Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[C:8]([F:15])[C:7]=1[CH:16]([CH3:18])[CH3:17])=[O:4].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[C:8]([F:15])[C:7]=2[CH:16]([CH3:18])[CH3:17])=[O:4])[CH2:24][CH2:23]1
Reactant: CC(C)c1ccc(F)c(C(C)C)c1NC(=O)CBr
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1ccc(F)c(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a solution of this acetamide (498 mg, 1.57 mmol) in acetonitrile (10 ml) were added 1-(2-hydroxyethyl)piperazine (371 mg, 2.85 mmol) and potassium carbonate (469 mg, 3.39 mmol) successively with ice-cooling, and stirred at room temperature for 12 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting reside was purified by a silica gel column chromatography (silica gel 50 g, developing solvent; chloroform:methanol=25:1 10:1) and recrystallized from ether-hexane to provide 575 mg (yield 99%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-(2,6-diisopropyl-3-fluorophenyl)acetamide as colorless needles.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([NH:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH:45](O)[CH2:44]3)=[N:9]2)=CC=1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>>[F:55][C:54]([F:57])([F:56])[C:52]([O:58][CH:45]1[CH2:46][CH2:47][CH2:48][CH:43]([NH:42][C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:30]=[CH:31][CH:32]=4)=[O:26])=[CH:20][C:19]=3[F:41])[NH:8][N:9]=2)[CH2:44]1)=[O:53]
Reactant: COc1ccc(Cn2nc(NC3CCCC(O)C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reactant: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCCC(OC(=O)C(F)(F)F)C4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 78 %

Procedure:
A solution of N-(4-(1-(4-methoxybenzyl)-3-(3-hydroxycyclohexylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (40 mg, 0.058 mmol) in TFA (1 mL) was heated to 50° C. for 1 hour. Excess TFA was evaporated and the residue was dissolved in EtOAc. The organic layer was then washed with saturated aqueous NaHCO3, brine, dried with Na2SO4, filtered and concentrated to afford the product (30 mg, 78% yield) as a yellow solid. LRMS (APCI pos) m/e 670.2 (M+H). 1H NMR (DMSO-d6, 400 MHz): δ 12.20 (d, 1H), 11.70 (s, 1H), 8.38 (d, 1H), 8.26 (d, 1H), 8.12 (dd, 1H), 8.02 (dd, 1H), 7.66-7.70 (m, 2H), 7.56-7.62 (m, 1H), 7.46-7.52 (m, 1H), 7.38-7.44 (m, 2H), 6.02 (d, 2H), 5.20-5.40 (m, 1H), 3.60-3.80 (m, 1H), 2.20-2.30 (m, 1H), 2.00-2.10 (m, 2H), 1.80-1.90 (m, 2H), 1.60-1.80 (m, 2H), 1.30-1.45 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:31])[C:24]([NH:26][C:27](=[O:30])[CH2:28]Br)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:31])[C:24]([NH:26][C:27](=[O:30])[CH2:28][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(NC(=O)CBr)c(Cl)cc3n2COCCOC)c1
Reactant: C1COCCN1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3cc(NC(=O)CN4CCOCC4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 0.83 h
Yield: 96 %

Procedure:
To a suspension of 1-[5-(2-bromo-acetylamino)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.100 g, 0.194 mmol) and dichloromethane (1 mL) was added morpholine (51.0 μL, 0.580 mmol). The reaction mixture was stirred at 23° C. for 50 min. The reaction mixture was partitioned between EtOAc (15 mL) and water (10 mL), and the aqueous layer was further extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (15 mL), dried, filtered, and concentrated under reduced pressure, to yield the titled compound (97 mg, 96% yield) as a 3:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C23H29ClN6O6, 520.2; m/z found, 521.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 10.00 (s, 1H), 8.89 (s, 1H), 8.85 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 6.12 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.87-3.80 (m, 4H), 3.67-3.60 (m, 2H), 3.48-3.42 (m, 2H), 3.32 (s, 2H), 3.24 (s, 3H), 2.73-2.67 (m, 4H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]2=[N:7][C:6]=1[CH3:16].[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:3][CH2:4][C:5]4[C:10](=[O:11])[N:9]5[C:12]([CH3:15])=[CH:13][S:14][C:8]5=[N:7][C:6]=4[CH3:16])[CH2:29][CH2:30]3)=[N:23][O:24][C:20]=2[CH:19]=1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 7.4 parts of 6-(2-bromoethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 10 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred overnight at 80°-85° C. After cooling, the reaction mixture was poured into water. The product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. 2-Propanol was added to the residue. The product was filtered off and dried, yielding 5.3 parts (62%) of 6-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 231.0° C. (compound 13).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Br[C:6]1[C:7]([C:12]#[N:13])=[N:8][CH:9]=[CH:10][CH:11]=1>C1COCC1>[C:12]([C:7]1[C:6]([S:3][CH2:1][CH3:2])=[CH:11][CH:10]=[CH:9][N:8]=1)#[N:13]
Reactant: CC[S-]
Reactant: N#Cc1ncccc1Br
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1cccnc1C#N

Procedure:
To a stirred suspension of sodium ethanethiolate (600 mg, 5.75 mmol) in dry THF (25 mL) was added 3-bromo-2-cyanopyridine (700 mg, 3.83 mmol). The reaction mixture was heated to reflux under N2 for 3 h. The solvent was removed in vacuo and the resulting residue was taken Lip in CH2Cl2 (35 mL). The solution was filtered to remove precipitated sodium bromide and the filtrate was concentrated at reduced pressure to afford the title compound as a yellow oil:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([OH:17])[C:10]([CH3:16])([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([O-:26])=[O:25].[OH-].[Na+]>CO>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([OH:17])[C:10]([CH3:15])([CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCCCC(C)(C)C(O)C=CC1CCC(O)C1C/C=C\CCCC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(C)(C)C(O)C=CC1CCC(O)C1C/C=C\CCCC(=O)O
Reaction time: 18 h

Procedure:
To a solution of methyl trans, cis-7-[2-hydroxy-5-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentyl]-5-heptenoate (0.536 g, Isomer B less polar epimer), described in Example 92, in methanol (5 ml) is added a solution of sodium hydroxide (10%, 1.32 ml). The mixture is stirred for 18 hr. The solvent is removed under reduced pressure and the residue taken up in water and extracted with ether. The aqueous liquor is then rendered acidic with HCl (10%, 1.32 ml). The precipitate is taken up with ether. The ether extract is washed with water, dried (Na2SO4) and the solvent is removed to yield the title compound, Isomer B less polar epimer, nmr (CDCl3) δ 0.84 (m, 9H), 3.80 (m, 1H), 4.23 (m, 1H), 5.27 (broad, 3H), 5.5 (m, 4H), (i.e., racemic trans, cis-7-[2α-hydroxy-4,4-dimethyl-1-octenyl)cyclopentyl]-5-heptenoic acid).
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7]1)(=[O:4])=[O:3].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][S:21][CH2:22][CH2:23][NH2:24].C1C=CC=CC=1>C(Cl)Cl>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][S:21][CH2:22][CH2:23][NH:24][C:6](=[N:5][S:2]([CH3:1])(=[O:3])=[O:4])[O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[OH:7]
Reactant: CS(=O)(=O)N=c1oc2ccccc2o1
Reactant: NCCSCc1ccco1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CS(=O)(=O)N=C(NCCSCc1ccco1)Oc1ccccc1O
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
42.6 g of 2-methanesulfonylimino-1,3benzodioxole was suspended in 126 ml of methylene chloride. Thereto was dropwise added 31.4 g of 2-[(2furyl)methylthio]ethylamine at 10° to 15° C. Stirring was effected at the same temperature for 30 minutes. The reaction mixture was mixed with 250 ml of benzene and the resulting mixture was stirred at the same temperature for 30 minutes. The crystals deposited were collected by filtration to obtain 65.5 g (yield: 88%) of N-[2-[(2-furyl)methylthio]ethyl]-O-(2-hydroxyphenyl)-N'-methanesulfonylisourea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH:29][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])=[CH:24][CH:23]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1ccc(Cl)nc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (1.0 g, 2.85 mmol) and (6-chloropyridin-3-yl)methylamine (488 mg, 3.42 mmol). The title compound was obtained as a solid (500 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.43 (1H, m), 9.00 (2H, s), 8.44 (1H, s), 8.34 (1H, s), 7.77 (1H, dd), 7.49 (1H, dd), 4.23 (2H, m). MS m/z: 473.05, 475.03 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]=[CH:11][C:12]([OH:14])=O.CN(C)C=O.S(Cl)([Cl:22])=O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12]([Cl:22])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(C=CC(=O)O)c(Br)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(/C=C/C(=O)Cl)c(Br)c1
Yield: 99 %

Procedure:
A solution of 5.07 g (19.9 mmol) of 3-(2-bromo-4,6-dimethylphenyl)-2-propenoic acid in 50 mL of thionyl chloride containing 50 μl of dimethylformamide (DMF) was stirred under nitrogen at room temperature for 20 hours. The volatiles were removed under reduced pressure to give 5.40 g (99%) of (E)-3-(2-bromo-4,6-dimethylphenyl)-2-propenoyl chloride as a dark brown solid: IR (film) 2960, 2920, 1750, 1620 and 1605 cm-1 ; NMR (CDCl3) δ 2.32 (3H, s), 2.40 (3H, s), 6.44 (1H, d, J=16 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>O1CCCC1>[C:39]([N:36]1[CH2:37][CH2:38][CH:33]([O:32][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(F)c2)N1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(F)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reaction time: 4 h

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.1 mmol), acetyl chloride (9.4 mg, 0.12 mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.027 mL, 0.2 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was triturated in dichloromethane and hexanes to give the title compound as a off white solid (Yield: 43 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=1)(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C(N)=O)c(Nc2cc(-c3ccccc3)no2)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cc(-c2ccccc2)no1
Yield: 20.9 %

Procedure:
Compound tert-butyl (1S,2R)-2-(4-carbamoyl-3-(3-phenylisoxazol-5-ylamino)phenylamino)cyclohexylcarbamate (6 mg) was dissolved in TFA (1 mL). After 10 min of standing, TFA removed in vacuo. The residue was purified by HPLC to give the titled compound (1 mg). MS 392.4 (M+H); UV 202.9, 294.0 nm
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([OH:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:11][C:10]([C:7]1[S:6][C:5]2[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][C:4]=2[C:8]=1[CH3:9])=[O:12])[CH3:21]
Reactant: CCO
Reactant: Cc1c(C(=O)O)sc2ccc(Br)cc12
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1sc2ccc(Br)cc2c1C

Procedure:
A mixture of 5-bromo-3-methylbenzo[b]thiophene-2-carboxylic acid (5.80 g.), ethanol (500 ml.) and concentrated sulphuric acid (2 ml.) was heated under reflux for 48 hours, and then evaporated. Dilute aqueous ammonia solution was added and the solid was filtered off, washed well with water and dried to give 5-bromo-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (5.70 g.), m.p. 87°-88° C., raised to 88°-89° on crystallization from petrol (b.p. 80°-100°).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C(C)C)cc1
Yield: 75.4 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(4-isopropylphenyl)-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.074 g; 0.181 mmol), sodium hydroxide 10N (0.200 mL; 2.00 mmol) in methanol (2 mL) at 60° C. for 18 h furnished 0.054 g (73%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:4]=1[NH2:5].O.O.O.O.[NH:16]1[C:24](=[O:25])[C:22](=[O:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]>O>[NH2:5][C:4]1[C:6]([O:10][CH3:11])=[CH:7][C:8]([C:22]2([OH:23])[C:20](=[O:21])[NH:19][C:17](=[O:18])[NH:16][C:24]2=[O:25])=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: COc1cccc(OC)c1N
Solvent: O
Product: COc1cc(C2(O)C(=O)NC(=O)NC2=O)cc(OC)c1N
Reaction time: 1 h
Yield: 91.7 %

Procedure:
25 g of 2,6-dimethoxyaniline were added to a solution of 35 g of alloxan tetrahydrate in 120 ml of water. While stirring vigorously, the initially heterogeneous mixture changed after one hour into a brown solution from which grey crystals separated after a short time. The reaction mixture was stirred at room temperature for an additional 24 hours until dimethoxyaniline was no longer detectable according to thin-layer chromatography (cyclohexane/ethyl acetate/water=60:30:1). The reaction mixture was suction filtered, the residue on the suction filter was suspended with 4 portions of water to 80 ml and sucked dry. The solid was dried at 100°/16 mbar for 16 hours. There were obtained 44.2 g of 5-(4-amino-3,5-dimethoxyphenyl)-5-hydroxybarbituric acid as a light grey powder of m.p. 240°-243° (under decomposition). For purification, the powder can be recrystallized from 1-butanol, there being obtained a product of m.p. 242°-244° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[C:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])(=[O:17])[CH3:16]>>[C:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13])(=[O:17])[CH3:16]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: CC(=O)c1ccccc1N
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1C(C)=O

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-acetylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][C:6]2([CH3:16])[CH3:15].[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:22]=1[C:23](O)=[O:24])([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:23]([C:22]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=[CH:29][C:21]=1[O:20][CH:17]([CH3:19])[CH3:18])=[O:24])[CH2:7][C:6]2([CH3:16])[CH3:15]
Reactant: COc1cc2c(cc1OC)C(C)(C)CNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: COc1cc2c(cc1OC)C(C)(C)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 6,7-dimethoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (CA [57553-25-0]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 462.5 (M+H+).
Reaction SMILES: [P:1]([O-:38])([O:34][CH2:35][CH2:36]Br)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[P:1]([O-:38])([O:34][CH2:35][CH2:36][N+:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)Oc1ccon1
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[n+]1ccccc1)Oc1ccon1

Procedure:
0.800 g of (2RS)-3-(N-heptadecylcarbamoyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in Example 11(a)] was reacted with pyridine in a similar manner to that described in Example 3, to afford 0.549 g of the title compound as a viscous resinous material.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:19]([F:21])[F:20])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](Cl)=O.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:19]([F:21])[F:20])[N:6]2[CH2:13][C:14]1[N:17]=[C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[O:16][N:15]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: [H]/N=C(/Cn1c(C(F)F)cc2c(Cl)c(C#N)ccc21)NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3ccccn3)n2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of (1Z)-2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.011 g, 0.035 mmol) in anhydrous THF (1.5 mL), under N2, was added picolinoyl chloride hydrochloride (0.0066 g, 0.037 mmol) and Et3N (0.0078 g, 0.077 mmol). The mixture was stirred at rt for 30 min. The reaction was monitored by TLC and additional acid chloride (0.003 g, 0.018 mmol) and Et3N (0.0035 g, 0.035 mmol) were added and stirring continued at rt for 1 h. The mixture was then heated in a microwave at 120° C. for 20 min, and subsequently at 150° C. for 2 h. Upon cooling, the mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with 0.1N HCl, sat'd NaHCO3 solution and sat'd brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (5-50% EtOAc-hexanes gradient), followed by a second purification by radial chromatography (5-70% EtOAc-hexanes gradient). The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.005 g, 38% yield): MS (ES) m/z 386 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]([C@H:28]([CH3:43])[CH2:29][N:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO.Cl.O1CCOCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]([C@H:28]([CH3:43])[CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: Cc1ccc2c(=O)n([C@H](C)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc2c(=O)n([C@H](C)CN3CCNCC3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 4-(2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl)piperazine-1-carboxylate (100 mg, 0.0002 mol) in methanol (6 mL, 0.1 mol) was added 4M hydrogen chloride in 1,4-dioxane(6 mL, 0.02 mol) at 0° C. The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(C#N)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Cyano-5-(trifluoromethyl)benzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (119 mg, 0.278 mmol) was dissolved in DCM (5 ml) and 4M HCl in Dioxane (0.696 ml, 2.78 mmol) was added with stirring at RT under nitrogen. After 3 hrs, the mixture was concentrated in vacuo to give the title compound as the hydrochloride salt.