Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.C(O)(=O)C.[Si:33]([O:40][CH2:41][CH:42]=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Si:33]([O:40][CH2:41][CH2:42][NH:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 15 (92 mg) in MeOH (2 mL) was added TEA (70 μL), acetic acid (30 μL), 2-(tert-butyldimethylsilyloxy)acetaldehyde (35 mg) and sodium triacetoxyborohydride (212 mg). The reaction mixture was stirred overnight at RT. Solvent was removed under reduced pressure and the product was carried on to next step without further purification.
Reaction SMILES: [H][H].[C:3]([C:7]1[CH:30]=[CH:29][C:10]2[CH2:11][CH2:12][C:13]3[CH:21]=[C:20]([CH:22]([N:24]([OH:28])[C:25]([NH2:27])=[O:26])[CH3:23])[CH:19]=[CH:18][C:14]=3[S:15](=[O:17])(=[O:16])[C:9]=2[CH:8]=1)([O:5]C)=[O:4].[OH-].[Na+]>C(O)C>[C:3]([C:7]1[CH:30]=[CH:29][C:10]2[CH2:11][CH2:12][C:13]3[CH:21]=[C:20]([CH:22]([N:24]([OH:28])[C:25]([NH2:27])=[O:26])[CH3:23])[CH:19]=[CH:18][C:14]=3[S:15](=[O:16])(=[O:17])[C:9]=2[CH:8]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccc(C(C)N(O)C(N)=O)cc1CC2
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2(=O)=O)N(O)C(N)=O

Procedure:
Where R1 is hydrogen and R2 is carbomethoxy, a compound of formula I, such as N-[1-(7-carbomethoxy-5,5-dioxo-10,11-dihydro dibenzo [b,f] thiepin-2-yl) ethyl]-N-hydroxy urea, may be hydrolyzed by base, such as aqueous sodium hydroxide, in an alcoholic solvent, such as ethanol to yield the N-[1-(7-carboxy-5,5-dioxo-10,11-dihydro dibenzo [b,f] thiepin-2-yl)ethyl]-N-hydroxy urea.
Reaction SMILES: Cl.[Cl:2][C:3]([O:5][CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:4].[C:14]1([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCCl>[ClH:2].[CH2:21]([N:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3](=[O:4])[O:5][CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OC1CN2CCC1CC2
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: Cl
Solvent: ClCCCl
Product: O=C(OC1CN2CCC1CC2)N(Cc1ccccc1)c1ccccc1

Procedure:
To a suspension of 750 mg (2.58 mmol) of hydrochloride of 3-quinuclidyl chloroformate in 20 mL of 1,2-dichloroethane, a solution of 395 mg (2.15 mmol) of N-phenylbenzylamine in 5 mL of 1,2-dichloroethane was added dropwise. Once completed the addition, the mixture was refluxed for three hours. The reaction crude was allowed to cool down and the solvent distilled off under reduced pressure. The residue was purified by column chromatography (eluent: chloroform-methanol 10:1) yielding 720 mg (1.95 mmol) of a hygroscopic foam corresponding to the title compound. IR (KBr, cm−1): 3400-3200, 2700-2300, 1700 cm−1. 1H-RMN (δTMS, CDCl3, ppm): 12.30 (1H, s), 7.20-6.90 (10H, m), 5.10 (1H, m), 4.83 (2H, m), 3.52 (1H, m), 3.18 (4H, m), 2.80 (1H, m), 2.34 (1H, s), 1.92 (2H, m), 1.60 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([S:20][CH3:21])[NH:16][C:15]=3[CH:14]=[C:13]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([S:20]([CH3:21])=[O:44])[NH:16][C:15]=3[CH:14]=[C:13]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])=[O:24])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(S(C)=O)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a solution of N-(3-chloro-2-methylphenyl)-2-(methylsulfanyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (26 mg) in THF (3 mL), was added an aqueous solution of m-chloroperbenzoic acid (75%, 12 mg) (1 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to yield the titled compound (10 mg) as pale yellow powder.
Reaction SMILES: [C:1]1([CH3:39])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([NH:12][C@H:13]([C:35]([O:37]C)=[O:36])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([NH:31][CH2:32][CH2:33][CH3:34])=[O:30])[CH:23]=2)=[CH:18][CH:17]=1)(=[O:11])=[O:10].[OH-].[Na+].Cl>C(O)(C)C>[C:1]1([CH3:39])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([NH:12][C@H:13]([C:35]([OH:37])=[O:36])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([NH:31][CH2:32][CH2:33][CH3:34])=[O:30])[CH:23]=2)=[CH:20][CH:21]=1)(=[O:11])=[O:10]
Reactant: CCCNC(=O)Nc1cccc(-c2ccc(OC[C@H](NS(=O)(=O)c3c(C)cc(C)cc3C)C(=O)OC)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCNC(=O)Nc1cccc(-c2ccc(OC[C@H](NS(=O)(=O)c3c(C)cc(C)cc3C)C(=O)O)cc2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The compound of Example 19 (60.0 mg, 0.11, 1 equiv) was dissolved in isopropanol (3.0 mL) and treated with a 1 M aqueous solution of NaOH (1 mL). The reaction mixture was warmed to 60° C. and stirred for 4 hours. It was acidified with a 0.1 M aqueous solution of HCl to pH 2 and cooled to 4° C. overnight. The white precipitate of the title compound was filtered off and dried under vacuum. Yield 30.0 mg, 51.3%. 1H NMR (DMSO; 200 MHz) δ 13.99 (broad s, 1H); 8.50 (s, 2H); 7.71 (s, 1H); 7.49 (d, 2H); 7.25 (d, 2H); 7.15-7.12 (m, 1H); 7.00 (s, 2H); 6.88 (d, 2H); 6.23-6.09 (m, 1H); 4.19-4.03 (m, 3H); 3.21-2.93 (m, 1H); 2.59 (s, 6H); 2.21 (3H), 1.43 (quin, 2H); 0.97 (t, 3H). MS (ESI) 540 (M+H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:17][C:18]1[C:23]2[NH:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([O:28][CH3:29])[CH:19]=1>>[Br:17][C:18]1[C:23]2[N:24]([C:2]3[C:3](=[O:16])[N:4]([CH:9]([CH:12]4[CH2:15][CH2:14][CH2:13]4)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=3)[CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: CCC(C1CCC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)OCCN2
Product: CCC(C1CCC1)n1cc(Cl)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give a brown oil. 1H NMR (300 MHz, CDCl3): δ 6.73 (d, J=2.9 Hz, 1H), 6.72 (s, 1H), 6.45 (d, J=2.6 Hz, 1H), 4.90–4.85 (m, 1H), 4.50–3.88 (m, 4H), 3.76 (s, 3H), 2.58–2.50 (m, 1H), 2.18–2.13 (m, 1H), 1.85–1.65 (m, 6H), 1.50–1.40 (m, 1H), 0.83 (t, J=7.4 Hz, 3H), HRMS (ESI) m/z 468.0665 [M+, calcd for C20H24N3O3BrCl 468.0690].
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].COP(O[C:15](=[C:22]([F:24])[F:23])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(OC)=O>COC(C)(C)C>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:15](=[C:22]([F:24])[F:23])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)CC(OP(=O)(OC)OC)=C(F)F
Solvent: COC(C)(C)C
Product: CCOC(=O)CC(=C(F)F)N(C(C)C)C(C)C
Temperature: 25 °C
Yield: 70.6 %

Procedure:
Diisopropylamine (15.2 g, 0.15 mol) is added dropwise over 10 min to a solution of ethyl 3-[(dimethoxyphosphoryl)oxy]-4,4-difluorobut-3-enoate (IV-1) (14.2 g, 97%, 0.05 mol) in 100 ml methyl-tert-butyl ether. After 19 h heating under reflux the reaction mixture is cooled to room temperature, washed twice with 10 ml 10% sodium chloride solution each time, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was distilled for further use. 8.8 g (95%, 67.4% of theory) of ethyl 3-(diisopropylamino)-4,4-difluorobut-3-enoate are obtained (boiling point 55-57° C. at 0.5 hPa).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]([OH:14])[CH:11]=[CH:12][CH3:13].CC1C(C(O)C=CC)C(C)(C)CCC=1>>[CH3:1][C:2]1[CH:3]([C:10](=[O:14])/[CH:11]=[CH:12]\[CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: CC=CC(O)C1=C(C)CCCC1(C)C
Agent: CC=CC(O)C1C(C)=CCCC1(C)C
Product: C/C=C\C(=O)C1C(C)=CCCC1(C)C

Procedure:
By replacing above 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene by 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-2-cyclohexene, cis-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[C:7]([OH:13])[CH:6]=[CH:5]2.Br[C:15]1C=C2C(=CC=1)C=C(O)C=C2.CNC.C=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:15])=[C:7]([OH:13])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Agent: C=O
Agent: CNC
Product: Cc1c(O)ccc2cc(Br)ccc12

Procedure:
Preparation of 6-bromo-1-chloro-2-naphthol 4 from the corresponding 6-bromo-2-naphthol 3 is described in the literature (Buu-Hoi, JOC 1951, 16, 185), Scheme II. 6-Bromo-1-methyl-2-naphthol 7 was prepared as depicted in reaction Scheme II. Reaction of 6-bromo-2-naphthol 3 with aqueous dimethyl amine and aqueous formaldehyde in alcohol afforded the Mannich product 5. Reaction of 5 with acetyl chloride in methylene chloride or chloroform afforded the acetate 6. Hydride reduction of 6 in a solvent such as ethanol followed by basic work-up yielded the desired 6-bromo-1-methyl-2-naphthol 7.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:17]=[O:18]>>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([CH:17]=[O:18])=[CH:5][CH:4]=1)[CH3:9]
Reactant: CN(C)c1ccccc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C=O)cc1

Procedure:
N,N-Di(loweralkyl)anilines, preferably N,N-dimethyl aniline, are reacted with phosphorus oxychloride in dialkyl formamide, preferably dimethyl formamide (DMF), according to the Vilsmeier Reaction to give 4-(N,N-di-loweralkylamino)benzaldehydes, preferably 4-(N,N-dimethylamino)benzaldehyde. The reaction is conducted using essentially two molar proportions of the N,N-dialkylaniline, essentially one molar proportion (or a slight excess) of phosphorus oxychloride, and essentially two molar proportions (or a slight excess) of dimethyl formamide. The phosphorus oxychloride is slowly added, with cooling, to the mixture of N,N-dialkylaniline and dimethyl formamide, keeping the temperature in the range of about 50°-70° C., preferably about 55°-65° C. The 4-(di-loweralkylamino)benzaldehyde thus formed may be isolated at this point for subsequent reaction with an N,N-di(loweralkyl)aniline and the sulfinic acid or the reaction may be continued without isolation in what is referred to herein as the "in situ" process.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:28])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:30]1C([N+]([O-])=O)=C(Cl)C2C(=CC=CC=2)N=1.ClC1C2C(=CC=CC=2)N=CC=1[N+]([O-])=O.Cl.N1C=CC=CC=1.C(OC(OCC)OCC)C>C1(C)C=CC=CC=1>[Cl:28][C:3]1[C:2]2[N:1]=[CH:30][N:12]([CH2:13][C:14]3([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNc2c(N)c(Cl)nc3ccccc23)CC1
Agent: Cl
Agent: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2cnc3c(Cl)nc4ccccc4c32)CC1

Procedure:
Under a nitrogen atmosphere, tert-butyl 4{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate (0.25 g, 0.61 mmol, prepared according to the general methods of Example 4 Parts A through D using 2,4-dichloro-3-nitroquinoline in lieu of 4-chloro-3-nitroquinoline in Part C), toluene (5 mL), pyridine hydrochloride (0.02 g), and triethylorthoformate (0.11 mL, 0.65 mmol) was heated at reflux for 2 hours. More triethylorthoformate (0.5 eq) was added and the reaction mixture was heated for an additional hour. The reaction was rerun in the same manner using 5.25 g of tert-butyl 4 {[(3-amino-2-chloroquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate. The small and larger scale reaction mixtures were combined and washed with water (50 mL). The aqueous layer was extracted with dichloromethane (2×100 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with a gradient of 0-10% methanol in ethyl acetate) to provide 4.08 g of tert-butyl 4-[(4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate as a tan frothy solid.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3NC4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3CCC)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CC3CC3)c2c1=O
Agent: CCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CC3CC3)c12
Yield: 206.2 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 6-(c) except for using 3.40 g (3.13 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-cyclopropylmethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 15-(d) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-propyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 2.50 g of the title compound was obtained as a white solid. (Yield: 93%)
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@@H:11]([CH3:20])[CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:3]=1.[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:33]=1)[C:27](N(OC)C)=[O:28]>>[Br:21][C:22]1[CH:33]=[C:26]([C:27]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([C@@H:11]([CH3:20])[CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:3]=2)=[O:28])[CH:25]=[N:24][CH:23]=1
Reactant: C[C@@H](COC1CCCCO1)n1cc(I)c2cncnc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: C[C@@H](COC1CCCCO1)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 24 using 5-iodo-7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 18) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a colourless oil in 32% yield, 181 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[CH3:25][CH:26]([CH3:31])[CH2:27][C:28](Cl)=[O:29]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH3:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[CH:11]=2)=[CH:3][C:2]=1[NH:1][C:28](=[O:29])[CH2:27][CH:26]([CH3:31])[CH3:25]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: CC(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (185 mg, 0.572 mmol) in N,N-dimethylacetamide (5 mL) was added 3-methylbutanoyl chloride (71.0 μL, 0.579 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (176 mg, 72%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])[C:17]([Cl:21])([CH3:20])[CH2:18]Cl)[C:11]2=[O:23])[CH:7]=[CH:8][CH:9]=1.[F-].[Cs+].O>C1COCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:18][C:17]([Cl:21])([CH3:20])[C:16]3=[O:22])[C:11]2=[O:23])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(Cl)(CCl)C(=O)NC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(Cl)CN(C2CCN(c3cccc(OC(F)(F)F)c3)C2=O)C1=O

Procedure:
A stirred solution of 1-(3-trifluoromethoxyphenyl)-3-(2,3-dichloro-2-methylpropanoyl)amino-2-pyrrolidinone (0.82 g) in THF (10 ml) was treated with caesium fluoride (1.29 g) followed by benzyltriethyl ammonium chloride (0.09 g). The mixture was heated under reflux, cooled and poured into water. The resultant mixture was extracted with chloroform (x3) and the combined extracts dried (Na2SO4). Evaporation of the solvent under reduced pressure left an oil which was purified by chromatography on silica-gel, eluting with ethyl acetate/hexane mixtures, to give the title compound as a mixture of diastereomers:
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1.[CH2:29]([OH:31])[CH3:30]>>[CH2:29]([O:31][C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:30]
Reactant: CCO
Reactant: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Agent: [H-]
Agent: [Na+]
Product: CCOc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Add sodium hydride (25.5 mg, 0.64 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (50 mg, 0.14 mmol) in ethanol (2.5 mL) at 0° C. Stir the reaction mixture at 0° C. for 10 minutes, room temperature for 10 minutes more, and reflux overnight. Cool the reaction mixture to room temperature, quench with saturated aqueous ammonium chloride (3 mL). Add water (20 mL) and extract the aqueous solution with methylene chloride (3×20 mL). Dry the combined organic layers with sodium sulfate and purify by flash column chromatography (SiO2, 50% ethyl acetate/hexanes) to give the title compound 48 mg (94%) as an off-white solid.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[F:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[C:18]([C:24]#[C:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:17]3[NH:30][C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][C:36]=4[C:16]3=[CH:15][C:14]2=1>>[F:37][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:17]1[C:18]([CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:19]3[NH:20][C:21]4[CH:22]=[CH:23][C:11]([F:10])=[CH:12][C:13]=4[C:14]3=[CH:15][C:16]2=1
Reactant: CN(C)CC#Cc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Agent: c1ccc2[nH]ccc2c1
Product: CN(C)CCCc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 144 except the starting indole is 3-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yl)-N,N-dimethylprop-2-yn-1-amine. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.13 (br s, 2 H), 8.67 (s, 1 H), 7.88 (dd, J=9.2, 2.4 Hz, 2 H), 7.44 (dd, J=8.8, 4.4 Hz, 2 H), 7.15 (td, J=9.2, 2.4 Hz, 2 H), 3.15 (t, J=5.2 Hz, 2 H), 2.29 (t, J=7.2 Hz, 2H), 2.18 (s, 6 H), 1.94-1.83 (m, 2 H); MS (ESI) m/z 376.3 (M−H)−; MS (ESI) m/z 378.1 (M+H)+
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.O.[CH3:12][N:13](C)C=O>Cl>[C:12]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1)#[N:13]
Reactant: CN(C)C=O
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cl
Solvent: O
Product: N#Cc1ccc(C=O)c(F)c1
Temperature: 150 °C

Procedure:
A stirred mixture of 4-bromo-2-fluorobenzaldehyde (39 g, 192 mmol) and cuprous cyanide (18.9 g, 211 mmol) in dimethylformamide (100 ml) was heated to 150° C. for 12 hours under nitrogen atmosphere. The dark solution was cooled and a solution of ferric chloride (34 g, 211 mmol) in hydrochloric acid (2M, 100 ml) was added, followed by water (100 ml). Solid crystallised from the mixture and was filtered, washed with water and dried at 40° C. in vacuo. Recrystallisation from cyclohexane (500 ml) gave 4-cyano-2-fluorobenzaldehyde (m.p. 79° C.) as yellow needles.
Reaction SMILES: NC1C=CC=C2C=1C(=O)[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])C(C)=N2.[CH3:22][C:23]1O[C:25](=[O:36])[C:26]2[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.NC1CCC(=O)NC1=O>>[CH3:22][C:23]1[N:5]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[C:25](=[O:36])[C:26]2[C:27](=[CH:29][CH:30]=[CH:31][C:32]=2[N+:33]([O-:35])=[O:34])[N:28]=1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: NC1CCC(=O)NC1=O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In one specific embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent in the presence of a coupling reagent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; and (b) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione via transfer hydrogenation in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, wherein steps (a) and (b) are each as described herein elsewhere.