mole) of 1,4-diaminobutane in 500 milliliters of o-dichlorobenzene was stirred and heated under reflux overnight (about 19 hours). During the heating a reaction took place with the evolution of a basic gas and methyl mercaptan and the formation of a dark oily layer. While the mixture was still warm, the solvent was decanted from the oily layer, diluted with about 1.5 liters of ether and cooled. Scratching of the ether solution caused light colored crystals to form. The dark oily residue was taken up in about 75 milliliters of isopropanol and stored at -23° C., whereupon it came a semisolid gum; the gum was separated from the mother liquor by decantation and redissolved in fresh isopropanol whereupon a dark solid separated. The light colored crystals from the ether and the dark solid from the isopropanol were separately recrystallized using activated carbon and methanol-isopropanol mixture as solvent to obtain white crystals. The white crystals separately obtained were combined and recrystallized from the same solvent pair to obtain a purified 2-diphenylmethylamino-4,5,6,7-tetrahydro-1H-1,3-diazepine hydroiodide product m.p. 215°-217.5° C.
Reaction SMILES: [OH:1][C:2]1([C:19]([F:22])([F:21])[F:20])[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=[C:10]([CH3:18])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Cl.[CH3:24][N:25]([CH3:32])[C:26]([CH:28]1[CH2:31][NH:30][CH2:29]1)=[O:27].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[CH3:24][N:25]([CH3:32])[C:26]([CH:28]1[CH2:31][N:30]([C:15]([C:12]2[CH:11]=[C:10]([CH3:18])[C:9]3[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:2]([OH:1])([C:19]([F:20])([F:21])[F:22])[C:14]=3[CH:13]=2)=[O:17])[CH2:29]1)=[O:27]
Reactant: CN(C)C(=O)C1CNC1
Reactant: Cc1cc(C(=O)O)cc2c1-c1ccccc1C2(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2CC(C(=O)N(C)C)C2)cc2c1-c1ccccc1C2(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To a mixture of an optically active form (0.080 g) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid, azetidine-3-carboxylic acid dimethylamide hydrochloride (0.060 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.065 g), 1-hydroxybenzotriazole hydrate (0.052 g) and dimethylformamide (2 ml) was added triethylamine (0.073 ml), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added ethyl acetate (15 ml), and the mixture was successively washed once with hydrochloric acid, once with water, twice with saturated aqueous sodium hydrogen carbonate and 3 times with water. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was treated with ethyl ether. This slurry was filtered and the obtained solid was dried to give the title compound (0.054 g, 50%).
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:10]([OH:12])=O)=[N:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.C(OCC)(=O)C>[CH2:17]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([C:4]1[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[N:1]=[CH:2][N:3]=1)=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc(C(=O)O)ncn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(O)c1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)ncn1
Temperature: 24 °C
Reaction time: 1 h

Procedure:
Pyrimidine-4,6-dicarboxylic acid is dissolved in dichloromethane (DCM) at 24° C. To the solution is added three equivalents of thionyl chloride. The reaction mixture is stirred at 24° C. for 1 hour. The reaction mixture is concentrated by evaporation of the solvent under reduced pressure to give an oil. The oil is dissolved in ethyl acetate, and three equivalents of benzylamine are added. The reaction mixture is stirred at 24° C. for 3 hours. The solvent is than removed by evaporation under reduced pressure to give an oil. The oil is purified by chromatography over silica gel, eluting with hexane-ethyl acetate (9:1) to 100% ethyl acetate. The fractions shown by thin layer chromatography to contain a single product component are combined and concentrated to dryness under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:14])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([NH:39][CH:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[O:8])=[C:4]([F:14])[CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: CCOc1cc(C(=O)O)c(F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Yield: 87.3 %

Procedure:
4-amino-5-ethoxy-2-fluorobenzoic acid (Intermediate 171; 190 mg, 0.95 mmol), HATU (545 mg, 1.43 mmol) and 4-amino-1-methylpiperidine (Fluorochem; 164 mg, 1.43 mmol) were stirred in DMF (3 mL) and diisopropylethylamine (0.58 ml, 2.86 mmol) added. The mixture was stirred over night and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (3% ammonia in methanol/DCM) to yield the title compound as a white crystalline solid (245 mg, 86%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1coc(N2CC(O)C2)n1)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCOCC3)co2)C1
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
To a solution of 3-hydroxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (370 mg, 1.48 mmol) (obtained as described in Reference Example 72(2)) in methylene chloride (19 ml) were added methanesulfonyl chloride (344 μl, 4.44 mmol) and triethylamine (622 μl, 4.44 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium chloride, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (93:7) as the eluant to afford 3-methanesulfonyloxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (404 mg, yield 100%) as pale yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61]C(=O)C)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.COC(=O)[C@@H](NC([C@@H]1CC2C=C3OC[C@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)OC3=CC=2CN1S(C1SC(N)=NC=1C)(=O)=O)=O)CC1C=CC(C2C=CN=C(C)C=2C)=CC=1>>[NH2:61][C:59]1[S:60][C:56]([S:53]([N:24]2[C@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=4[CH3:19])=[CH:10][CH:11]=3)[C:3]([OH:66])=[O:2])=[O:22])[CH2:32][C:31]3[CH:30]=[C:29]4[O:33][CH2:34][C@H:35]([C:37]5[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]6[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=6)=[CH:39][CH:38]=5)[O:36][C:28]4=[CH:27][C:26]=3[CH2:25]2)(=[O:54])=[O:55])=[C:57]([CH3:65])[N:58]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: Cc1nc(N)sc1S(=O)(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-2-({(3S,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)phenyl]-propionic acid methyl ester was converted to (S)-2-({(3S,8S)-7-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester according to General Procedure N. This ester (20 mg) was hydrolyzed according to General Procedure B to give the title compound (17 mg). LCMS (m/z): 915.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)=[N+:2]=[N-:3].[C:12]([O:16][CH3:17])(=[O:15])[C:13]#[CH:14]>C1(C)C=CC=CC=1>[Br:11][C:7]1[N:6]=[C:5]([CH2:4][N:1]2[C:13]([C:12]([O:16][CH3:17])=[O:15])=[CH:14][N:3]=[N:2]2)[CH:10]=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=NCc1cccc(Br)n1
Reactant: C#CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1cnnn1Cc1cccc(Br)n1

Procedure:
2-(Azidomethyl)-6-bromopyridine (Example 470 Step 1) (600 mg, 2.82 mmol) and methyl propiolate (355 μL, 4.22 mmol) were combined in toluene (10 mL) and stirred at reflux overnight. The solvent was evaporated, and the residue was purified by flash chromatography (20-100% EtOAc/hexanes), whereby good separation of the two regioisomeric products was achieved. TLC, LC/MS, and 1H NMR analysis confirmed that the first spot (less polar, higher Rf) corresponded to the desired regioisomer. The title compound was isolated as a colorless oil.