Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:16]=[C:17]([S:21]([CH2:24][CH2:25][OH:26])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH2:24][CH2:25][OH:26])(=[O:23])=[O:22])[CH:16]=1)=[O:8]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(S(=O)(=O)CCO)c1
Reaction time: 8 h

Procedure:
To 2,4-dichlorophenoxyacetic acid (110.6 mg, 0.5 mmol), 2-(3-amino-benzenesulfonyl)-ethanol (151.0 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (102.1 mg, 0.75 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by preparative (CH2CH2:MeOH=30:1) to give 2-(2,4-dichloro-phenoxy)-N-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-acetamide as a yell foam (21.5 mg, 10.6% yield).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15]([CH2:18][CH3:19])([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[CH2:18]([C:15]1([OH:17])[CH2:16][N:9]([C:7](=[O:8])[CH2:6][CH2:5][SH:4])[C@H:10]([C:11]([OH:13])=[O:12])[CH2:14]1)[CH3:19]
Reactant: CCC1(O)C[C@@H](C(=O)O)N(C(=O)CCSC(C)=O)C1
Agent: N
Product: CCC1(O)C[C@@H](C(=O)O)N(C(=O)CCS)C1

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 2 to yield 4-ethyl-4-hydroxy-1-(3-mercapto-1-oxopropyl)-L-proline.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:16]O.S(=O)(=O)(O)O>>[CH3:16][O:14][C:13](=[O:15])[CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)NC(Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(Cc1ccccc1)NC(C)=O

Procedure:
Into a 100 milliliter round bottom flask were placed 10.36 grams (50 millimoles) of N-acetyl-D,L-phenylalanine, 48 grams (1.5 moles) of methanol and 2 grams of sulfuric acid (0.02 moles). The mixture was refluxed for 3 hours. The solvent was then removed under vacuum and the resulting oily residue was taken up in 100 milliliters of ether, washed with 50 milliliters of 5% sodium bicarbonate, 50 milliliters of saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent removed under water aspirator vacuum to leave an oily residue. The oily residue was titurated with 100 milliliters of petroleum ether and then the petroleum ether was removed with a water aspirator. The oily residue was vacuum dried in 3 minutes. The white mass was broken up and washed with additional petroleum ether, filtered and vacuum dried. Yield of the white product, N-acetyl-D,L-phenylalanine methyl ester, was 75%. The melting point was 62°-64°. The proton NMR and infrared spectra agreed with the conclusion that the methyl ester of N-acetyl-D,L-phenylalanine was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:4]2[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]2)=[CH:10][CH:9]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Nc1cc[nH]n1
Product: Nc1ccn(Cc2ccc(F)cc2)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 4-fluorobenzylbromide. The title compound was obtained as a colorless solid (Yield=34%). MS ISP (m/e): 192.2 (100) [(M+H)+].
Reaction SMILES: ClC1C(Cl)=C(C(=O)CCCCCBr)C=CC=1OC.Cl.CNC.C=O.[Cl:25][C:26]1[C:31]([Cl:32])=[C:30]([C:33](=[O:41])[C:34](=[CH2:40])[CH2:35][CH2:36][CH2:37][CH2:38][Cl:39])[CH:29]=[CH:28][C:27]=1[O:42][CH3:43].S(=O)(=O)(O)O>O.CN(C)C=O.C(O)(=O)C>[Cl:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[CH2:40][C:29]2[C:30](=[C:31]([Cl:32])[C:26]([Cl:25])=[C:27]([O:42][CH3:43])[CH:28]=2)[C:33]1=[O:41]
Reactant: C=C(CCCCCl)C(=O)c1ccc(OC)c(Cl)c1Cl
Agent: C=O
Agent: CNC
Agent: COc1ccc(C(=O)CCCCCBr)c(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCCCl)C2

Procedure:
A stirred mixture of 2,3-dichloro-4-(6-bromohexanoyl)anisole (10 g.), dimethylamine hydrochloride (4 g.), paraformaldehyde (2 g.) and acetic acid (0.5 ml.) is heated on a steam bath for two hours, treated with dimethylformamide (30 ml.) and heated an additional 2 1/2 hours. The reaction mixture is poured into water, extracted with ether, washed with water and dried over magnesium sulfate. Evaporation of the ether affords 9 g. of crude 2,3-dichloro-4-(6-chloro-2-methylenehexanoyl)-anisole which is cyclialkylated by treatment with concentrated sulfuric acid (50 ml.). The sulfuric acid solution is poured into water (300 ml.) affording 5.8 g. of 2-(4-chlorobutyl)-5-methoxy-6,7-dichloro-1-indanone which melts at 92°C. after recrystallization from cyclohexane.
Reaction SMILES: [ClH:1].C(O[C:7]([N:9]1[CH2:14][CH2:13][N:12](C)[CH2:11][CH:10]1[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:17]=1)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[N:17]=[C:16]([CH:10]3[CH2:11][NH:12][CH2:13][CH2:14][N:9]3[CH3:7])[O:20][N:19]=2)=[CH:22][CH:23]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)C(c2nc(-c3ccc(F)cc3)no2)C1
Agent: Cl
Solvent: CO
Product: CN1CCNCC1c1nc(-c2ccc(F)cc2)no1
Reaction time: 8 h
Yield: 100 %

Procedure:
HCl 4N (3 mL dioxane solution) was dropped into a solution of -[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.312 g, 0.86 mmol) in methanol (8 mL) and the solution was kept under stiffing overnight at R.T. Evaporation of the volatiles under reduced pressure provided 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-piperazine dihydrochloride as a white solid (0.285 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:25][CH3:26])=[CH:13][C:14]2[O:19][C:18](=[O:20])[C:17]3[CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:24]=1)(=O)=O.[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(O)(C)C>[CH3:26][O:25][C:12]1[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:36]2[CH2:35][CH2:34][CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:38][CH2:37]2)=[CH:24][C:15]2[C:16]3[CH2:23][CH2:22][CH2:21][C:17]=3[C:18](=[O:20])[O:19][C:14]=2[CH:13]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCOS(C)(=O)=O)CCC3
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCCN1CCC(c2ccccc2)CC1)CCC3
Yield: 73 %

Procedure:
Method B (16 h at 60° C.); starting materials: 2,3-dihydro-8-[4-(methanesulfonyloxy)butyloxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 84) and 4-phenylpiperidine; yield 73%; fusion point 104°-105° C. (from TBME). Fumarate: method E; yield 77%; fusion point 192°-193° C. (from isopropanol).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([CH3:40])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([OH:18])=[C:10]([C:19]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([NH:29]C(=O)OC(C)(C)C)=[CH:28][C:22]=4[S:21](=[O:38])(=[O:37])[N:20]=3)[C:9]2=[O:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:41]>O1CCOCC1>[ClH:41].[NH2:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:10]3[C:9](=[O:39])[C:8]([CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)([CH3:40])[C:17]4[C:12]([C:11]=3[OH:18])=[CH:13][CH:14]=[CH:15][CH:16]=4)=[N:20][S:21](=[O:38])(=[O:37])[C:22]=2[CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CC3CCCCC3)C1=O)N2
Agent: Cl
Solvent: C1COCCO1
Product: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 91 %

Procedure:
A solution of Example 41G (1.44, 2.56 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (1.17 g, 91%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.78 (m, 7H) 1.35 (m, 7H) 2.20 (m, 2H) 7.02 (m, 2H) 7.50 (m, 2H) 7.76 (m, 2H) 8.16 (m, 1H) 13.61 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[C:23](O)(=[O:25])[CH3:24]>C1C=CC=CC=1>[C:23]([NH:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
In 5 ml of benzene was dissolved 2.00 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, and 0.61 ml of anhydrous acetic acid was added thereto and the mixture was refluxed for one hour. Benzene was removed by distillation to obtain a crude product. This was washed with hexane to obtain 2.20 g of the desired compound as white crystal.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:16])[CH:5]=2)[CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=1.C(O)C>C(=O)(O)[O-].[Na+]>[CH:1]1([C:4]2[C:13]([C:14]3[NH:24][C:19]4[CH:18]=[N:17][CH:22]=[CH:21][C:20]=4[N:23]=3)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:16])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccncc1N
Reactant: COC(=O)c1cc(C=O)c(C2CC2)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(-c2nc3ccncc3[nH]2)c(C2CC2)cc1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 38.1 %

Procedure:
Into a 100-mL round-bottom flask was placed a mixture of methyl 4-cyclopropyl-5-formyl-2-methylbenzoate (compound 87.1, 500 mg, 2.29 mmol), pyridine-3,4-diamine (500 mg, 4.58 mmol), NH4OAc (1.42 g, 18.4 mmol) and ethanol (50 mL). The resulting mixture was stirred open to the air for 3 days at 70° C., then cooled to room temperature and diluted with aqueous sodium bicarbonate (sat., 50 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as the eluent to yield 268 mg (38%) of the title compound as a yellow semi-solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[CH3:9][O:10][C:11]1[CH:32]=[CH:31][C:14]([C:15](Cl)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([O:6][CH2:5][CH:4]([OH:7])[CH2:3][N:2]([CH3:8])[CH3:1])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[CH:31]=[CH:32][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:21][CH:20]=1
Reactant: CN(C)CC(O)CO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OCC(O)CN(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
3-Dimethylamino-1,2-propanediol (6.0 g, 50 mmol) was weighed into a 1 L round bottomed flask with a stir bar. The flask was sealed, flushed with argon, charged with pyridine and cooled to 0° C. 4,4′-Dimethoxytrityl chloride (17.9 g, 1.05 equiv.) was weighed into a 100 mL round bottomed flask, sealed and then dissolved in pyridine (80 mL). The 4,4′-dimethoxytrityl chloride solution was transferred to the stirring reaction mixture slowly, using additional fresh pyridine (20 mL) to effect the transfer of residual 4,4′-dimethoxytrityl chloride. The reaction was allowed to come to room temperature while stirring overnight. The reaction was concentrated in vacuo and re-dissolved in dichloromethane (300 mL). The organic phase was washed with saturated bicarbonate (2×200 mL) and brine (1×200 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum to afford 22.19 g of a yellow gum that was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([S:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3].[C:29]([C:33]1[O:37][N:36]=[C:35]([OH:38])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:29]([C:33]1[O:37][N:36]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=2[S:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:14])=[O:13])[C:35](=[O:38])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: CCCCCCCCCCCCCCS(=O)(=O)c1cc(S(C)(=O)=O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCS(=O)(=O)c1cc(S(C)(=O)=O)ccc1-n1oc(C(C)(C)C)cc1=O
Reaction time: 4 h
Yield: 50.7 %

Procedure:
After mixing 32 g of 4-methanesulfonyl-2-tetradecylsulfonylchlorobenzene, 20 g of 5-t-butyl-3-hydroxyisoxazole, 20 g of potassium carbonate, and 140 ml of dimethyl sulfoxide, the reaction was performed for 4 hours at 80° C. After the reaction was over, the reaction mixture formed was poured into water and extracted with ethyl acetate. The organic phase obtained was purified by silica gel column chromatography and 20.0 g of the desired compound was obtained as the main product with a yield of 50.8%. The melting point thereof was 85° C. to 86° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[N:23]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:24])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[N:23]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N(CCc2ccccc2)CC1(F)F
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(CCc2ccccc2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 61.2 %

Procedure:
To a solution of 0.64 g (0.0019 mole) of 2-chloro-7,7-difluoro-9-phenethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-275) in 15 mL of dimethylformamide was added 0.92 g (0.0029 mole) of cesium carbonate, followed by 0.35 mL (0.0057 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water and dichloromethane were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.41 g of 2-chloro-7,7-difluoro-5-methyl-9-phenethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-275) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>C(Cl)Cl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1F
Temperature: 100 °C

Procedure:
A solution of methyl 2-bromo-4-nitrobenzoate (5.20 g), 2-fluorophenylboronic acid (3.92 g) and potassium carbonate (4.98 g) in a 10:1 mixture of DME:water (120 ml) was degassed by gently bubbling though nitrogen for 30 minutes. Tetrakis(triphenylphosphine) palladium(0) (2.32 g) was then added and the mixture was degassed for a further 10 minutes before being sealed under nitrogen. The reaction mixture was heated to 100° C. for 14 hours. The solvents were removed under vacuum. The residue obtained was redissolved in DCM and washed with water (2×). The organic phase was passed through a hydrophobic frit and then concentrated to dryness under vacuum. The crude residue was purified by chromatography on silica gel, eluting with petrol containing increasing amounts of ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:5]=[CH:4][N:3]=1.[C:23]([O:27][C:28]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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.CCOC(C)=O>[C:23]([O:27][C:28]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([C:2]2[CH:7]=[C:6]([C@@H:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C@@H:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH3:14])[CH:5]=[CH:4][N:3]=2)=[CH:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2ccnc(Br)c2)cc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc21
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: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](C)N2CCC[C@H]2c2ccnc(-c3cn(C(=O)OC(C)(C)C)c4ccccc34)c2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 2-Bromo-4-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (160 mg, 0.44 mmol) in a mixture of toluene (9 mL) and ethanol (3 mL) are added 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester (228 mg, 0.66 mmol), Pd(PPh3)4 (51 mg, 0.04 mmol) and sodium carbonate (2N) (0.7 mL, 1.40 mmol). The reaction mixture is stirred at 85° C. overnight, cooled to room temperature. Water and EtOAc are added to the mixture. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 10%˜90%) to give 3-(4-{(S)-1-[(R)-1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-2-yl)-indole-1-carboxylic acid tert-butyl ester as a yellow solid (175 mg, 79%). M/Z=498.32 [M+1]
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([O:14]C)=O)[C:8]([S:16][CH3:17])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:19]1[CH:24]=[CH:23][C:22]([C:25](N)=[NH:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)=[N:26][C:12](=[O:14])[C:9]3=[C:8]([S:16][CH3:17])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1c(SC)nn(C2CCCC2)c1N
Reactant: N=C(N)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CSc1[nH]n(C2CCCC2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 0 °C
Yield: 12.2 %

Procedure:
A mixture of methyl 1-cyclopentyl-3-methylthio-5-amino-1H-pyrazole-4-carboxylate (3.0 g, 0.012 mol), 4-pyridine carboxamidine hydrochloride (1.9 g, 0.012 mol), potassium carbonate (1.6 g, 0.012 mol) and DMF (25 ml) were refluxed for 4 hours. Additional 4-pyridinecarboxamidine hydrochloride (1.9 g) and potassium carbonate (1.6 g) were added and the reaction mixture was refluxed for 24 hours. The solution was poured into ice-water, neutralized with acetic acid and the resulting precipitate was collected by filtration and washed with water. Recrystallization of the solid from DMF afforded 0.48 g (12%) of 1-cyclopentyl-3-methylthio-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one as a white powder, m.p. 272°-274° C. when dried at 110° C. for 16 hours in high vacuum.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)OC(C)(C)C)C3)ccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
A solution of 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.1 mmol) in DCM (6.5 mL) was treated with TFA (6.5 mL). The reaction mixture was stirred at RT for 4 hours then concentrated in vacuo. The residue was azeotroped with DCM then dissolved in DCM and washed with an aqueous saturated sodium bicarbonate solution (×2) followed by brine. The mixture was passed through a phase separator cartridge and concentrated in vacuo to give 235 as a pale orange gum (397 mg, quant.). LCMS: RT=3.13 min, [M+H]+=368. 1H NMR δ (ppm) (DMSO-d6): 9.34 (1 H, s), 9.05 (1 H, s), 8.30 (1 H, d, J=8.19 Hz), 8.06 (1 H, d, J=0.58 Hz), 7.23 (1 H, dd, J=8.24, 1.89 Hz), 7.13 (1 H, d, J=1.84 Hz), 5.82-5.72 (1 H, m), 4.36-4.30 (2 H, m), 4.25-4.17 (2 H, m), 4.13-3.97 (3 H, m), 3.43-3.37 (2 H, m), 1.50 (6 H, d, J=6.59 Hz).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]([CH3:13])[C:8]([CH3:12])([CH3:11])[C:9]#[N:10].[OH-:14].[Ba+2].[OH-]>>[CH3:6][N:7]([CH3:13])[C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:14]
Reactant: [OH-]
Reactant: CN(C)C(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Product: CN(C)C(C)(C)C(N)=O
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 43.1 %

Procedure:
Conc. Sulphuric acid (8 ml.) was added to 2-dimethylamino-2-methyl-propionitrile (2 g.), and was heated to 90° C. and allowed to stand for five mins. The reaction mixture was added to ice cold water (100 ml.), barium hydroxide (32 g.) was added to neutralise the acid and the mixture was filtered (hyflo). The filtrate was evaporated under reduced pressure to give a solid residue which was crystallised from light petroleum (80°-100° C.) to give 2-dimethylamino-2-methylpropionamide (1 g. 45%) m.p. 109°-111° C.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]2[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[N:7]=1.C(N(CC)CC)C.[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(#N)C>[CH3:25][C:24]([CH3:27])([CH3:26])[CH2:28][C:29]([NH:2][C:3]1[S:4][C:5]2[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[N:7]=1)=[O:30]
Reactant: CCOC(=O)C1CCCc2sc(N)nc21
Reactant: CC(C)(C)CC(=O)Cl
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCc2sc(NC(=O)CC(C)(C)C)nc21
Temperature: 0 °C

Procedure:
To a solution of ethyl 2-amino-4,5,6,7-tetrahydrobenzthiazole-4-carboxyate hydrobromide (0.92 g, 0.3 mol) in acetonitrile (25 mL) there was added triethylamine (Et3N, 0.41 g, 0.4 mol). Following cooling to 0° C., tert-butylacetyl chloride (0.55 g, 0.4 mol) was slowly added, and the resultant mixture was then stirred overnight at room temperature. Following removal of the solvent and purification by column chromatography, there was obtained ethyl 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylate in a yield of 185 mg (corresponding to 19% of theory).