Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:18][CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.N1CCCCC1.[NH:35]1[CH2:41][C:39](=[O:40])[NH:38][C:36]1=[O:37]>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:41]4[C:39](=[O:40])[NH:38][C:36](=[O:37])[NH:35]4)=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:18][CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1
Reactant: COCCCNC(=O)c1ccc(-c2cc(NC3CC3)n3ncc(C=O)c3n2)s1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COCCCNC(=O)c1ccc(-c2cc(NC3CC3)n3ncc(C=C4NC(=O)NC4=O)c3n2)s1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-N-(3-methoxypropyl)thiophene-2-carboxamide (30 mg, 0.075 mmol) in EtOH (1 mL) was added piperidine (20 μL, 0.150 mmol), and hydantoin (10 mg, 0.075 mmol). The reaction mixture was stirred at 85° C. for 3 hours. The solid formed was isolated by filtration to provide 5-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)-N-(3-methoxypropyl)thiophene-2-carboxamide. LCMS (M+1=482)
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]([C:25](Cl)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.CCN(CC)CC>C(Cl)Cl>[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:3]1[CH2:4][CH2:5][C@@H:6]2[C@@H:1]([N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7]2)[CH2:2]1)=[O:26]
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1-c1ccccc1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1
Yield: 119.1 %

Procedure:
A mixture of (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)quinoxaline (179 mg, 0.745 mmol), biphenyl-2-carbonyl chloride (210 mg, 0.97 mmol), Et3N (196 mg, 1.95 mmol) was stirred into DCM (7.0 mL) for 18 h at room temperature. Then reaction mixture was diluted with more DCM (25 mL) and washed successively with 1N aq. NaOH (5 mL) and water (2×15 mL). The organic phase was concentrated under reduced pressure. The crude residue was purified on HPLC (basic system) to yield pure title compound (373 mg, 99%). MS (ESI) mass calcd. for C27H24N4O, 420.52; m/z found, 421.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.00-7.32 (m, 11H), 7.29-7.18 (m, 1H), 6.75 (dd, J=9.9, 4.2, 2H), 4.70-4.42 (m, 1H), 4.30-3.90 (m, 3H), 3.8-3.74 (m, 0.66H), 3.51-3.30 (m, 1.35H), 3.13-3.03 (m, 0.5H), 2.90-2.80 (m, 0.5H), 2.68-2.51 (m, 0.5H), 1.96-1.68 (m, 2H), 1.59-1.43 (m, 0.5H).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([OH:2])[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC1CCCNC1
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OC1CCCN(Cc2ccccc2)C1
Yield: 56.6 %

Procedure:
A mixture of 15.0 g of 3-hydroxypiperidine hydrochloride, 13.8 g of benzyl chloride, 22.1 g of triethylamine and 120 ml of toluene was stirred at reflux for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated and distilled under reduced pressure to obtain 11.8 g of 1-benzyl-3-hydroxypiperidine (yield: 56.9%). b.p.: 125°-126° C./3.5 mmHg
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[N:13]2)=[N:6][CH:7]=1.Cl.Cl[CH2:34][CH2:35][N:36](CCCl)[CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH3:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][C:10]3[CH:29]=[CH:30][CH:31]=[C:8]([C:5]4[N:4]=[CH:3][C:2]([N:1]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:7][N:6]=4)[CH:9]=3)[N:13]=2)=[CH:24][CH:23]=1)(=[O:27])=[O:26]
Reactant: CCN(CCCl)CCCl
Reactant: CS(=O)(=O)c1ccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(N)cn4)c3)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(N5CCNCC5)cn4)c3)n2)cc1
Temperature: 130 °C
Reaction time: 120 h

Procedure:
53.3 1.4 g (3.23 mmol) of 2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(4-methanesulfonylphenyl)-2H-pyridazin-3-one are dissolved in 30 ml of NMP, and 1.59 g (8.72 mmol) of bis(2-chloroethyl)ethylamine hydrochloride and 1.22 g (8.72 mmol) of potassium carbonate are added. The suspension is stirred at 130° C. for 5 days under an argon atmosphere. The reaction mixture is filtered, and the filtrate is stirred into 200 ml of diethyl ether. An oily residue deposits in the process. The residue is purified by means of column chromatography on silica gel. The resultant product is purified by means of preparative HPLC; yield: 41 mg of “A289” trifluoroacetate; HPLC: Rt=2.19 min (method C); LC-MS: 503 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])=[C:12](Cl)[N:11]3[CH:25]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:26]([O:29][C:30]1([CH3:59])[CH2:35][CH2:34][N:33](C2N3C=C(C4C=CC=C(Br)C=4)N=C3C=C(C)C=2C(=O)C(OC)=O)[CH2:32][CH2:31]1)[CH:27]=[CH2:28]>>[CH2:26]([O:29][C:30]1([CH3:59])[CH2:31][CH2:32][N:33]([C:12]2[N:11]3[CH:25]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]=2[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])[CH2:34][CH2:35]1)[CH:27]=[CH2:28]
Reactant: COC(=O)C(=O)c1c(C)c(C)c2nc(-c3cccc(Br)c3)cn2c1Cl
Reactant: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Yield: 60 %

Procedure:
Prepared from methyl 2-(2-(3-bromophenyl)-5-chloro-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate in 60% yield following the same procedure as methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate. LCMS (ESI, M+1): 540.20.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:17]([NH2:21])([NH2:20])(=[O:19])=[O:18].Cl>C(O)C>[C:1]1([C:7]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:21][S:17](=[O:19])(=[O:18])[N:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: CCO
Product: O=S1(=O)N=C(c2ccccc2)C(c2ccccc2)=N1
Reaction time: 8 h

Procedure:
Benzil (10 g, 48 mmol) and sulfamide (4.6 g, 48 mmol) were combined in anhydrous, denatured ethanol (100 mL) and dry hydrogen chloride gas was bubbled into the reaction mixture until the temperature reached 55° C. The mixture was heated at reflux for 2 hrs, allowed to equilibrate and proceed overnight at room temperature. Concentration of the mixture gave a light yellow solid which was triturated first with water then with ether yielding 10.74 g (83%) of a white solid. The solids may be recrystallized if necessary from acetone to give white crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[C@@H:15]([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:21]1([C:27]2[S:28][CH:29]=[C:30]([C:32](O)=[O:33])[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:20])[C@@H:15]([NH:19][C:32]([C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)=[O:33])[CH:16]([CH3:17])[CH3:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)C(C)C)CC1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](NC(=O)c2csc(-c3ccccc3)n2)C(C)C)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 8, step 8.3, 4-((S)-2-amino-3-methyl-butyryl)-piperazine-1-carboxylic acid butyl ester (prepared as described in WO2008044217) replacing piperazine-1-carboxylic acid butyl ester, phenyl-1,3-thiazole-4-carboxylic acid replacing intermediate 8.2 and using CH2Cl2 instead of CH2Cl2/THF. The compound was however purified by CC (EtOAc/Hept 0:1 to EtOAc/Hept 1:0).
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[CH2:19]([O:24][CH:25]1[CH:27]([C:28](O)=[O:29])[C:26]1([CH3:32])[CH3:31])[CH2:20][CH2:21][CH2:22][CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[CH2:19]([O:24][CH:25]1[CH:27]([C:28]([O:18][CH:3]([C:1]#[N:2])[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=2)=[O:29])[C:26]1([CH3:31])[CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CCCCCOC1C(C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCOC1C(C(=O)OC(C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of α-cyano-4-fluoro-3-phenoxybenzyl alcohol (437 mg., 1.8 mmol), 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of DMF is added N,N'-dicyclohexylcarbodiimide (2 mmol). The reaction mixture is stirred, under nitrogen, for about two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueons sodium bocarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph eluting with ether/hexane to yield α-cyano-4-fluoro-3-phenoxybenzyl 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:36]I)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:36][O:14][C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1cnc(-c2ccc(Cl)cc2)cn1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OCC)C1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)cn2)CCN(C(=O)c2ccccc2OCC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 5-(4-chloro-phenyl)-pyrazin-2-ol (Preparation 25) and 1-(2-ethoxy-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 16) to afford the racemate as a white solid (86 mg, 30%)
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[K+].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C([O-])=O.CCN(CC)CC.[Mg+2].[Cl-].[Cl-]>CC#N>[CH2:18]([O:17][C:11](=[O:16])[CH2:12][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Cl:1])=[O:8])[CH3:19]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1sccc1Cl

Procedure:
Prepared from 3-chloro-2-thiophenecarbonyl chloride [CAS-No. 86427-02-3] by reaction with ethyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure H (method a). Obtained as a brown oil (6.84 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:20][C:21]1[N:22]=[C:23]([NH2:28])[N:24]=[C:25]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:26]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)n1

Procedure:
67 mg (0.24 mmol) of 3-fluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 40 mg (0.24 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 4 ml of water/ethanol 1:1. 25 μl (0.29 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7 and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)OCC2C=CC=CC=2)=[C:11]([C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[CH:10][C:11]=1[C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27]
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
To a solution of benzyl (4-{[tert-butyl(dimethyl)silyl]-oxy}-2-{[methoxy(methyl)amino]carbonyl}phenyl)carbamate (91 g, 0.20 mol) in ethanol (250 ml)-tetrahydrofuran (250 ml) was added 5% palladium-carbon (25 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was crystallized from n-hexane to give 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (44 g, yield 70%) as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]([C:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[C:4]([CH3:8])=[N:3]1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(=O)n(C)[nH]1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1=NN(C)C(=O)C1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
1,3-Dimethylpyrazole-5-one above (11.2 g) and triethylamine (10.2 g) were dissolved in dry benzene and phenyl isocyanate (12 g) added. The mixture was stirred 16-18 hrs at room temperature, whereupon it was extracted with water (4 × 50 ml). The combined aqueous extracts were acidified with dilute hydrochloric acid and the mixture refrigerated for several hours. The product was then recovered by filtration and dried. 4,5-dihydro-1,3-dimethyl-5-oxo-N-phenyl-4-pyrazolecarboxamide (17.5 g, 76%) was obtained as a colourless powder, m.p. 231-233° C.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[NH:28][C:29](=[O:37])[O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:13]1=[O:38])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:19][C@H:18]2[NH:28][C:29](=[O:37])[O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[C:13]1=[O:38]
Reactant: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Reaction time: 1 h
Yield: 99 %

Procedure:
A sample of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate and its 5S diastereomer (68 mg, 0.141 mmol; see Example 11, Step 4) was dissolved in MeOH (3 mL) prior to the addition of 10% Pd/C (100 mg, 0.940 mmol) and a hydrogen balloon. After 1 h, the solution was filtered and concentrated in vacuo. The reaction was then set-up again with fresh reagents. After 1 h, the solution was filtered and concentrated to give 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate as a mixture with its 5S diastereomer (139.4 mg, 0.338 mmol, 99% yield): LC/MS found [M+H]+=413.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([Sn](CCCC)(CCCC)CCCC)=[N:29][CH:30]=1>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.C1(C)C=CC=CC=1>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[C:4]([CH:16]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:18]=2)[C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:6])=[N:29][CH:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(OC(F)(F)F)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(OC(F)(F)F)cc(C(=O)NCc3ccc(C)nc3)c2)nc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-N-((6-methylpyridin-3-yl)methyl)-5-(trifluoromethoxy)benzamide (60 mg, 0.15 mmol), 5-methyl-2-(tributylstannyl)pyridine (0.1 mL, 0.3 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) and toluene (4 mL) under argon was subjected to microwave irradiation at 120° C. for 2 hours. LC-MS indicated strong peak of starting material. The mixture was degassed with nitrogen and re-applied to microwave irradiation at 120° C. for 2 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified via preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the desired product as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCC3)c(F)c21
Yield: 66.5 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (0.43 g), pyrrolidine (1.2 g), and pyridine (3 ml) was refluxed for 6 hours. The solvent was evaporated off. The residue was treated with water, acidified with acetic acid, and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The solid was recrystallized from a mixture of DMF and ethanol and gave 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)quinoline-3-carboxylic acid (0.34 g), mp 284°-286° C. (decomp.).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:5]=1.[OH-].[Li+].Cl>O1CCCC1.CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][C:6]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(OC)c(OCCN2CCOCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1OCCN1CCOCC1
Reaction time: 8 h

Procedure:
To stirred solution of the product of step 1 (0.740 g, 2.5 1 mmol) in 1:1 tetrahydrofuran/methanol (20 mL) was added 1 N aqueous lithium hydroxide (5.0 mL, 5.0 mmol). The reaction was allowed to stir overnight and then treated with 1 N aqueous hydrochloric acid (5.0 mL, 5.0 mmol). The solution was concentrated with 1 N aqueous of crude product and sodium chloride as a tacky white solid. This material was used without further purification in the next step.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:19](OCC)(OCC)(OCC)[CH3:20]>>[CH3:19][C:20]1[N:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[N:8][C:3]2=[N:1][N:2]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1nccc(-c2cccc(C(F)(F)F)c2)n1
Product: Cc1nnc2nc(-c3cccc(C(F)(F)F)c3)ccn12

Procedure:
A mixture of 1.0 g. of 2-hydrazino-4-(m-trifluoromethylphenyl)pyrimidine and 25 ml. of triethyl orthoacetate is refluxed for 12 hours. On cooling the desired compound is isolated by filtration, m.p. 232°-234° C.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:17][O:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][CH2:13]2)(=O)=O)=CC=1.CN(C=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>O>[N:29]([CH:12]1[CH2:17][O:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:14][CH2:13]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC2COC(c3ccccc3)OC2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1COC(c2ccccc2)OC1
Temperature: 105 °C
Reaction time: 48 h
Yield: 84.1 %

Procedure:
To a 1 L round bottom flask was added 2-phenyl-1,3-dioxan-5-yl 4-methylbenzenesulfonate (40 g, 120 mmol) and DMF (500 mL). NaN3 (31.3 g, 478 mmol) was added as a solution in water (150 mL). The reaction was stirred at 105° C. for 2 days. The reaction was then concentrated to dryness. The solid was dissolved in water (700 mL) and extracted into EtOAc (3×500 mL). The combined organic layers were washed with water (5×) and concentrated to dryness to afford an orange solid. The material was then recrystallized from hexanes to afford 20.7 g (84% yield) of 22 as a pale brown solid. 1H NMR (CDCl3, 400 MHz), δ: 3.67 (2H, pseudo t, J=11.59 Hz), 3.78-3.88 (1H, m), 4.36-4.04 (2H, m), 7.36-7.39 (3H, m), 7.45-7.47 (2H, m). Mass Spec (lo-res): Calc'd for C10H11N3O2: 205.09; found: 178.1 (M+H−N2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.C(O)(=O)C>O>[CH2:12]([N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[C:19](=[O:20])[C:18]4[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=4[C:16]3=[O:21])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[C:13]#[CH:14]
Reactant: C#CCN1C(=O)COc2ccc(N)cc21
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: C#CCN1C(=O)COc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 30.1 %

Procedure:
A mixture of 6-amino-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.8 g), 3,4,5,6-tetrahydrophthalic anhydride (0.61 g) and acetic acid (20 ml) was heated under reflux for 2 hours. After being allowed to cool, water was added to the mixture, and the precipitated crystals were collected by filtration and washed with water. Recrystallization from ethanol gave 2-[4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.4 g). m.p., 205°-206° C.