Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:9]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[CH:20]=[CH:19][C:10]([C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:8]=2)[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COc1c(C)c(Cc2ccc(C(=O)N3CCCCC3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCCCC3)c(-c3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
N-[4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoyl]piperidine (70 mg, 0.1428 mmol) was dissolved in a mixed solvent of acetonitrile (6 ml) and water (2 ml), then CAN (231 mg, 0.4293 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (26 mg, 0.0565 mmol, 40%).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:40])C(=O)C1>C(Cl)Cl>[Br:40][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(CO)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)cc1C

Procedure:
410 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M and purified by ISCO Combi-Flash to afford 4-(methoxycarbonyl)-3-methylbenzoic acid. 255 mg of 4-(methoxycarbonyl)-3-methylbenzoic acid was cooled to 0° C. in 2 mL of THF before a solution of 2.6 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction was re-cooled to 0° C. and another 2.6 mL of BH3-THF was added dropwise before the ice bath was removed. Upon completion, the reaction was re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted 2 times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(hydroxymethyl)-2-methylbenzoate. 220 mg of methyl 4-(hydroxymethyl)-2-methylbenzoate was cooled to 0° C. in 5 mL of DCM before adding 260 mg of Triphenylphosphine and 395 mg of NBS. The reaction was concentrated and directly purified via ISCO Combi-Flash to give pure methyl 4-(bromomethyl)-2-methylbenzoate. 255 mg of methyl 4-(bromomethyl)-2-methylbenzoate was reacted via Procedure O to give methyl 2-methyl-4-(methylsulfonylmethyl)benzoate. 250 mg of methyl 2-methyl-4-(methylsulfonylmethyl)benzoate was then hydrolyzed upon heating to 45° C. for 1 hour via Procedure M to give 2-methyl-4-(methylsulfonylmethyl)benzoic acid. 202 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonylmethyl)benzamide. MS (Q1) 415 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[CH:13]([Sn](C=C)(C=C)C=C)=[CH2:14].C(OCC)(=O)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH:13]=[CH2:14])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Reactant: C=C[Sn](C=C)(C=C)C=C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cc(C(C)O)nc(Cl)c1O
Temperature: 50 °C
Yield: 70.1 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-iodo-6-(1-hydroxyethyl)-pyridine (3.6 g, 12 mmol) in 36 mL of N,N-dimethylformamide is treated with bis(triphenylphosphine)-palladium dichloride (632 mg, 0.9 mmol) and tetravinyltin (2.7 mL, 15 mmol) and heated at 50° C. for 24 h and at room temperature for 40 h. The mixture is poured into 300 mL of ethyl acetate, filtered through a celite pad and the filtrate is washed with 4×50 mL of saturated sodium chloride. The organics are concentrated in vacuo and the crude material is chromatographed over 150 g of silica gel (230-400 mesh), eluting with 25% ethyl acetate/hexanes to provide 1.68 g (70%) of 2-chloro-3-hydroxy-4-vinyl-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH:21]C(=O)C)=[N:18][C:17]=3[CH3:25])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C.Cl>[N:1]1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH2:21])=[N:18][C:17]=3[CH3:25])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1

Procedure:
A stirred solution of N-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 80) (0.80 g, 2.13 mmol) in ethanol (15 ml) and 7M aqueous HCl (20 ml) is heated at 90° C. for 2 hours. The solution is allowed to cool, brought to pH 10 by addition of aqueous NaOH and extracted with n-butanol. The organic extract is dried (MgSO4), the solvent is removed and the residue is triturated with ethanol to give the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[Sn](Cl)(Cl)Cl.[CH2:14]=[O:15].Cl>C1(C)C=CC=CC=1.O>[OH:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15]
Reactant: C=O
Reactant: Cc1cccc(O)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C=O)c(O)c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
To a stirred solution of 3-methyl-phenol (1 g, 9.2 mmol) in toluene (5 ml) at room temperature under nitrogen was added SnCl4 (241 mg, 0.92 mmol) and tri-nbutylamine (0.6 ml, 2.77 mmol). After 20 min, paraformaldehyde (611 mg, 20.3 mmol) was added and the whole stirred at 100° C. for 16 h. The reaction mixture was diluted with water (20 ml) and acidified with 2N HCl to pH 2. The solution was extracted with ether (25 ml), washed with brine (20 ml), dried (MgSO4) filtered and evaporated to a brown oil. This oil was purified by column chromatography using 5% EtOAc in pentane as eluant to provide the title product (319 mg, 25%); 1HNMR (400 MHz, CDCl3) δ: 2.3 (s, 3H), 6.75 (m, 2H), 7.35 (d, 1H), 9.75 (s, 1H), 11.00 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][NH:5][N:4]=1)=[O:2].[CH2:8]=[O:9].C(N(CC)CC)C>CC(C)=O>[OH:9][CH2:8][N:5]1[CH:6]=[CH:7][C:3]([CH:1]=[O:2])=[N:4]1
Reactant: C=O
Reactant: O=Cc1cc[nH]n1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=Cc1ccn(CO)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
The mixture of 0.96 g of 3-formyl-1H-pyrazole, 0.60 g of paraformaldehyde and 0.3 ml of triethylamine was stirred at 100° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure to obtain 1.21 g of 1-(hydroxymethyl)-3-formyl-1H-pyrazole. The crude product was used for next process without purification.
Reaction SMILES: NCCN(C)CCN.N[C:10]1[C:11]([C:18]([N:20]2C=CN=C2)=[O:19])=[N:12][C:13]([Cl:17])=[C:14](N)[N:15]=1>O1CCCC1>[Cl:17][C:13]1[N:12]=[C:11]([C:18]([NH2:20])=[O:19])[CH:10]=[N:15][CH:14]=1
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Cl
Agent: CN(CCN)CCN
Solvent: C1CCOC1
Product: NC(=O)c1cncc(Cl)n1

Procedure:
To a stirred solution of 84.0 g (0.744 mol) of N-(2-aminoethyl)-N-methyl-1,2-ethanediamine (see U.S. Pat. No. 3,201,472 for an example of how to obtain this material) in 700 ml of tetrahydrofuran was added 88.6 g (0.372 mol) of 1-(3,5-diamino-6-chloropyrazinoyl)imidazole in 10 portions over 1.5 hours. After 1 hour at ambient temperature the reaction mixture was filtered and concentrated to 300 ml. The solution was added dropwise to 1.4 liters of ether with vigorous stirring. The solid was filtered, washed with ether and dried. There was obtained 74.3 g (0.258 mol, 70%) of 3,5-diamino-N-2-[(2-aminoethyl)methylamino]ethyl]-6-chloropyrazinecarboxamide. A sample was filtered through a pad of silica gel and eluted with 5:95 (v/v) methanol:methylene chloride saturated wth ammonia gas; mp 138°-139.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH2:19][CH2:18][CH2:17][CH:16]4[C:11]3([CH2:12][CH2:13][NH:14][CH2:15]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:20](Br)[CH:21]=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>>[CH2:22]([N:14]1[CH2:13][CH2:12][C:11]23[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[O:9][CH:10]2[CH2:19][CH2:18][CH2:17][CH:16]3[CH2:15]1)[CH:21]=[CH2:20]
Reactant: COc1cccc2c1OC1CCCC3CNCCC231
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCN1CCC23c4cccc(OC)c4OC2CCCC3C1

Procedure:
Thus, 9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline, when treated with allyl bromide in the presence of a base such as potassium carbonate, gives 3-allyl-9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (R1 =CH2CH=CH2 ; R2 =MeO; R3, R4, R5 =H). Also, thienyl or furyl carbonyl chlorides followed by reduction with lithium aluminum hydride give 3-(2-thienylmethyl or 2-furylmethyl-9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline ##STR81##
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][C:12]([OH:14])=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([CH2:11][C:12]([Cl:3])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1

Procedure:
An amount described in Table 1 of thionyl chloride was added to an amount described in Table 1 of a derivative of phenylacetic acid and heated under reflux for one to four hours. Excess of thionyl chloride was distilled out under reduced pressure to obtain a derivative of phenylacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19](O)=[O:20])[C:5](=[O:18])[NH:6][C:7]=1[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]([N:36]([CH2:37][CH3:38])[CH2:34][CH3:35])=[O:20])[C:5](=[O:18])[NH:6][C:7]=1[C:8]([F:16])([F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11]
Reactant: CCNCC
Reactant: O=C(O)c1cc(Cl)c(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cc(Cl)c(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolution of 355 mg (1.04 mmol) of 5-chloro-6-(heptafluoropropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid in 30 ml tetrahydrofuran and addition of 337 mg (2.08 mmol) of N,N-carbonyldiimidazole, the mixture was stirred initially at room temperature for 30 min and then under reflux for 30 min. 152 mg (0.22 ml, 2.08 mmol) of diethylamine were then added, and the mixture was heated under reflux for a further 2 h. The solution was evaporated to dryness and then taken up in dichloromethane, washed with 1N hydrochloric acid and water, dried and concentrated. This gave 300 mg (72% of theory) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]=[C:11]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:13]=[CH:12]2)[CH:9]=1)[C:5]#[N:6].Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CC(CC)CO>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11](=[N:10][C:8]3[CH:7]=[C:4]([CH:3]=[C:2]([NH:1][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:9]=3)[C:5]#[N:6])[CH:12]=[CH:13][N:14]2[CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1
Reactant: N#Cc1cc(N)cc(N=c2ccn(CCN3CCCCC3)c3cc(Cl)ccc23)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)CO
Product: N#Cc1cc(N=c2ccn(CCN3CCCCC3)c3cc(Cl)ccc23)cc(NCCN2CCCCC2)c1
Yield: 16.9 %

Procedure:
3-amino-5-({7-chloro-1-[2-(piperidin-1-yl)ethyl]-1,4-dihydroquinolin-4-ylidene}amino)benzonitrile prepared from example 21 (132 mg, 0.32 mmol), 1-(2-chloroethyl)piperidine hydrochloride (182 mg, 3 eq) and DIEA (0.51 mL, 9.3 eq) were refluxed in 15 mL of 2-methylbutan-1-ol for 10 h. The reaction mixture was then evaporated and the residue and was purified by preparative thin-layer chromatography (DCM/MeOH/NH4OH//95/5/1) to yield expected compound as a yellow oil (28 mg, 17% yield). m/z (ESI) 517.5 [M+H]+.
Reaction SMILES: C([NH:3][CH2:4][C:5](CNC1C=CC=C2C=1C=NN2C1C=CC=CC=1)(O)[C:6](F)(F)F)C.C(N)CC.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([NH:48][CH2:49][C:50]4([C:53]([F:56])([F:55])[F:54])[CH2:52][O:51]4)[C:42]=3[CH:41]=[N:40]2)=[CH:35][CH:34]=1>>[F:54][C:53]([F:56])([F:55])[C:50]([CH2:52][NH:3][CH2:4][CH2:5][CH3:6])([OH:51])[CH2:49][NH:48][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]2[C:42]=1[CH:41]=[N:40][N:39]2[C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=1
Reactant: Fc1ccc(-n2ncc3c(NCC4(C(F)(F)F)CO4)cccc32)cc1
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Solvent: CCCN
Product: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 15 from n-propylamine and 1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine.
Reaction SMILES: Cl.[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](Br)[CH3:31])=[CH:26][CH:25]=1>CN(C)C=O.O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([N:13]2[CH2:12][CH2:11][C:9]3([O:8][CH2:7][C:6](=[O:16])[N:5]([CH:2]4[CH2:4][CH2:3]4)[CH2:10]3)[CH2:15][CH2:14]2)[CH3:31])=[CH:26][CH:25]=1
Reactant: CC(Br)c1ccc(Br)cc1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(Br)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.341 mmol) in N,N-dimethylformamide (1.5 mL) was treated with potassium carbonate (0.682 mmol) and 1-bromo-4-(1-bromoethyl)benzene (0.341 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with water (50 mL) and was extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a brown residue (117 mg, 87%). MS(ES)+ m/e 392.9/394.7 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:42][O:43][C:44]([C:46]1[N:47]=[C:48]([NH:51][C:52](=[O:62])[C@@H:53]([NH2:61])[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:49][CH:50]=1)=[O:45]>O1CCCC1>[CH3:42][O:43][C:44]([C:46]1[N:47]=[C:48]([NH:51][C:52](=[O:62])[C@@H:53]([NH:61][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=2)[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:49][CH:50]=1)=[O:45]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Reactant: COCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCOc1ccc(C(NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2nc(C(=O)OC)cs2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(R)-tert-butoxycarbonylamino-{4-[2-(methoxy)-ethoxy]-phenyl}-acetic acid (0.6 g, 1.84 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.32 g, 1.84 mmol) and N-methylmorpholine (0.19 g, 1.84 mmol) in anhydrous tetrahydrofuran (20 mL) were stirred at room temperature for 4 hours. Then a solution of 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (0.56 g, 1.84 mmol) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred at room temperature for 20 hours. The mixture was filtered though a short pad of silica gel and the residual material eluted from the silica gel with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography over silica gel eluted with 1:1 ethyl acetate/hexanes to give 2-((S)-2-{2-tert-butoxycarbonylamino-2-[4-(2-methoxy-ethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a mixture of two epimers (R/S=85:15) (0.21 g,
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:17]I>C1COCC1>[CH3:17][O:3][CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To the sodium hydride (48 mg, 2 mmol) in THF (5 ml) at −78° C., (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate was slowly added. After 15 min, methyl iodide (0.124 ml, 2 mmol) was added and the reaction mixture was slowly allowed to come to rt overnight. Then the reaction mixture was quenched with MeOH and diluted with water (15 ml). Aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over sodium sulfate and then filtered. The solvent was removed under vacuum, and the crude product was purified by silica gel chromatography (eluting with 15% EtOAc/hexanes) to afford (R)-tert-butyl 2-(methoxymethyl)pyrrolidine-1-carboxylate in 80% yield. (R)-2-(methoxymethyl)pyrrolidine was generated by removal of the Boc protecting group by treatment with trifluoroacetic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([CH2:24]O)[CH:17]=[N:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].S(Cl)([Cl:28])=O>ClCCl>[Cl:28][CH2:24][C:18]1[CH:17]=[N:16][N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[C:19]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=S(Cl)Cl
Reactant: CCc1cnc(N2CCC(n3ncc(CO)c3C(F)(F)F)CC2)nc1
Solvent: ClCCl
Product: CCc1cnc(N2CCC(n3ncc(CCl)c3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution (1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.13 g, 0.366 mmol) in dichloromethane (3 mL) was added thionyl chloride (1.2 mL) and the solution was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and the crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=O)[NH:11][N:10]=1.P(Br)(Br)([Br:25])=O>C(#N)C>[Br:25][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:9]([CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:22])=[N:10][N:11]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Solvent: CC#N
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Br)c2c1
Yield: 82.5 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-2H-phthalazin-1-one (10 g, 25.5 mmoles), prepared as described in example 38, in acetonitrile (300 ml), was added with POBr3 (22 g, 76.5 mmoles) and the mixture was refluxed. After 1 night under reflux and another to stand, the solution was concentrated, taken up in water, cooled in ice and alkalinised with concentrated NaOH. There was extracted three times with CH2Cl2 and the organic phases were discoloured with charcoal, anhydrified and concentrated. The crude was purified by flash chromatography (eluent: petrolatum/ethyl acetate 8:2, then 6:4) to give 8.4 g of the title compound (yield: 82%).
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH2:1]([NH:9][C:10](=[O:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:12][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(NCCc1ccccc1)C(O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NCCc1ccccc1)C(OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
N-phenethyl mandelic amide 51 g is dissolved in 200 ml of pyridine, and benzoyl chloride 42 ml is added with stirring. Exothermic benzoylation takes place immediately and the reaction mixture is cooled externally with a cold water bath. The stirring is continued for 5 hours, and the reaction mixture is mixed with 1 liter of ice water. The product is extracted with 250 ml of chloroform, washed with 300 ml of 5% sodium bicarbonate, followed by 300 ml of 0.5N HCL and is dried over anhydrous sodium sulfate. On evaporation of chloroform a crystalline product is obtained. The crystals are washed with n-hexane and dried. The yield is 85 g.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)([CH3:3])[CH3:2].O.[O:18]1CCOCC1>O1CCOCC1>[CH:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:18])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1OC(C)C)CCCC2
Reactant: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1OC(C)C)CCCC2=O
Reaction time: 12 h
Yield: 71 %

Procedure:
34 (120 mg, 0.55 mmol) was weighed in a 100 mL round bottom flask and a solution of 5 mL of water:dioxane (5:95) was added and the reaction was set up under nitrogen. A solution of 2,4-dichloro-5,6-dicyanobenzoquinone (0.25 g, 1.09 mmol) dissolved in 5 mL of dioxane was added dropwise to the reaction mixture. The reaction mixture was stirred for 12 h. The solid separated was filtered and washed with ethylacetate. The filtrate was concentrated under reduced pressure and 10 mL of saturated sodium bicarbonate solution was added and the resulting reaction mixture was extracted with ether (3×20 mL) and the combined organic phases dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. Purification by flash column chromatography (silica gel, 30:70 EtOAc:Hexanes) yielded 90 mg (71%) of 35. Rf value: 0.458 (40:60 EtOAc:Hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[C:9]3([CH2:11][CH2:10]3)[O:8][C:7]=2[CH:14]=1.C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:22]([O-:24])=[O:23])=[CH:5][C:6]2[C:12](=[O:13])[C:9]3([CH2:10][CH2:11]3)[O:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)OC1(CC1)C2=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)C1(CC1)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.4 g. of 6-Methoxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one was dissolved in a mixture of 25 ml. of acetic anhydride and 7 ml. of glacial acetic acid. While keeping the reaction temperature at 10°-15° C., 3 ml. of fuming nitric acid (d=1.52) was added dropwise to the mixture. After stirring for 30 minutes, the reaction mixture was poured into ice-water. The resulting precipitates were collected by filtration, washed with water and recrystallized from ethanol. By the above procedure, there was obtained 6-methoxy-5-nitrospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one as pale yellow prisms melting at 160°-163° C. Yield: 4.5 g.