Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1.BrC1C=CC(N)=C(F)C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].ClC1N=C(Cl)C=CC=1C(O)=[O:43]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:17][C:16](=[O:43])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Nc1ccc(Br)cc1F
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid: To a solution of 4-bromo-2-fluorophenylamine (10.4 g, 54.7 mmol) in THF (25 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (83.3 mL, 83.3 mmol, 1 M solution in hexanes) dropwise over 15 minutes. The reaction mixture was stirred for one hour at −78° C. 2,6-Dichloro-nicotinic acid (5.00 g, 26.0 mmol) was then added dropwise as a solution in THF (15 mL) and the reaction mixture was allowed to warm from −78° C. to room temperature and stir for 16 hours. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to 0-2 with 6 N HCl and then diluted with EtOAc. The organic layer was separated and washed with H2O, saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated several times with ethyl acetate and the resulting solid was collected, washed with dichloromethane and dried under vacuum to yield 7.50 g (83%) pure desired product as a dark pink solid.
Reaction SMILES: [C:1]([NH:6][CH:7]([C:14]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=[O:15])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:2]([C:1]1[O:15][C:14]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(NC(=O)C(C)C)C(=O)c1ccco1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(C(C)C)oc1-c1ccco1
Yield: 89 %

Procedure:
12.0 g of ethyl 3-isobutyrylamino-3-(2-furylcarbonyl)propionate, 60 ml of chloroform and 32.7 g of phosphorus oxychloride are treated in the same manner as described in Example 2. 10.0 g of ethyl 2-[2-isopropyl-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained as an oil. Yield: 89.2%
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:32]=[CH:31][C:15]([O:16][CH2:17][C@@H:18]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][C:13]=1F)(=[O:5])[NH2:4]>O1CCCC1>[CH3:21][CH:20]([CH3:22])[CH2:19][C@H:18]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:17][O:16][C:15]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:3](=[O:5])[NH:4][C:32]=2[CH:31]=1
Reactant: CC(C)C[C@@H](COc1ccc(-c2ccncc2C(N)=O)c(F)c1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](COc1ccc2c(c1)[nH]c(=O)c1cnccc12)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Sodium hydride (5.56 mg, 0.232 mmol, 60% in mineral oil) was taken in tetrahydrofuran (1 mL) and cooled to 0° C. The suspension was treated with (S)-tert-butyl (1-(4-(3-carbamoylpyridin-4-yl)-3-fluorophenoxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.116 mmol) in THF (1 mL) dropwise and the temperature was maintained at 0° C. for 30 min. The reaction mixture was then allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with ice and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (1×5 mL), dried (Na2SO4) and concentrated under reduced pressure to afford (S)-tert-butyl (4-methyl-1-((5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (40 mg, 0.097 mmol, 84% yield) as a colorless solid. LC/MS (ESI) m/e 412.2 [(M+H)+, calcd for C23H30N3O4 412.2]; LC/MS retention time (method C): tR=1.97 min.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH3:19])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:20]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:20][C:9]1[S:8][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH3:19])=[N:6][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)cs1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(Br)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
4-(4-tert-Butylthiazol-2-yl)-3-methylbenzoic acid (Step B, 7.0 g, 25.4 mmol) was dissolved in 30 mL of acetic acid, and bromine (8.1 g, 50.8 mmol) was added. The red mixture was stirred at room temperature for 20 minutes to see complete conversion by LCMS. Excess sodium bisulfite was added until the reaction mixture became colorless. The mixture was concentrated to dryness, dry-loaded to a silica gel column, and purified, eluting with 10% methanol in methylene chloride, to get 4-(5-bromo-4-tert-butylthiazol-2-yl)-3-methylbenzoic acid as a white solid (8.5 g, 94% yield over 2 steps). LCMS (M+H)+: 355.9; 353.9. 1H NMR (CDCl3, 500 MHz): 7.92 (s, 1H), 7.84 (m, 2H), 2.60 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH:25]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>C(O)(=O)C>[CH3:25][O:21][C:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[N:19][CH:18]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To 2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (150 mg, 0.486 mmol) in an oven dried round-bottom flask is added methanol (1.0 mL) and benzene (3.7 mL) under nitrogen, and the reaction stirred for 10 min. Trimethylsilyldiazomethane (0.34 ml, 0.678 mmol) is added and the reaction stirred for 1 h. Glacial acetic acid (0.05 ml) is then added until the yellow color has disappeared. The reaction mixture is concentrated under reduced pressure and co-evaporated with benzene. It is dried under high vacuum to yield the title compound as a white solid (155 mg, 99% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(O[CH2:32][CH3:33])(=O)C>CCC(C)=O>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:11][CH2:12][N:13]3[CH2:33][CH2:32][CH2:15][CH2:14]3)[CH:18]=2)[NH:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1[nH]c2ccc(OCCN3CCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 26.8 %

Procedure:
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (5.0 g, 17.8 mmol), K2CO3 (6.14 g, 44.4 mmol), KI (0.029 g, 1.78 mmol) and N(chloroethyl)cyclopentyl hydrochloride (3.02 g, 17.8 mmol) were mixed together in MEK (100 mL) and refluxed at 80° C. for 72 hours. The reaction was then permitted to cool and diluted with ethyl acetate. Then solution was washed with deionized water and brine, dried on Na2SO4, filtered and concentrated under reduced pressure. The resulting crude mixture was then chromatographed (10% MeOH/CH2Cl2) to give 1.20 g (26.8%) of the desired ester as a white solid, mp 110-116° C. 1HNMR (400 MHz, DMSO): δ 1.64 (b,4H), 2.45 (b, 4H), 2.59 (s, 3H, ArCH3), 4.00 (m, 2H), 5.27 (s, 2H), 6.70 (dd, J=8.54 Hz, J=2.44 Hz, 1H), 7.15 (d, J=8.79 Hz, 1H), 7.28-7.47 (m, 5H), 11.71 (s, NH); MS(APCI+) m/z 379.1(MH+). Anal. Calcd for C23H26N2O3.0.42H2O: C, 71.56;H, 7.01; N, 7.26. Found: C, 71.36: H, 6.93: N, 7.04; IR(KBr): 3371, 2909, 1665, 1481, 1448, 1178, 1087 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[CH:14]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:1][C:2]1[C:3]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][C:5]2[O:9][C:8]([C:10]([N:30]3[CH2:31][CH2:32][C:27]([F:33])([F:26])[CH2:28][CH2:29]3)=[O:12])=[C:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: FC1(F)CCNCC1
Reactant: Cc1c(C(=O)O)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCC(F)(F)CC2)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Yield: 99.1 %

Procedure:
In a flask were mixed together the above prepared 5-chloro-6-(1-isopropyl-piperidin-4-yloxy)-3-methyl-benzofuran-2-carboxylic acid (0.200 g, 0.406 mmol, corrected for purity), 4,4-difluoropiperidine hydrochloride (0.077 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.216 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.166 mL) in 4 mL of abs. THF and stirred over night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) yielded 0.183 g of the title compound as white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:32])[N:16]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:17]2[CH2:22][C:23](OCC)=[O:24]>O>[CH2:28]([N:16]1[C:15](=[O:32])[C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[CH3:12])[CH:17]1[CH2:22][C:23]([NH:10][C:9]([NH2:11])=[NH:8])=[O:24])[CH:29]([CH3:31])[CH3:30]
Reactant: CCOC(=O)CC1c2cccc(C)c2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1cccc2c1C(=O)N(CC(C)C)C2CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 55.8 %

Procedure:
N-[2-(2-Isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 1, starting with 0.68 of potassium tert-butoxide, 0.58 g of guanidinium chloride and 0.36 g of ethyl (4-methyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 20 cm3 of water. The aqueous phase is extracted with 3 times 100 cm3 of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure (0.5 kPa) at a temperature in the region of 40° C. The residue is taken up in dichloromethane and then concentrated again under the same conditions. The residue is taken up in water, triturated and filtered, and then taken up in dichloromethane, triturated and filtered. The solid is then dried in a desiccator. 0.21 g of N-[2-(2-Isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a white powder melting at 270-272° C. (decomposition). 1NMR (300 MHz, d6-(CD3)2SO, δ in ppm): 0.76 (d, J=7 Hz: 3H); 0.91 (d, J=7 Hz: 3H); 2.03 (mt: 1H); 2.42 (dd, J=15.5 and 6.5 Hz: 1H); 2.60 (dd, J=15.5 and 6.5 Hz: 1H); 2.62 (s: 3H); 3.00 (dd, J=14 and 5.5 Hz: 1H); 3.56 (dd, J=14 and 10 Hz: 1H); 4.98 (t, J=6.5 Hz: 1H); from 6.40 to 7.10 (broad multiplet: 2H); 7.21 (broad d, J=7.5 Hz: 1H); 7.36 (broad d, J=7.5 Hz: 1H); 7.42 (t, J=7.5 Hz: 1H); from 7.50 to 8.30 (broad multiplet: 2H).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([C:34]([F:37])([F:36])[F:35])[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([C:34]([F:36])([F:35])[F:37])[CH:23]=2)=[O:20])=[CH:38][C:39]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 153-155° C.; 1H NMR (300 MHz, CDCl3) δ: 10.34 (1H, s), 8.36 (1H, s), 8.24-8.27 (1H, d, J=8.1 Hz), 8.03 (1H, s), 7.82-7.85 (1H, d, J=8.1 Hz), 7.48 (1H, s), 7.41-7.44 (1H, d, J=8.7 Hz), 7.34-7.37 (2H, t, J=9.3 and 8.7 Hz), 6.80 (1H, s), 6.61-6.64 (1H, d, J=9.6 Hz), 5.57-5.59 (1H, d, J=6.0 Hz), 4.22-4.29 (1H, m), 2.45-2.48 (2H, m), 2.28 (3H, s), 1.76-2.01 (4H, m). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C28H24ClF3N6O: 276.0821. found: 276.0817.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:20]3[CH2:25][CH2:24][O:23][C:22](=[O:26])[CH2:21]3)[C:11]=2[Cl:27])[CH:5]=[N:4]1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:20]3[CH2:25][CH2:24][O:23][CH:22]([OH:26])[CH2:21]3)[C:11]=2[Cl:27])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N3CCOC(=O)C3)c2Cl)c1O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N3CCOC(O)C3)c2Cl)c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.38 g (3.22 mmol) of 1-ethyl-4-(2-chloro-3-(morpholin-2-on-4-yl)-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 200 mL of dichloromethane was cooled to -78° C. and treated dropwise with stirring with 7.0 ml, (7.0 mmol) of a 1M solution of diisobutylaluminum hydride in dichloromethane. After 15 min, the reaction was quenched with 5 mL of methanol and 100 mL of 1N aqueous hydrochloric acid and was then allowed to warm to room temperature with vigorous stirring for 30 min. The layers were separated and the aqueous layer was washed with dichloromethane. The organic layers were combined and concentrated by evaporation under reduced pressure. The residue was dissolved in a mixture of acetonitrile and 1N aqueous hydrochloric acid. The mixture was stirred for a few minutes and was then diluted with dichloromethane. The solution obtained was washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The resulting solid residue was extracted with ethanol and dried to obtain 1.20 g (87 percent of theory) of the title compound as a tan powder melting at 209-210° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])/[CH:17]=[CH:11]/[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To a sealed tube equipped with a magnetic stir bar, containing 1,1-dimethoxy-N,N-dimethylmethanamine (50 mL) was placed 1-(3-nitrophenyl)ethanone (5 g, 30 mmol, 1.0 equiv). The reaction was allowed to stir at 115° C. for 15 h. After the reaction was complete by LCMS, the solid product was filtered and washed with ether to yield 5.3 g (80%) of DHK-7-12 as an yellow solid. MS (ESI, Pos.) m/z: 221.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][NH:15][C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:20]=1)=[O:4].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([C:36]([OH:39])([CH3:38])[CH3:37])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:26]4[N:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[C:29]([C:36]([OH:39])([CH3:37])[CH3:38])=[CH:28][N:27]=4)[C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:20]=1)=[O:4]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: CC(C)(O)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)(C)O)c(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 165 °C
Reaction time: 21 h
Yield: 61.7 %

Procedure:
(R)-methyl-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (224 mg, 0.639 mmol) and 2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (192 mg, 0.799 mmol) were combined in a small vial and azeotroped with benzene to remove any residual water. A mixture of dioxane (1 mL) and iPr2NEt (0.22 mL, 1.28 mmol) was degassed with N2 for 10 minutes. This mixture was then added to the reaction vial and sealed with a Teflon® coated cap which was then wrapped with Teflon® tape. The resulting suspension was then placed in a 165° C. silicone oil bath at which point the mixture became homogeneous. The resulting solution stirred at 165° C. for 21 h. After the solvents were removed by rotovap, the mixture was purified using ISCO FCC, eluting with 50% EtOAc in Hexanes to obtain 219 mg of (R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate as a white solid (62% yield, 40% ee).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:65])([F:64])[C:25]1[CH:26]=[C:27]([CH:57]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=1)[CH2:28][N:29]1[C:33]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:32]([C:40]([C:42]2[C:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[Cl:56])=[N:44][O:45][C:46]=2[CH:47]([OH:49])[CH3:48])=[O:41])[N:31]=[N:30]1>>[F:65][C:24]([F:23])([F:64])[C:25]1[CH:26]=[C:27]([CH:57]=[C:58]([C:60]([F:63])([F:61])[F:62])[CH:59]=1)[CH2:28][N:29]1[C:33]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[C:32]([C:40]([C:42]2[C:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[Cl:56])=[N:44][O:45][C:46]=2[C:47](=[O:49])[CH3:48])=[O:41])[N:31]=[N:30]1
Reactant: CC(O)c1onc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC(=O)c1onc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Add Dess-Martin periodinane (27.0 mg, 0.064 mmol) to a solution of [1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-(1-hydroxy-ethyl)-isoxazol-4-yl]-methanone (20.0 mg, 0.032 mmol). Stir at RT for 1 h., then concentrate in vacuo and dilute the residue with ether and wash with saturated aqueous sodium bicarbonate solution. Dry the organic layer with anhydrous MgSO4, filter, and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to provide the title compound (99% yield) as a brown oil. MS (ES) 628.1 (M++1); TLC Rf=0.1 (50% EtOAc in hexanes).
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)C.[C:29]([NH:37][NH2:38])(=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(O)=O.C(Cl)Cl>[CH:22]([N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13](=[O:14])[CH2:12][N:8]1[C:9](=[O:11])[CH2:10][C:4]2[N:5]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:37][N:38]=2)[C:6]2[CH:28]=[CH:27][CH:26]=[CH:25][C:7]1=2)([CH3:24])[CH3:23]
Reactant: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Reactant: NNC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (71.14 g, 0.187 mol) in 1.04 L of AcOH was added benzoic acid hydrazide (27.28 g, 0.196 mol) in one portion. The reaction was heated to 80° C. and was stirred for 4 hours. The reaction was cooled to room temperature and the AcOH was removed in vacuo to give an off-white solid. The solid was dissolved in 1 L of methylene chloride. The organic solution was washed with 1 L of saturated NaHCO3 solution followed by brine and was dried over Na2SO4. The methylene chloride solution was diluted with an equal volume of methyl tert-butyl ether and the resulting solution was concentrated in vacuo to low volume causing a white solid to precipitate. The precipitate was collected on a sintered glass funnel and was rinsed with methyl tert-butyl ether. The solid was dried in vacuo to give 81.41 g of N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide as a white solid. 1H NMR (CD2Cl2) δ 7.57-7.35 (m, 10H), 7.27 (br s, 1H), 7.21 (br s, 1H), 7.10 (t, 1H), 6.87 (d, 1H), 4.89 (m, 1H), 4.19-3.99 (m, 3H), 3.53 (d, 1H), 1.03 (m, 6H); MS 452.3 (M+1), 450.5 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[OH:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Clc1ccsc1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2sccc2Cl)CC1

Procedure:
From 3-chlorothiophene (612 mg) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.00 g) by procedure D. Yield: 420 mg (27%). Yellow solid. MS (m/z): 332.2 ([M+H]+).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])[CH3:4]>O1CCCC1.CO>[CH2:3]([N:5]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])[CH3:4]
Reactant: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(/C=C/C(=O)O)cc2)c1
Yield: 77 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 5.5 eq) of sodium hydroxide and 775 mg (1.83 mmol, 1 eq) of methyl (E)-3-[3′-(1-ethyl-3-heptylureido)biphenyl-4-yl]acrylate in 15 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from dichloromethane/heptane, 580 mg of (E)-3-[3′-(1-ethyl-3-heptylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder (m.p.=116° C.). Yield=77%
Reaction SMILES: [CH2:1]([NH:3][NH2:4])[CH3:2].[CH3:5][C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1.NN>C(Cl)Cl>[CH2:1]([N:3]([C:12]([NH:11][C:9]1[S:10][C:6]([CH3:5])=[N:7][N:8]=1)=[O:13])[NH2:4])[CH3:2]
Reactant: CCNN
Reactant: Cc1nnc(N=C=O)s1
Agent: NN
Solvent: ClCCl
Product: CCN(N)C(=O)Nc1nnc(C)s1
Temperature: 25 °C

Procedure:
A solution of ethylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-ethyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.