Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(C)C.[NH2:22][C:23]([NH2:25])=[S:24]>>[NH2:25][C:23]1[S:24][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:22]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)Cc1ccc(Cl)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1sc(N)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
In a 100 mL round bottomed flask, to a solution of ethyl 2-bromo-4-(4-chlorophenyl)-3-oxobutanoate (990 mg, 3.1 mmol) in isopropyl alcohol (20 mL, 300 mmol) was added thiourea (590 mg, 7.8 mmol) and the resulting mixture was stirred at reflux for 16 hours. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was suspended in EtOAc (50 mL) and then washed with a saturated aqueous solution of NaHCO3 (50 mL), brine (50 mL). The resulting organic layer was dried over anhydrous MgSO4, filtered, and concentrated to afford ethyl 2-amino-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (900 mg, yield>99%) as a yellowish solid that was used without further purification. LC/MS (FA) ES+ 297, 299.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCNCCO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCNCCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-[(2-aminoethyl)amino]ethanol. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (d, J=7.6 Hz, 1 H), 7.81 (d, J=6.8 Hz, 1 H), 7.61-7.57 (m, 2 H), 7.43-7.38 (m, 2 H), 7.24 (d, J=7.6 Hz, 1 H), 6.02 (s, 1 H), 5.12 (s, 2 H), 4.51 (brs, 2 H), 3.69 (t, J=5.2 Hz, 2 H), 3.55-3.52 (m, 2 H), 3.49 (t, J=6.0 Hz, 2 H), 3.01 (t, J=6.0 Hz, 2 H), 2.83 (t, J=5.6 Hz, 2 H), 2.38 (s, 3 H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH:19]=[CH:20]N(C)C)[CH:15]=[CH:16][CH:17]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=CC(=O)c1cccc(Cl)c1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccc(Cl)c3)ccnc12
Yield: 43.7 %

Procedure:
A mixture of 13.9 g of 4-amino-5-imidazolecarboxamide hydrochloride, 24.0 g of 3'-chloro-3-dimethylaminoacrylophenone (U.S. Pat. No. 4,209,621, Ex. 50) and 200 ml glacial acetic acid was heated at reflux for 5 hours. The liquid was evaporated in vacuo to give a yellow solid. The excess acid was neutralized with saturated sodium bicarbonate solution and this mixture was filtered and the solid was washed with water and then was dried. Recrystallization from ethanol-methanol gave 10.2 g of the desired product as yellow crystals, mp 252°-254° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:47]([O:49]CC=C)=[O:48])[CH2:6][C:7]1[CH:44]=[CH:43][C:10]([N:11]([C:34](=[O:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:12]2[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=2[C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:9]([CH2:45][CH3:46])[CH:8]=1)(=[O:3])[CH3:2].N1CCOCC1>ClCCl.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>[C:1]([NH:4][C@H:5]([C:47]([OH:49])=[O:48])[CH2:6][C:7]1[CH:44]=[CH:43][C:10]([N:11]([C:34](=[O:42])[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:12]2[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=2[C:14]([O:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])=[C:9]([CH2:45][CH3:46])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)C(Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)c(CC)c1)NC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: CCc1cc(C[C@H](NC(C)=O)C(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 103.4 %

Procedure:
A mixture benzhydryl 2-{4-[2-(acetylamino)-3-(allyloxy)-3-oxopropyl][tert-butoxy(oxo)acetyl]-2-ethylanilino}benzoate (3.4 g, 4.8 mmol), Pd(Ph3P)4 (166 mg, 0.144 mmol) and morpholine (0.5 ml, 5.8 mmol) in dichloromethane (25 mL) was stirred under N2 atmosphere for 2 hours, partitioned between ethyl acetate and water (75 mL, 1:1). The organic phase was washed with 1N HCl (1×25 mL), brine (1×25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide the titled compound (3.3 g). MS (ESI(+)) m/e 665 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.51-7.98(m, 2H), 7.73-6.86 (m, 16H), 4.53-4.33 (m, 1H), 3.12-2.76 (m, 2H), 2.58-2.42 (m, 2H), 1.82-1.77 (m, 3H), 1.22-0.78 (m, 3H), 1.06, 1.04, 1.00 (s, s, s, 9H).
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:69][C:70]1([CH3:83])[O:74][C:73](=[O:75])[NH:72][C@H:71]1[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=1[CH3:82]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:69][C:70]1([CH3:83])[O:74][C:73](=[O:75])[N:72]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18]=3[N:17]=[CH:16][CH:15]=[CH:14]4)=[O:7])=[CH:4][CH:3]=2)[C@H:71]1[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=1[CH3:82]
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Reactant: Cc1ccccc1[C@@H]1NC(=O)OC1(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccccc1[C@@H]1N(c2ccc(C(=O)Nc3cccc4cccnc34)cc2)C(=O)OC1(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 26.8 %

Procedure:
To a nitrogen purged solution of 4-iodo-N-(quinolin-8-yl)benzamide (Intermediate A) (250 mg, 0.66 mmol) in 1,4-dioxane (3 mL) were added cesium carbonate (435.37 mg, 1.33 mmol), xantphos (77.31 mg, 0.13 mmol), Pd2(dba)3 (61.18 mg, 0.06 mmol) and (S)-5,5-dimethyl-4-(o-tolyl)oxazolidin-2-one (164.55 mg, 0.80 mmol). The mixture was purged with nitrogen for 5-10 minutes and then stirred for 3 hours at 100° C. After completion of the reaction (monitored by TLC, TLC system: 30% EtOAc in hexane), the reaction mixture was allowed to cool to ambient temperature and filtered through Celite® brand filter aid. The filtrate was concentrated and purified by column chromatography using silica gel and eluting with 30-40% EtOAc in hexane to afford (S)-4-(5,5-dimethyl-2-oxo-4-(o-tolyl)oxazolidin-3-yl)-N-(quinolin-8-yl)benzamide (80 mg, 26.51%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.68-8.66 (m, 1H), 8.46 (dd, J=8.3, 1.5 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.73-7.61 (m, 5H), 7.31 (d, J=7.2 Hz, 1H), 7.23-7.15 (m, 2H), 6.96 (d, J=6.7 Hz, 1H), 5.68 (s, 1H), 1.71 (s, 3H), 0.95 (s, 3H). In CD3OD: the singlet appeared for 3H at δ 2.52 (s, 3H). m/z (ESI) 452.2 (M+H)+.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=3)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.C(P(CCCC)CCCC)CCC.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([CH:17]=[C:18]([CH3:20])[CH:19]=3)[O:21][CH2:35][CH2:36][CH2:37][OH:38])(=[O:11])=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of 3-(benzo-2,1,3-thiadiazole-4-sulfonyloxy)-5-methylphenol (645 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a pale yellow oil (615 mg, 82%). 1H-NMR (300 MHz, CDCl3) δ 8.35 (d, J=8.7 Hz, 1H), 8.26 (d, J=7.1 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 6.59 (s, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.80 (t, J=6.0 Hz, 2H), 2.21 (s, 3H), 1,96 (m, 2H), 1.65 (br s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[ClH:14].[H][H]>C(O)C.[Pd]>[ClH:14].[NH2:2][CH2:1][C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(C#N)nc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(CN)nc1
Reaction time: 12 h

Procedure:
To a solution of ethyl 6-cyano-3-pyridinecarboxylate (3.75 g) and cone. HCl (7.5 mL) in 225 mL ethanol was added 10% Pd/C (wet, 375 mg) and the reaction mixture was hydrogenated using hydrogen balloon and stirred for 12 h. Solution was filtered through celite and ethanol was evaporated to give ethyl 6-(aminomethyl)-3-pyridinecarboxylate HCl as a white solid, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16](O)=[O:17]>C(OC(=O)C)(=O)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]1[CH2:15][C:16](=[O:17])[O:21][C:20](=[O:22])[CH2:19]1
Reactant: O=C(O)CC(CC(=O)O)c1ccc2oc3c(c2c1)CCCC3
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2ccc3oc4c(c3c2)CCCC4)CC(=O)O1

Procedure:
30.2 g (0.1 mol) of 3-(6,7,8,9-tetrahydro-2-dibenzofuranyl)-glutaric acid are refluxed with 100 ml of acetic anhydride for 11/2 hours. On leaving the cooled dark solution to stand, a crystalline precipitate forms and is filtered off after 48 hours and washed with cold toluene. The 3-(6,7,8,9-tetrahydro-2-dibenzofuranyl)-glutaric anhydride thus obtained melts at 164°-166°. After concentrating the filtrate under a waterpump vacuum, an addititonal amount of 3-(6,7,8,9-tetrahydro-2-dibenzofuranyl)-glutaric anhydride is obtained as yellowish crystals with the same melting point.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]([C:11]#[N:12])=[N:7][C:8]=1[O:9][CH3:10].Cl>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]([CH2:11][NH2:12])=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C)c(C#N)nc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c(CN)nc1OC
Reaction time: 8 h

Procedure:
To a solution of 5,6-dimethoxy-3-methylpyridine-2-carbonitrile (1-6e, 577 mg, 3.24 mmol) in MeOH (27 mL) was added Pearlman's catalyst (455 mg, 0.648 mmol, 20 weight percent) and concentrated HCl (2.13 mL, 25.9 mmol, 12M). The system was then stirred under an atmosphere of hydrogen (45 psi) overnight. The reaction contents were filtered through a pad of celite and methanol was removed in vacuo. The crude mixture was then basified using saturated Na2CO3 and then extracted using 4:1 Chloroform:Ethanol. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to yield a crude product which was purified through column chromatography (SiO2, 0-12% MeOH (containing 10% NH4OH) in dichlormethane) to give the desired product (1-6) as a yellow oil. ESI+ MS [M+H]+ C9H15N2O2: M−16 (—NH2)=167.3.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][N:15]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]2)[CH2:8][C:7]1=[O:22])(=O)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:26][NH2:27])[CH:24]=[CH2:25]>C(O)C>[CH2:23]([O:26][NH:27][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][N:15]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]2)[CH2:8][C:7]1=[O:22])[CH2:2][CH2:3][CH3:4])[CH:24]=[CH2:25]
Reactant: CCCC(=O)C1C(=O)CC(CCn2nc(C)cc2C)CC1=O
Reactant: C=CCON
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CCn2nc(C)cc2C)CC1=O

Procedure:
10 parts by weight of 2-butyryl-5-[2-(3,5-dimethylpyrazol-1-yl)-ethyl]-cyclohexane-1,3-dione and 2.5 parts by weight of allyloxyamine in 100 parts by volume of ethanol were stirred for 12 hours at room temperature. The mixture was worked up by a method similar to that described in Example 1. 8.8 parts by weight of 2-(1-allyloxyaminobutylidene)-5-[2-(3,5-dimethylpyrazol-1-yl)-ethyl]-cyclohexane-1,3-dione of nD28 =1.5329 were obtained (Compound No. 2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[N:17]=[CH:18][N:19]=[C:20]3[C:27]=2[C:26]2[C@H:25]([CH2:28][C:29](OCC)=[O:30])[CH2:24][CH2:23][C:22]=2[S:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[OH:30][CH2:29][CH2:28][C@@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:27](=[C:16]([O:15][CH:12]4[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:14][CH2:13]4)[N:17]=[CH:18][N:19]=3)[C:26]1=2
Reactant: CCOC(=O)C[C@@H]1CCc2sc3ncnc(OC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a 50-mL round-bottom flask containing 16.4 (180 mg, 0.38 mmol, 1.00 equiv) in distilled tetrahydrofuran (10 mL) was added LiAlH4 (30 mg, 0.79 mmol, 2.00 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to afford tert-butyl N-(4-[[(3S)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)carbamate (16.5, 100 mg, 61%) as a yellow oil. MS: m/z 434 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li]CCCC.[C:17]([O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:33])N(OC)C)([CH3:20])([CH3:19])[CH3:18]>C(OCC)C>[C:17]([O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:33])[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1cnc2ccccc2c1
Reactant: CON(C)C(=O)CCCCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCCCC(=O)c1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-bromoquinoline (25 g, 120 mmol) in diethyl ether −78° C. was added nBuLi (2.5M THF, 48 ml, 120 mmol) dropwise over 30 minutes. After 30 minutes, 21-2 (3.9 g, 15 mmol), dissolved in 50 ml ether was added dropwise over 10 minutes. After 30 minutes, the cooling bath was removed. After 1.0 hour, the reaction was quenched with sat. NH4Cl. The organic portion was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel, 20-50% ethyl acetate/hexanes) to give 21-3 as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][C:22]([N:32]1[CH:36]=[C:35]([NH2:37])[N:34]=[CH:33]1)([CH3:31])[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>>[CH3:31][C:22]([N:32]1[CH:36]=[C:35]([NH:37][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:34]=[CH:33]1)([CH3:21])[CH2:23][N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: CN1CCN(CC(C)(C)n2cnc(N)c2)CC1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCN(C)CC2)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-[1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-1H-imidazol-4-ylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 25.8, 25.9, 28.2, 28.9, 29.7, 36.5, 46.1, 52.9, 55.0, 55.7, 59.0, 60.9, 68.2, 101.1, 101.3, 104.5, 110.9, 131.3, 137.3, 172.3; MS m/z 503.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:16]([CH:19]3[CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH2:10]2)[CH:5]=[C:4]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24](S(C3C=CC=CC=3)(=O)=O)[CH:23]=2)[CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:16]([CH:19]3[CH2:20][CH2:21]3)(=[O:18])=[O:17])[CH2:10]2)[CH:5]=[C:4]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[NH:24][CH:23]=2)[CH:3]=1
Reactant: COc1cnc2c(c1)c(-c1cc(Cl)nc(NC3CCCC(NS(=O)(=O)C4CC4)C3)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(NC4CCCC(NS(=O)(=O)C5CC5)C4)c3)c2c1
Temperature: 70 °C
Yield: 67.2 %

Procedure:
A solution of Example 260c (0.083 g, 0.135 mmol) in dioxane (2 mL) was treated with 20% NaOH (0.08 mL, 0.135 mmol). The mixture was heated at 70° C. for 90 minutes. The solvent was evaporated. The residue was treated with water and sonicated. The solid was filtered, washed with water, and purified by reverse-phase HPLC as described in Example 56 to give the title compound (43.2 mg) as trifluoroacetic acid salts. 1H NMR (400 MHz, DMSO-d6) ppm 0.83-0.98 (m, 4H), 0.98-1.26 (m, 3H), 1.38 (m, 1H), 1.74 (m, 1H), 1.86-1.98 (m, 2H), 2.31 (d, J=13.43 Hz, 1H), 2.56 (m, 1H), 3.24 (m, 1H, 3.73 (m, 1H), 3.90 (s, 3H), 6.81 (s, 1H), 6.88 (d, J=1.22 Hz, 1H), 7.14 (d, J=8.24 Hz, 1H), 7.79 (d, J=2.75 Hz, 1H), 8.09 (dd, J=7.93, 2.75 Hz, 2H), 12.04 (s, 1H). MS (ESI+) m/z 476.2 (M+H)+.
Reaction SMILES: [C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10]([C:15]#[N:16])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[OH-:17].[Na+].OO>CS(C)=O>[C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10]([C:15]([NH2:16])=[O:17])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:2]1)[CH2:4]2
Reactant: CSc1nc(NC23CC(C2)C3)ncc1C#N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1nc(NC23CC(C2)C3)ncc1C(N)=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a stirring solution of 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carbonitrile (566 mg, 2.436 mmol) in DMSO (7 mL) was added 6 M aqueous sodium hydroxide solution (2.030 mL, 12.18 mmol) and 30% aqueous hydrogen peroxide solution (1.381 mL, 12.18 mmol) at 0° C. The mixture was then stirred at 50° C. for 30 min and then was poured into ice water (50 mL). The solids that formed were stirred in an ice bath for 30 min, filtered, washed with water, and then dried in a vacuum oven overnight at 45° C. to afford 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carboxamide (410 mg, 1.638 mmol, 67.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1H), 7.03-8.34 (m, 2H), 2.43-2.48 (m, 1H), 2.35 (br. s., 3H), 2.09 (s, 6H). MS (ESI) m/z 251.3 [M+1]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:6][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C/C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 104.4 %

Procedure:
Crotonic acid (70 g, 812 mmol) was dissolved in N,N-dimethylformamide (467 ml), which was cooled in an ice bath under nitrogen, and potassium carbonate (61.6 g, 447 mmol) was added. Benzyl bromide (91.7 ml, 772 mmol) was added dropwise to the reaction mixture over 20 minutes. The reaction mixture was stirred at mom temperature for 18 hours. Ethyl acetate was added to the reaction mixture, which was filtered through Celite. The filtered ethyl acetate solution was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (142 g, yield: 99.4%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl.O>CS(C)=O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][N:5]1[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]1
Reactant: Cc1cc(C)[nH]n1
Reactant: ClCc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)n(Cc2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
Powdered potassium hydroxide (1.751 g, 31.2 mmol) was added to a solution of 3,5-dimethylpyrazole (2 g, 20.81 mmol) in anhydrous DMSO (10.40 ml) and the resulting heterogeneous solution was stirred for 1.5 hr at 80° C. before being cooled to room temperature. 2-Chloro benzylchloride (2.64 ml, 20.81 mmol) was then added in 6 M DMSO over 15 min, and the solution was stirred for a further 1.5 hrs. Upon completion as observed by TLC, the reaction was poured over water and the resulting aqueous phase was extracted with two 20 mL portions of CHCl3. The combined organic layers were washed with 100 mL of water, dried with anhydrous MgSO4 and concentrated under reduced pressure to yield 4.55 g (99%) of 1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazole as a clear liquid. 1H NMR (300 MHz, CDCl3) δ 7.41-7.31 (m, 1H), 7.24-7.09 (m, 2H), 6.59-6.50 (m, 1H), 5.90 (s, 1H), 5.31 (s, 2H), 2.26 (s, 3H), 2.15 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 148.32, 139.96, 135.46, 131.96, 129.42, 128.76, 127.72, 127.48, 105.84, 50.12, 13.80, 11.15. HRMS (m/z): [MNa]+ calc for C12H13ClN2Na+243.07. found 243.0651.