Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([N:11]2[C@@H:17]([CH3:18])[C@H:16]([NH2:19])[C:15](=[O:20])[NH:14][C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]2=3)=[O:10])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[C:27]([O:31][C:32]([N:34]([CH3:40])[C@@H:35]([CH3:39])[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:27]([O:31][C:32](=[O:33])[N:34]([C@H:35]([C:36](=[O:37])[NH:19][C@H:16]1[C@H:17]([CH3:18])[N:11]([C:9](=[O:10])[C:8]2[CH:25]=[CH:26][C:5]([C:2](=[O:4])[CH3:3])=[CH:6][CH:7]=2)[C:12]2[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=2[NH:14][C:15]1=[O:20])[CH3:39])[CH3:40])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(=O)c1ccc(C(=O)N2c3ccccc3NC(=O)[C@@H](N)[C@@H]2C)cc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(C(=O)N2c3ccccc3NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]2C)cc1
Reaction time: 2 h

Procedure:
To a solution of (3S,4S)-5-(4-acetyl-benzoyl)-3-amino-4-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride (0.39 g, 1.03 mmol) in N,N-dimethylformamide (6.0 mL) at 0° C. was added (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (0.23 g, 1.13 mmol), N,N-diisopropylethylamine (0.72 mL, 4.12 mmol) and 0-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (0.43 g, 1.13 mmol), the reaction was stirred for 2 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×40 mL). The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (1×20 mL), water (1×25 mL), dried over sodium sulfate, filtered through a plug of silica gel and concentrated in vacuo to give {(S)-1-[(2S,3S)-1-(4-acetyl-benzoyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester which was used in the subsequent step without further purification (0.53 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.O.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Yield: 40.9 %

Procedure:
To a solution of ethyl 4-(4-chlorobenzyl)-2-morpholinothiazole-5-carboxylate (3.44 g, 9.38 mmol) in THF (53 mL) was added water (26 mL) and 1 N LiOH (28.2 mL, 28.2 mmol) and the resulting mixture was heated to 40 degrees overnight. The reaction was cooled, acidified with 1 N HCl, and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate layers were dried over MgSO4, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (methanol/DCM=0/100→20/80). Recrystallization from ethyl acetate/hexanes gave 1.3 g of the title compound as a white solid. (41% yield). LC/MS (FA) ES+ 339. 1H NMR (400 MHz, DMSO-d6) δ: 12.74 (s, 1H), 7.33-7.30 (m, 2H), 7.26-7.23 (m, 2H), 4.21 (s, 2H), 3.67-3.64 (m, 4H), 3.42-3.40 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=O)[CH3:2].[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=[C:21]1[S:17][C:18](=[O:23])[NH:19][C:20]1=[O:22])[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCOC(=O)COc1ccc(Br)cc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(Br)cc1C=C1SC(=O)NC1=O
Temperature: 120 °C
Yield: 70.8 %

Procedure:
4-Bromo-2-formylphenoxyacetic acid ethyl ester (2.47 g, 8.7 mmol), 2,4-thiazolidinedione (1.13 g (90%), 8.7 mmol), and ammonium acetate (671 mg, 8.7 mmol) was mixed with toluene (9 mL) in a sealed vial and heated by microwaves to 120° C. for 600 s. After cooling to room temperature and scratching the inside of the glass, the product precipitated out. The precipitate was filtered and washed with toluene to give the title compound as a yellow solid (2.38 g, 71%).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.CCOCC>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([N:20]2[CH2:21][CH2:22][C:17]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:18][CH2:19]2)=[CH:3][CH:4]=1)[CH3:10]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
A mixture of 50 g (0.349 mol) of ethyl p-fluorobenzoate, 185 g (1.29 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 73 g (0.5282 mol) of K2CO3, and 400 ml of acetonitrile is stirred at 90°-100° C. for three days. The reaction mixture is allowed to cool to ambient temperature, diluted with water, and extracted with methylene chloride. The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pasty solid. Trituration with ether furnishes 31 g (23%) of title compound: IR (KBr) 1695 and 1610 cm-1 ; NMR (CDCl3) δ 7.98 (d, 2H), 6.96 (m, 2H), 4.36 (q, 2H), 4.02 (s, 4H), 3.58-3.48 (m, 4H), 1.92-1.80 (m, 4H), and 1.38 (t, 3H).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[NH2:8][C:9]1[CH:10]=[C:11]([O:15][CH3:16])[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([NH:8][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(=O)Cl
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.9 ml of methyl chlorooxalate in 10 ml of methylene chloride is added dropwise to a solution of 2.5 g of 3-aminoanisole and 1.5 ml of pyridine in 40 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 3 hours, the mixture is poured onto water and extracted with methylene chloride. The extracts are dried over sodium sulfate and evaporated and the residue is crystallised from ether/hexane. Methyl N-(3-methoxyphenyl)-oxamate is obtained.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16].O>C(O)(=O)C>[F:16][C:10]1[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5](=[O:7])[CH3:6]
Reactant: Nc1ccc(O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (1.3 ml, 13.8 mmol) was added dropwise to a solution of 4-amino-3-fluorophenol (1.0 g, 7.9 mmol) in acetic acid (25 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h and water (2 ml) was added and the stirring was continued for 30 minutes at room temperature. The mixture was evaporated to dryness in vacuo. The yield of the crude product was 1.3 g (100%) and it was used without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[S-:13][C:14]#[N:15].[K+].BrBr.C>C(O)(=O)C>[F:12][C:2]([F:11])([F:1])[S:3][C:4]1[CH:10]=[CH:9][C:7]2[N:8]=[C:14]([NH2:15])[S:13][C:6]=2[CH:5]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(SC(F)(F)F)cc2s1
Temperature: 10 °C
Yield: 58.1 %

Procedure:
The procedure is as in Example 1, starting with 4-trifluoromethylthioaniline (3.85 g), potassium thiocyanate (7 g) and bromine (1 cc) in acetic acid (30 cc). The light brown crude product is taken up with acetic acid (250 cc) at 80° C. and the solution obtained is treated with decolorizing charcoal (0.4 g) and filtered; the filtrate is cooled to about 10° C., diluted with water (150 cc) and alkalinized with 28% strength ammonia solution (400 cc). The precipitate obtained is drained, dried in the air and recrystallized in a mixture of cyclohexane (250 cc) and isopropyl ether (30 cc). 6-Trifluoromethylthio-2-benzothiazolamine (2.9 g), m.p. 155° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.C1(C(Cl)=[O:28])CC1.[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=CC=1>>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:36]([CH2:30][CH:35]1[CH2:34][CH2:33]1)=[O:28]
Reactant: CCCOCc1ccc(OCCN)c(Cl)c1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Product: CCCOCc1ccc(OCCNC(=O)CC2CC2)c(Cl)c1
Reaction time: 2 h

Procedure:
To a mixture of 162 g (0.667 mol) of 2-(2-chloro-4-propoxymethylphenoxy)ethylamine, 81 g (0.80 mol) of triethylamine and 8 liter of toluene, there is added dropwise a solution of 70 g (0.67 mol) of cyclopropane carbonyl chloride in 2 liter of toluene with stirring at a temperature of from 5° C. to 10° C. After 2 hours, the reaction mixture is stirred at a room temperature for 15 hours. After the reaction is completed, the resultant mixture is washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give N-[2-(2-chloro-4-propoxymethylphenoxy)ethyl]-cyclopropane carboxyamide.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][C@H:11]2[CH2:16][C@@H:15]([CH3:17])[CH2:14][CH2:13][C@@H:12]2[CH:18]([CH3:20])[CH3:19])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C(O)C>[F:31][C@@:7]1([C:8]([O:10][C@H:11]2[CH2:16][C@@H:15]([CH3:17])[CH2:14][CH2:13][C@@H:12]2[CH:18]([CH3:20])[CH3:19])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:1]
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)C1CCCNC1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: CCO
Product: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)[C@]1(F)CCCNC1=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
(1S,2R,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-oxo-3-piperidinecarboxylate (1 wt) is dissolved in ethanol (1.5 vol) and N-fluorobenzenesulfonimide (NFSI) (1.07 wt) added, followed by [(S)-BINAP]Pd(CH3CN)2(OTf)2 (0.038 wt) at 20° C. Residual NFSI and catalyst were washed in with ethanol (3 vol). The jacket is cooled to 0° C. and 2,6-lutidine (0.21 vol) charged slowly, maintaining the temperature below 20° C. The jacket temperature is then raised to 20° C. The reaction mixture is stirred for 24 h, cooled to 0° C. and stirred for an additional 2 h. The solids are isolated by filtration, washing with ethanol (3 vol) and dried under vacuum at 40° C. The dried crude solid is charged to a reactor, and dichloromethane (5 vol) added. The dichloromethane phase is washed sequentially with 2M aqueous NaOH (3 vol), water (3 vol), 5% w/w aqueous HCl (3 vol) and water (3 vol). The dichloromethane extract is transferred to a rotary evaporator and solvent swapped with n-heptane under reduced pressure to give a mobile slurry and a final volume of ca 11 vol. The product is isolated by filtration, washed with heptane (3 vol) and dried under vacuum at 40° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6]C(C#N)=[CH:8][CH:9]=2)[CH2:4][NH:3]1.BrCC1C=C(C#N)C=CC=1C(OC)=O.N.CC[O:30][C:31]([CH3:33])=[O:32]>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:33]([C:31]([OH:30])=[O:32])=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc2c(c1)CNC2=O
Agent: COC(=O)c1ccc(C#N)cc1CBr
Agent: N
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CNC2=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
1-oxoisoindoline-5-carbonitrile. To methyl 2-(bromomethyl)-4-cyanobenzoate (0.3 g, 1.18 mmol) in a sealed tube, was added 7N NH3 in MeOH (10 mL). The tube was then sealed and the reaction stirred at 40° C. for 18 h. The reaction progress was monitored by TLC (90% EtOAc in hexanes). The reaction was filtered to give the title compound as a white solid. 1H NMR (400MHz, DMSO-d6): δ 8.95 (s, 1H), 8.1 (s, 1H), 7.9 (d, J=8.0 Hz, 1H), 7.8 (d, J=8.0 Hz, 1H), 4.4 (s, 2H).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=3)[N:14]=[C:13]([C:37]#[N:38])[C:12]=2[N:11]=[N:10]1.Cl[CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42].CCN(C(C)C)C(C)C>CO>[CH3:44][N:43]([CH3:45])[C:41](=[O:42])[CH2:40][N:30]1[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([C:15]3[N:14]=[C:13]([C:37]#[N:38])[C:12]4[N:11]=[N:10][N:9]([CH3:8])[C:17]=4[CH:16]=3)=[CH:19][C:20]=2[C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: CN(C)C(=O)CCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C)C(=O)CN1CCC(CCOc2ccc(-c3cc4c(nnn4C)c(C#N)n3)cc2C(F)(F)F)CC1
Temperature: 90 °C

Procedure:
To 1-methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile TFA salt (150 mg) in methanol (2 ml) was added 2-chloro-N,N-dimethylacetamide (67 mg) and DIPEA (0.23 ml). The mixture was heated at 90° C. for 40 minutes, then purified by basic HPLC to give 6-(4-(2-(1-(2-dimethylamino-2-oxoethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile which was then converted to HCl salt by lypholising with 1M hydrochloric acid (1 ml) (130 mg).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=1>CS(C)=O>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[N:11]=1
Reactant: CC(C)(C)CO
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)COc1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
A solution of neopentyl alcohol (1.065 mL, 9.81 mmol) in DMSO (82 mL) was cooled to 0° C. NaH (60% in mineral oil; 0.490 g, 12.26 mmol) were added in one portion, the reaction mixture was warmed to rt and stirred for 20 minutes. 2,6-Difluoropyridine (0.941 mL, 8.175 mmol) was added and the reaction mixture was stirred at overnight. The reaction mixture was quenched with aqueous, saturated ammonium chloride solution, diluted with water and EtOAc. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford 2-fluoro-6-(neopentyloxy)pyridine (1.48 g, 8.08 mmol) as a colorless liquid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:35][CH2:36]O)[C:6]([C:8]2[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:9]=2)=[O:7])[CH2:3][CH2:2]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C.O>ClCCl>[CH2:15]([O:14][C:13]1[C:12](=[O:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)[N:9]2[CH2:36][CH2:35][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6](=[O:7])[C:8]=12)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccn4)CCCC3)n2CCN1CC1CC1
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacidcyclopropylmethyl-(2-hydroxyethyl)-amide (447) (80 mg, 0.159 mmol), in dichloromethane (5 mL), TPP (146.13 mg, 0.558 mmol) and diisopropyl azodicarboxylate (0.094 mL, 0.478 mmol) were added and stirring was continued for 1 h at room temperature while silica thin layer chromatography was performed (100% ethyl acetate; Rf=0.2). After completion of the reaction, water (5 mL) was added and the mixture was extracted with dichloromethane (2×30 mL) and the organic phase was dried and concentrated. The resulting crude product was purified by normal silica gel (100-200) column chromatography using 60-70% ethyl acetate in hexane as a gradient polarity mobile phase to get 9-benzyloxy-2-cyclopropylmethyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (448) (45.0 mg, 58%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH:9]=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1>C1(C)C=CC=CC=1.NC1SC=CN=1>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[N:16]=[CH:9][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C=O)c1ccccc1
Reactant: Nc1nccs1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C=Nc1nccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
To a stirred suspension of N-methylformanilide (67.6 g; 0.50 mole), toluene (25 g) and 2-aminothiazole (2.0 g; 0.02 mole) was added phosphorus oxychloride (45.8 mL; 0.50 mole) over 15 minutes. The temperature was maintained below 45° C. during this addition. Stirring was continued for 10 minutes, after which time a hot solution of 2-aminothiazole (48.0 g; 0.48 mole) in toluene (250 g) was added at 60°-65° C. over 45 minutes. The reaction was allowed to cool to room temperature with stirring and was quenched by dropwise addition into a mixture of 30% sodium hydroxide (325 g) and ice (300 g). The organic phase was washed with a mixture of water (100 g), sodium chloride (10 g), and sodium bicarbonate (7.5 g), followed by a saturated solution of sodium chloride (125 g); the resultant organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 98.3 g of crude product. Vacuum distillation gave pure 1 (60.0 g; 55.3%) as a yellow oil: bp 177° C. @ 0.5 mm Hg. 1H-NMR (CDCl3) 8.72 (s, 1H), 7.4-6.9 (m, 7H), 3.50 (S, 3H); IR(neat) 3075, 2950, 1615, 1580, 1490, 1345, 1310, 1120; MS (m/e) 217 (M+, base).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:44]([NH2:49])[CH2:45][CH2:46][CH:47]=[CH2:48].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:49][CH2:44][CH2:45][CH2:46][CH:47]=[CH2:48])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCCN
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (100 mg) in dichloromethane (0.30 mL) at room temperature was added pent-4-en-1-amine hydrochloride (51 mg) and diisopropylethylamine (97 μL), and the resulting solution was stirred at room temperature for 2 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used in Step B without purification. retention time: 2.14 min (method A). MS (ESI) (M+H)+ 703.24.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:2]1=2.[CH3:12][C:13]([CH3:15])=[O:14].[OH-].[Na+].Cl>C(Cl)Cl.O>[O:1]1[C:2]2[CH:9]=[CH:8][C:7](/[CH:10]=[CH:12]/[C:13](=[O:14])[CH3:15])=[CH:6][C:3]=2[CH2:4][CH2:5]1
Reactant: CC(C)=O
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)/C=C/c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
2,3-Dihydrobenzo[b]furan-5-carboxaldehyde (Aldrich Chemicals) (2 g, 13.5 mmol), acetone (2.73 ml, 37.1 mmol), water (1.35 ml) and 10% NaOH (aq.) (0.34 ml) were added together and the whole stirred at room temperature for 16 h. The yellow solid was redissolved in approx. 15 ml DCM and 2N HCl added to achieve a solution of pH 2. Water (10 ml) was added and the organic layer was extracted with DCM (2×20 ml). The aqueous layers were separated, and re-extracted with DCM (2×15 ml). The combined organics were dried (MgSO4) and concentrated in vacuo to a yellow solid which was purified by column chromatography using 15-30% EtOAc in pentane as eluant to provide the title product (2.13 g, 84%); 1HNMR (400 MHz, CDCl3) δ: 2.3 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 6.5 (d, 1H), 6.75 (d, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.45 (d, 1H); LRMS: M+H, 189. (ES+).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:18]([O:20][CH2:21]C)=[O:19])[CH:10]=[C:11]([CH:17]=1)[C:12]([O:14]CC)=[O:13])(=[O:4])=[O:3].[OH-].[Na+]>C1COCC1.CO.O>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[C:11]([CH:17]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)[C:12]([OH:14])=[O:13])=[O:19]
Reactant: CCOC(=O)c1cc(CNS(C)(=O)=O)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(CNS(C)(=O)=O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a solution of 901 mg (2.73 mmol) of diethyl 5-(methylsulfonamidomethyl)isophthalate in 10 mL of THF and 10 mL of MeOH was added 115 mg of NaOH in 2.7 mL of H2O. After the solution was stirred at r.t. for 50 h, the solution was concentrated, and H2O and CHCl3 were added. The aqueous layer was acidified to pH=1-2 with 1N HCl and extracted with the extract of (40 mL of CHCl3: 5 mL of MeOH, and 5 mL of H2O) several times. The combined extracts were dried over Na2SO4, filtered, and concentrated to give crude 3-(methoxycarbonyl)-5-(methylsulfonamidomethyl)benzoic acid which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([NH:12][C@H:13]2[C@@H:19]([OH:20])[CH2:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([NH:12][C@H:13]2[C@H:19]([O:20][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:43][CH:42]=3)[CH2:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(OC(C)(C)C)cc2)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
262 mg of diethyl azadicarboxylate in 2 ml of tetrahydrofuran were added while stirring to 407 mg of the compound prepared in Example 16, 253 mg of 4-(tert-butoxy)-benzoic acid and 394 g of triphenylphosphine in 8 ml of tetrahydrofuran. After stirring at 50° C. for 4hours, the solvent was removed under reduced pressure and the residue was taken up in 20 ml of cyclohexane and washed once with 20 ml of water and twice with 10 ml of 70% methanol/water each time. The aqueous-alcoholic phase was extracted twice with 10 ml of cyclohexane each time. The combined cyclohexane phases were dried over sodium sulphate and the solvent was removed under reduced pressure. The residual viscous oil was dissolved in 10 ml of hot heptane, seeded with pure end product and left to crystallize at room temperature for 18 hours and yielded 241 mg of tert-butyl (3R,4R)-3-(4-tert-butoxy-benzoylamino)-4-(4-tert-butoxy-benzoyloxy)-azepan-1-carboxylate of melting point 126-128° C. This compound can be reacted further as in Example 12b.