Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:17]=3[NH:16][C:15]2=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:27]C(OC(Cl)C)=O>ClCCCl>[ClH:27].[F:25][C:24]1[C:17]2[NH:16][C:15](=[O:26])[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:20][CH2:19][C:18]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2c(F)cccc2CCN1C1CCN(Cc2ccccc2)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: O=C1Nc2c(F)cccc2CCN1C1CCNCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
3-(1-Benzylpiperidin-4-yl)-9-fluoro-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (530 mg, 1.500 mmol) was suspended in 1,2-dichloroethane (10 mL). Mixture was cooled to 0° C. 1-Chloroethyl chloroformate (175 μl, 1.603 mmol) was added to the mixture drop-wise. Reaction was then warmed to reflux and held for 45 minutes. Mixture was concentrated by roto-vap. Residue was dissolved in methanol (10 mL). Reaction was warmed to reflux and held with stirring for 3 hours. Mixture was concentrated by roto-vap. Residue was treated with 20 mL acetone and warmed to reflux for 20 minutes. Resulting solids were filtered off and washed with acetone. Title compound was obtained as tan solid in 67% yield. MS (M+H)+=264.4.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([CH:6](O)[C:7](O)=[O:8])=[CH:4][CH:3]=1.COC(=O)CC1C=CC=CC=1.O.[NH2:25][NH2:26]>C(O)C>[C:5]1([CH2:6][C:7]([NH:25][NH2:26])=[O:8])[CH:11]=[CH:12][CH:2]=[CH:3][CH:4]=1
Reactant: NN
Reactant: O=C(O)C(O)c1ccc(F)cc1
Agent: COC(=O)Cc1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1ccccc1

Procedure:
The following representative compounds in Table 1 were synthesized according to (i) the foregoing procedures by selecting appropriate starting materials (for example, 4-fluoro mandelic acid derivatives (e.g., examples 12-1 and 12-3) were synthesized using commercially available 4-fluoromandelic acid) and (ii) known organic synthesis techniques (for example, treatment of commercially available α-phenylacetic acid methyl ester with hydrazine hydrate in ethanol under with heating provides phenyl-acetic acid hydrazide (see, e.g., Pandeye, S, N.; Manjula, H.; Stables, J. P.; Pharmazie; 2001, 56, 121-124) and treatment of phenyl acetic acid hydrazide with a substituted benzaldehyde in ethanol with heating and in the presence of catalytic acetic acid provides the corresponding substituted phenyl-acetic acid benzylidenehydrazide (see, e.g., Stephanidou-Stephanatou, J.; Lefkopoulou, S; Journal of Heterocyclic Chemistry; 1982; 19; 705-711.0)).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:18]=[CH:17][O:16][CH:15]=1.[NH:19]1[C:27](=[O:28])[C:25](=O)[C:23](=[O:24])[NH:22][C:20]1=[O:21]>O1CCCC1>[Cl:13][C:14]1[CH:18]=[CH:17][O:16][C:15]=1[CH:25]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[NH:19][C:27]1=[O:28]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Clc1ccoc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2occc2Cl)C(=O)N1
Temperature: 25 °C

Procedure:
n-Butyl lithium and an equivalent of diisopropylamine are reacted with an equivalent of 3-chlorofuran for 1.5 hours in tetrahydrofuran at -80° C. according to the procedure of Ly and Schlosser [Helv. Chim. Acta 60 (6), p. 2087 (1977)]. At the same temperature, an equivalent of alloxan in tetrahydrofuran is added dropwise and the mixture allowed to warm to room temperature for 2 hours. 5-(3-Chloro-2-furyl)-2,4,6-(1H,3H,5H)pyrimidinetrione is isolated by the procedure of Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12]>[Pt].[Br-].[Br-].[Zn+2].CO>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12])[NH2:8]
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1Br
Agent: [Pt]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Product: CC(C)c1ccc(N)cc1Br
Yield: 104.1 %

Procedure:
2-Bromo-1-isopropyl-4-nitrobenzene (XI) (20 g, 78.1 mmol, 95.8 GC % by area), methanol (400 ml), platinum on carbon (5% of platinum, poisoned with sulphur, moist with water) (1.0 g, 0.090 mmol) and zinc dibromide (265 mg, 1.18 mmol) were placed in a 600 ml autoclave. The autoclave was subsequently flushed with nitrogen and pressurized to 5 bar with hydrogen at room temperature. The contents of the autoclave were filtered through Celite, washed with methanol and the solvent was distilled off under reduced pressure. 3-Bromo-4-isopropylaniline (17.4 g, 94.5 LC-% by area, 97.7 GC-% by area, >99% of theory) was obtained as a brown oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[N:11]1[CH2:20][CH:19]=[CH:18][C:17]2[N:16]=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]1=2.[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>ClCCl>[N+:21]([C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:11][CH:20]=[CH:19][CH:18]=2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnc2c(c1)N(Cl)CC=C2
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Yield: 0.7 %

Procedure:
A solution of diisopropylethylamine (13.47 g, 0.10 mole) in dichloromethane (25 mL) was added to a solution of 5-chloro-3-nitro[1,5]naphthyridine (18.2 g, 0.086 mol) in dichloromethane (250 mL). A solution of tert-butyl N-(2-aminoethyl)carbamate (16.7 g, 0.10 mol) in dichloromethane (75 mL) was slowly added to the reaction mixture. The reaction mixture was heated at reflux overnight. Additional tert-butyl N-(2-aminoethyl)carbamate (1 g) was added and the reaction mixture was heated at reflux for an additional 3 hours. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with additional dichloromethane, washed with water and with brine, dried, and then concentrated under vacuum to provide a dark solid. This solid was purified by flash chromatography (silica gel eluting with dichloromethane) to provide 24.8 g of 1,1-dimethylethyl N-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethylcarbamate as a canary yellow solid. A portion (0.3 g) was recrystallized from toluene (10 mL) and heptane (10 mL) to provide 0.2 g of canary yellow needles, m.p. 149-151° C. Analysis: Calculated for C15H19N5O4: % C, 54.05; % H, 5.75; % N, 21.01; Found: % C, 54.17; % H, 5.73; % N, 20.90.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@@:12]([CH2:23][CH:24]=[CH2:25])([CH3:22])[C:11]1=[O:26])=[O:4].B1C2CCCC1CCC2.[OH-:42].[Na+].OO>C1COCC1.CCO>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:30])[CH3:31])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[C:11](=[O:26])[C@:12]([CH2:23][CH2:24][CH2:25][OH:42])([CH3:22])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=CC[C@@]1(C)OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@@](C)(CCCO)OC[C@H]2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-((2R,5R)-2-allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (50 mg, 0.11 mmol, 1.0 equiv) in THF (1.0 mL) was added 9-BBN (0.5 M solution in THF, 0.55 ml, 0.27 mmol, 2.5 equiv) at 0° C. The reaction mixture was then stirred at room temperature for 2 hours. To the solution was then cooled in an ice water bath and was added EtOH, followed by aq. NaOH solution and H2O2 aq. solution. During addition the reaction internal temperature was kept between 5° C. and 10° C. The reaction mixture was then heated to reflux for 90 minutes. After cooled at room temperature, the reaction mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the product 26 mg. MW: 462.2 [M+H]+. 1H-NMR (400 MHz, MeOD): δ 6.91 (s, 1H), 4.23 (d, 1H), 3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m, 10H), 1.45 (s, 3H), 1.32 (s, 9H), 1.21 (m, 4H), 1.05 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]3=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.C(O[CH2:24][CH3:25])(=O)C.[CH3:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH:28]1[C:27]2[CH:18]=[C:19]([C:25]3[CH:24]=[CH:12][C:13]([C:2]4[CH:11]=[N:10][C:9]5[C:4](=[C:5]6[CH:19]=[CH:18][CH:17]=[CH:16][C:6]6=[C:7]6[CH:15]=[CH:14][CH:13]=[CH:12][C:8]6=5)[N:3]=4)=[CH:14][CH:15]=3)[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:26]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(C)=O
Reactant: Clc1cnc2c3ccccc3c3ccccc3c2n1
Reactant: CCCCCC
Product: c1ccc2c(c1)cc(-c1ccc(-c3cnc4c5ccccc5c5ccccc5c4n3)cc1)c1ccccc12

Procedure:
The Rf values of the objective substance and 2-chlorodibenzo[f,h]quinoxaline were respectively 0.20 and 0.55, which were found by silica gel thin layer chromatography (TLC) (with a developing solvent of ethyl acetate and hexane in a ratio of 1:10).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])[CH:20]=3)[N:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:14]=2[C:37]([OH:39])=O)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].COS([O:45][CH3:46])(=O)=O.O1CCC[CH2:48]1>>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N:22]([C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])[CH3:48])[CH:20]=3)[N:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:14]=2[C:37]([O:45][CH3:46])=[O:39])=[CH:11][CH:12]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: COc1cccc(Cn2c(C(=O)O)c(-c3ccc(C(C)(C)C)cc3)c3cc(NC(=O)C4CC4)ccc32)c1
Reactant: C1CCOC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N(C)C(=O)C3CC3)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Sodium hydride (192 mg, 0.800 mmol) was added to a cooled (0° C.) and stirred solution of 3-(4-tert-butylphenyl)-5-[(cyclopropylcarbonyl)amino]-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid (Example 167, 94.5 mg, 0.190 mmol) in tetrahydrofuran (5 mL). The cold bath was removed and stirring was continued for 1 h. Dimethylsulfate (0.75 mL, 101 mg, 0.80 mmol) was added and the reaction was stirred for an additional 2 h. The reaction was quenched with water (50 mL) and then extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography of the residue over silica gel using 40% ethyl acetate/hexane afforded 894 mg (90%) of the desired product. The product had: 1H NMR (300 MHz, CDCl3) δ 7.38-7.50 (m, 3 H), 7.28-7.36 (m, 3 H), 7.11-7.24 (m, 2 H), 6.59-6.76 (m, 3 H), 5.70 (s, 2 H), 3.90 (s, 3 H), 3.69 (s, 3 H) 3.21 (s, 3 H), 1.34 (s, 9 H), 1.15-1.35 (m, 1 H), 0.87-0.97 (m, 2 H), 0.48-0.58 (m, 2 H); mass spectroscopy gave MH+=525.3 (calc'd exact mass for C33H36N2O4=524.27).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH:4]=[CH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]2[CH3:1]
Reactant: Cn1ccc2c(C#N)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ccc2c(CN)cccc21
Temperature: 50 °C
Yield: 90.9 %

Procedure:
Dissolve 1-methylindole-4-carbonitrile (1.0 g, 6.18 mmol) in anhydrous THF (10 mL) and add slowly to 1M lithium aluminum hydride in THF (12.4 mL, 12.37 mmol) at ambient temperature. Heat the reaction mixture at 50° C. for 17 h and cool to ambient temperature. Quench the reaction mixture with water until a granular precipitate starts to form and filter through a pad of Celite®. Evaporate the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.9 g, 91%). GC-MS m/z: 160 (M*).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)#[N:2].[Br:12]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.Br>[Br:12][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:11]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: BrBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(C(=O)CBr)cc1

Procedure:
To a mixture of para-cyanoacetophenone (52 g, 0.36 mol) in chloroform (520 ml) and 48% HBr (5.2 ml), a solution of bromine (19.3 ml) in chloroform (52 ml) was added dropwise over a period of 20 min. The mixture was stirred for 3 h at room temperature and neutralized to pH7 with sat. NaHCO3. The organic layer was washed with sat. NaCl and dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel (AcOEt/n-hexane=1/3 as an eluent) and recrystallized to obtain 2-bromo-4′-cyanoacetophenone as a colourless plate (23.4 g, 29%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[CH2:5]2.Cl[C:16]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=1>CC(O)(C)C>[CH3:14][O:13][C:3]1[C:2]([NH:1][C:16]2[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([CH3:12])[C:7]2=[O:11]
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1c(N)ccc2c1CN(C)C2=O
Solvent: CC(C)(C)O
Product: CNc1nc(Nc2ccc3c(c2OC)CN(C)C3=O)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 22.7 %

Procedure:
To a solution of 5-amino-4-methoxy-2-methylisoindolin-1-one (81 mg, 0.42 mmol) in t-BuOH (3 mL) was added 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (89 mg, 0.42 mmol). The mixture was heated at 100° C. for 1 h under microwave irradiation. The solvent was evaporated in vacuo and the residue was purified by reverse-phase prep-HPLC to afford the title compound as a white solid (35 mg, yield 23%). m/z (ES+APCI)+: [M+H]+368.1. 1H-NMR (Bruker, 500 MHz, MeOD) δ 8.65 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 7.43 (d, J=8.5 Hz, 1H), 4.69 (s, 2H), 4.06 (s, 3H), 3.19 (s, 3H), 3.05 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].ClCCl.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(=O)O)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(CO)ccc1OC
Reaction time: 2 h
Yield: 87 %

Procedure:
At 0° C., under an inert atmosphere, 1.5 g of 4-(2-chloro-4-methoxyphenyl)-5methyl-2-[N-(5-carboxy-2-methoxyphenyl)-N-propylamino]thiazole are dissolved in 11 ml of tetrahydrofuran. 5 ml of a 1 M solution of lithium aluminium hydride in tetrahydrofuran are added slowly so that the temperature of the mixture does not exceed 10° C. After 2 hours at room temperature, the reaction mixture is cooled with the aid of an ice bath and then hydrolyzed slowly. The crude material is alkalanized before being filtered over sodium sulphate. After evaporation under vacuum, the product is obtained by purification on a silica gel; eluent: dichloro-methane/ethyl acetate 95/5 (v/v); yield=87%. The expected product is in the form of a powder; m.p.=115° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:41][CH2:40][O:39][CH2:38]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (3.89 g) in dry N,N-dimethylformamide (46 ml) at room temperature and under was added potassium carbonate (6.14 g) in one go. The reaction was heated to 60° C., under nitrogen, for 1.5 hours. A solution of tetrahydro-3-furanylmethyl methanesulfonate, Isomer 1 (2.2 g) in dry N,N-dimethylformamide (2 ml) was added via a Pasteur pipette and the reaction heated at 70° C. for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with brine (20 ml). The organic layer was concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluant (10-50%) to afford the title compound as a clear viscous oil (2.79 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:18].C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])[CH2:23][NH:22][CH2:21]1)=[O:18]
Reactant: COCCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(5-methoxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (123 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (76 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH:24](/B(O)O)=[CH:25]/[CH3:26]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][C:11]1[S:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:17])[N:4]=[CH:3][C:2]=1/[CH:24]=[CH:25]\[CH3:26]
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Reactant: C/C=C\B(O)O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C/C=C\c1cnn(C)c1-c1cc(C(=O)OC)sc1C
Yield: 87.1 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (320 mg, 1.015 mmol)[prepared in Example 99], potassium carbonate (702 mg, 5.08 mmol), bis(tri-t-butylphosphine)palladium(0) (25.9 mg, 0.05 mmol) and (1Z)-1-propen-1-ylboronic acid (87 mg, 1.01 mmol) in 1,4-dioxane (5.3 ml) and water (1.3 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-methyl-4-{1-methyl-4-[(1Z)-1-propen-1-yl]-1H-pyrazol-5-yl}-2-thiophenecarboxylate (243 mg, 0.88 mmol, 87% yield) as a yellow oil: LCMS (ES) m/z=277 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=C)[CH:5]=[C:6]([F:8])[CH:7]=1.I([O-])(=O)(=O)=[O:21].[Na+].[OH2:26]>C(Cl)(Cl)(Cl)Cl.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[C:10]([OH:21])=[O:26])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O
Reactant: C=C[C@H](NC(=O)OC(C)(C)C)c1cc(F)cc(Br)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1cc(F)cc(Br)c1
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of (S)-tert-butyl (1-(3-bromo-5-fluorophenyl)allyl)carbamate (1.235 g, 3.74 mmol) in CCl4 (4 mL), acetonitrile (4 mL) and water (6 mL) was treated with sodium periodate (1.680 g, 7.85 mmol) and RuCl3 (16 mg, 0.075 mmol). After 1 h, the reaction was complete. The reaction was partitioned between ethyl acetate and water. The organics were washed with brine, then filtered over celite and concentrated. The crude was redissolved in benzene, then filtered and concentrated again to provide crude (R)-2-(3-bromo-5-fluorophenyl)-2-((tert-butoxycarbonyl)amino)acetic acid (1.30 g, 99% yield) which was used directly. LCMS (m/z): 348.2 (MH+), 0.52 min.
Reaction SMILES: [Li][CH:2]([CH2:4][CH3:5])[CH3:3].[C:6](#[N:9])[CH2:7][CH3:8].[OH2:10]>C1COCC1>[CH2:4]([C:2]1[NH:9][C:6](=[O:10])[C:7]2[C:5]([CH:3]=1)=[CH:4][CH:2]=[CH:3][CH:8]=2)[CH3:5]
Reactant: O
Reactant: [Li]C(C)CC
Reactant: CCC#N
Solvent: C1CCOC1
Product: CCc1cc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
O-Toluic acid (2.0 g. 14.7 mmol) in THF (75 ml) was cooled to −78° and sec—BuLi (22.5 ml) added slowly. The resulting red solution was warmed to 0° for 30 min then cooled to −78°. Propionitrile (1.05 ml) in THF (10 ml) was added. the solution allowed to warm and stirred to RT for 16 h. Water (100 ml) was added and the product extracted into EtOAc (100 ml), washed with dilute HCl solution, water, brine, dried ((Na2SO4), and concentrated in vacuo. The crude product was purified by chromatography (SiO2; 1-5% DCM/MeOH) ) to give the title compound (1.12 g, 44%) as a white solid. δH (CDCl3) 8.37 (1H, d, J 8.0 Hz). 7.63 (1H, t, J 8.0 Hz), 7.48 (1H, d, J 8.0 Hz). 7.42 (1H, t, J 8.0 Hz), 6.33 (1H, s), 2.67 (2H, q, J 7.6 Hz), 1.33 (3H, t, J 7.6 Hz). m/z (ES+, 70V) 174 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)[CH3:2].[C:18](O)(=O)C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[C:5]2[NH:4][C:1]([CH3:2])=[N:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:8])[CH3:18]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(C)=O
Reactant: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(C)[nH]c12

Procedure:
A mixture of 8.03 g of methyl 2-acetylamino-3-nitrobenzoate, 18.8 g of reduced iron, 20 ml of acetic acid and 40 ml of ethanol was heat-refluxed for 18 hours. After the solvent was concentrated, chloroform and 10% hydrochloric acid were added to the residue for extraction. The aqueous layer was acidified with a saturated aqueous solution of sodium hydrogencarbonate, and was extracted with chloroform. Chloroform was then distilled off under reduced pressure to give 1.61 g of 4-ethoxycarbonyl-2-methylbenzimidazole (296).