Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1.[NH2:23][NH2:24]>>[NH:23]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1)[NH2:24]
Reactant: NN
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1Cl
Product: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1NN
Yield: 60 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6.3 g, 29 mmol) with 4-trifluoromethylphenylbenzamidine (5.5 g, 29 mmol) to afford 50% of ethyl 4-hydroxy-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (3 g, 9.6 mmol) with POCl3 (49 g, 322 mmol) to afford 97% of ethyl 4-chloro-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with hydrazine (0.6 g, 18 mmol) to afford 60% of ethyl 4-hydrazino-2-(4'trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (1 g, 3 mmol) with citraconic anhydride (1 g, 9 mmol) to afford 40% (0.5 g) of the title compound (m.p. 148-150° C.) in analogy to Example 21.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>[Pd]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:13]=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
The procedure described in Example 26 is repeated, but using 5.05 g (25 mmols) of 4-bromonitrobenzene and 2.99 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 3 hours at 130° C., 4.86 g (22.0 mmols) of ethyl 4-nitrocinnamate are obtained, corresponding to a yield of 88% of theory (conversion figure 8800; Pd content 0.01 mol %).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12](=[O:20])[CH2:11][CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:23])[CH:3]=1.[CH3:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C1CCCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[N:8]([C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[CH3:24])=[CH:3][C:4]=3[CH3:23])[CH2:9][CH2:10][CH2:11][C:12](=[O:20])[C:13]=2[CH:18]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1cc(N)ccc1C(=O)N1CCCC(=O)c2cc(Cl)ccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1

Procedure:
Typically, 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is reacted with 2-methylbenzoylchloride in water immiscible solvent selected from methylene chloride, toluene or cyclohexane in the presence of aqueous inorganic base such as aqueous sodium bicarbonate or aqueous sodium carbonate to form a biphasic system to obtain 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
Reaction SMILES: BrCCBr.[Li+].[Br-].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1.C(O)C.[Zn]>[C:31]([O:30][C:28]([C:25]1[CH:26]=[CH:27][C:22](/[CH:21]=[CH:20]\[C:17]2[CH:16]=[CH:15][C:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])=[CH:19][CH:18]=2)=[CH:23][CH:24]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(C(=O)OC(C)(C)C)cc2)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn]
Solvent: BrCCBr
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(/C=C\c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
52.6 g of Zn and 70 ml of ethanol are heated together with 13 g of 1,2-dibromoethane until evolution of gas ceases. A solution of 13 g of CuBr and 15.8 g of anhydrous LiBr in 70 ml of THF is added at 40° to 50° C. and the reaction mixture is stirred for 10 minutes. A hot solution of 50 g of 4,4'-tolan-dicarboxylic acid di-tert.-butyl ester in 70 ml of ethanol and 130 ml of THF is added and the mixture is heated under reflux for 72 hours. After filtration, the filtrate is concentrated by evaporation, taken up with CH2Cl2, washed twice with dilute HCl and H2O, dried and concentrated by evaporation. 46.3 g of Z-4,4'-stilbene dicarboxylic acid di-tert.-butyl ester are obtained.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1cccc(F)c1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cccc(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 62.1 %

Procedure:
A mixture of intermediate 59 (2.0 g, 5.42 mmol), 3-fluorobenzylamine (1.86 mL, 16.2 mmol) and MeOH (0.5 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and is purified twice by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 1.5 g of the product 87. 1H NMR (CDCl3) δ 7.50 (s, 1 H), 7.40-7.30 (m, 1 H), 7.30-7.15 (m, 2 H), 7.10-6.90 (m, 9 H), 7.85-7.75 (m, 2 H), 5.50-5.30 (m, 2 H), 4.80-4.55 (m, 2 H), 1.15 (s, 9 H); MS: m/z 446 (M++1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:21]([C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[CH3:22]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:21]([C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[CH3:22]
Reactant: CCc1ccccc1C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1C(C)Br
Temperature: 80 °C
Yield: 82.1 %

Procedure:
N-Bromosuccinimide (10.7 g) and azodiisobutyronitrile (catalytic) were added to a solution of methyl 2-ethylbenzoate (10 g) in carbon tetrachloride (50 ml), and the resulting mixture was heated at 80° C. for 6 hours under reflux. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give methyl 2-(1-bromoethyl)benzoate (12 g), almost pure by GC and NMR, as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Solvent: CCOCC
Product: O=C(c1cc2cc([N+](=O)[O-])ccc2[nH]1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-nitroindole-2-carboxylic acid (J. Am. Chem. Soc., 4621 (1958)] and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: 220-224° C. (diethylether).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:40]=[C:39](I)[CH:38]=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24].[C:42]([NH:48][C:49]1[N:50]=[C:51]([OH:61])[C:52]2[CH:58]=[C:57]([C:59]#[CH:60])[CH:56]=[N:55][C:53]=2[N:54]=1)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl.[Cu](I)I>[F:20][C:21]1[CH:40]=[C:39]([C:60]#[C:59][C:57]2[CH:56]=[N:55][C:53]3[N:54]=[C:49]([NH:48][C:42](=[O:47])[C:43]([CH3:46])([CH3:44])[CH3:45])[N:50]=[C:51]([OH:61])[C:52]=3[CH:58]=2)[CH:38]=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(I)cc1F)C(=O)OC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A mixture of 0.44 g (2.56 mmol) of palladium chloride and 1.34 g (5.12 mmol) of triphenylphosphine in 200 mL of acetonitrile is stirred under nitrogen at room temperature for 30 minutes. To this mixture is added an additional 150 mL of acetonitrile, 22.09 g (52.2 mmol) of dimethyl N-(2-fluoro-4-iodobenzoyl)-L-glutamate, 13.830 g (51.2 mmol) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 0.0244 g (1.28 mmol) of copper iodide, and 15 mL (107.5 mmol) of triethylamine. The reaction mixture is then heated at reflux for 3 hours and then cooled to room temperature, the solvent is then removed in vacuo and the crude solid chromatographed on silica gel with 1:19 methanol:methylene chloride to give 18.1 g (62.5%) of dimethyl N-(2-fluoro-4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]-pyrimidin-6-yl)ethynyl]-benzoyl)-L-glutamate as a white solid m.p. 204°-207° C. (dec); Rf =0.60 (1:19 methanol: chloroform), Mass (FD)=565; IR (KBr, cm-1)=813, 1151, 1201, 1270, 1375, 1444, 1481, 1490, 1527, 1548, 1598, 1623, 1649, 1670, 1741, 1753; UV (EtOH) λmax =325 (epsilon=41100), 266 (epsilon=14600), 210 (epsilon=35700).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:16][CH:17]([CH3:19])[CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].C(OC(=O)COC(C)C)C.C(OC1C=CC(C=O)=CC=1OC)C1C=CC=CC=1.[CH3:49][C:50]1[S:54][C:53]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)=[N:52][C:51]=1[CH2:62][CH2:63]O.COC(=O)CC(=O)C(Br)C.CC1C=CC(C(N)=S)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:16][CH:17]([CH3:19])[CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:63][CH2:62][C:51]2[N:52]=[C:53]([C:55]3[CH:56]=[CH:57][C:58]([CH3:61])=[CH:59][CH:60]=3)[S:54][C:50]=2[CH3:49])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: Cc1ccc(-c2nc(CCO)c(C)s2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OC(C)C
Agent: CCOC(=O)COC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C)cc3)sc2C)c(OC)c1)OC(C)C

Procedure:
In analogy to the procedure described in example 1 d], [rac]-3-(4-hydroxy-3-methoxy-phenyl)-2-isopropoxy-propionic acid ethyl ester [prepared from isopropoxy-acetic acid ethyl ester (Tetrahedron (1982), 38(17), 2733-9) and 4-benzyloxy-3-methoxy-benzaldehyde in analogy to the procedures described in examples 54 a]to c)] was reacted with 2-(5-methyl-2-p-tolyl-thiazol-4-yl)-ethanol (prepared from [rac]4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-methyl-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-isopropoxy-3-{3-methoxy-4-[2-(5-methyl-2-p-tolyl-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-isopropoxy-3-{3-methoxy-4-[2-(5-methyl-2-p-tolyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless amporphous solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:19][N:20]([CH3:30])[C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC.CCO.CCO.O>[NH2:11][C@@H:3]([CH2:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[C@H:2]([OH:1])[CH2:19][N:20]([CH3:30])[C:21](=[O:22])[O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27]
Reactant: CN(C[C@@H](O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CN(C[C@@H](O)[C@@H](N)CC1CCOCC1)C(=O)OCC[Si](C)(C)C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
tert-butyl (2S,3R)-3-hydroxy-4-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(tetrahydro-2H-pyran-4-yl)butan-2-ylcarbamate (180 mg, 0.4 mmol) was dissolved in a minimal volume of Et2O (5 mL) and added to a solution of TsOH (76 mg, 0.44 mmol) in EtOH (15 mL). The solution was placed on a rotary evaporator and the Et2O was removed at rt. The flask was then lowered into the water bath and the selective deprotection of the Boc group proceeded concurrent with removal of the remainder of solvent. The reaction was completed after 2 h and gave a white solid. The residue was dissolved in EtOH/H2O (1:1, 50 mL) and washed with hexane/EtOAc (5:1, 3×15 mL). 1N aq NaOH was added until the pH>10 and the mixture was extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-2-hydroxy-4-(tetrahydro-2H-pyran-4-yl)butyl(methyl)carbamate (100 mg, 72%).
Reaction SMILES: [NH2-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][CH:6](O)[CH2:5]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:21][N:22]([CH3:38])[C:23](=[O:37])[CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.Cl>C1(C)C=CC=CC=1>[CH3:38][N:22]([CH3:21])[C:23](=[O:37])[C:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:6]1[CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]1
Reactant: CN1CCC(O)C1
Reactant: CN(C)C(=O)C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN1CCC(C(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h

Procedure:
To a suspension of 20 g. (0.5 mole) of sodamide in 750 ml. of dry toluene was added dropwise 50.58 g. (0.5 mole) of 1-methyl-3-pyrrolidinol with cooling below 30° C. After stirring for 1 hour, 95.32 g. (0.5 mole) of p-toluene sulfonyl chloride in 500 ml. of dry toluene was added rapidly at a temperature below 10° C. maintained by dry ice/acetone bath. The temperature was allowed to come to room temperature and stirred for 2 hours. The reaction mixture was cooled, washed with 500 ml. of cold water and the toluene layer was dried over calcium sulfate, filtered and the dried toluene solution concentrated at reduced pressure. To 93.5 g. (0.39 mole) of N,N-dimethyl-α,α-diphenylacetamide in 500 ml. of dry toluene was added 15.6 g. (0.4 mole) of sodamide and the mixture was slowly brought to reflux with stirring. After refluxing for 3 hours, the tosylate in 250 ml. of dry toluene was added at a convenient rate to the refluxing reaction mixture which was then refluxed for 3 hours. The resulting suspension was filtered and the toluene filtrate was evaporated under water pump vacuum, leaving an oil which on cooling became semi-crystalline and was taken into 6N hydrochloric acid. The acid solution was extracted with ether, made basic with 6N sodium hydroxide and the base insoluble oil extracted with ether. The ether extracts were dried over calcium sulfate, filtered, and evaporated leaving an amber oil. The product was distilled at 175°-180° C./0.005 mm. to give 22 g. (38%) of product.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)C.[Li+].[OH-]>>[CH:25]1([C:23]([C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[NH:15][C:13](=[O:14])[NH:12][C:9]2[S:10][CH:11]=[C:7]([CH2:6][CH2:5][C:4]([OH:30])=[O:3])[N:8]=2)=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)Nc2nc(CCC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Yield: 93.4 %

Procedure:
3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid (15 mg, 88%) was prepared from 3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid ethyl ester (0.03 g, 0.04 mmol) and 2.5M LiOH (20 ΞL) following the general procedure J.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:38])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:38])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1cc(-c2ccnc3[nH]c(C4=CCNCC4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reaction time: 2 h
Yield: 42 %

Procedure:
1,1-dimethylethyl 4-{4-[1-ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-3,6-dihydro-1(2H)-pyridinecarboxylate (0.362 mmol) was treated with 4N hydrogen chloride in 1,4-dioxane (2 mL). The suspension was stirred vigorously for 2 h, then concentrated under reduced pressure. Purification of the residue by reverse phase HPLC afforded the title compound as a yellow solid (42%). ESMS [M+H]+: 504.4
Reaction SMILES: C(Cl)(=O)C.[CH3:5][O:6][C:7]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][NH:16]C(OC(C)(C)C)=O)=[O:14])=[CH:11][CH:10]=1)=[O:8]>CO>[NH:15]([C:13]([C:12]1[CH:24]=[CH:25][C:9]([C:7]([O:6][CH3:5])=[O:8])=[CH:10][CH:11]=1)=[O:14])[NH2:16]
Reactant: COC(=O)c1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
Acetyl chloride (11.8 g, 150 mmol) was added at 0° C. to methanol (200 mL) followed by the tert-butyl 2-(4-(methoxycarbonyl)benzoyl)hydrazine carboxylate (12.7 g, 43 mmol) (added as a solid). The reaction mixture was stirred at room temperature for 20 hours. The volatiles were removed in vacuo, affording methyl 4-(hydrazinecarbonyl)benzoate (8 g, 96%). The product was used without further purification. LCMS [M+H]: 195.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]2([CH3:39])[CH2:38][O:37][CH2:36]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[C:40](B1OC(C)(C)C(C)(C)O1)([CH3:42])=[CH2:41].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.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>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([C:40]([CH3:42])=[CH2:41])[CH:3]=[CH:4][C:5]=4[O:33][CH2:34][C:35]4([CH3:39])[CH2:38][O:37][CH2:36]4)[CH2:13][C:12](=[O:14])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Br)ccc2OCC2(C)COC2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OCC2(C)COC2)c(C2CC(=O)NC(c3cc(Cl)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 80 °C
Yield: 12.7 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.08 mmol), isopropenylboronic acid pinacol ester (40 mg, 0.24 mmol) and K3PO4 (50 mg, 0.24 mmol) in THF was added Pd(PPh3)4 (15 mg). The mixture was heated at 80° C. for 8 h under an argon atmosphere, purified by prep-HPLC to give the title compound as a white solid (6 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[NH3:20]>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: N
Reactant: COCc1ccc(-c2cnnc(S(C)(=O)=O)n2)cc1
Solvent: C1CCOC1
Product: COCc1ccc(-c2cnnc(N)n2)cc1
Yield: 85 %

Procedure:
5-[4-(methoxymethyl)phenyl]-1,2,4-triazin-3-amine (2.2 g, 85%) was prepared from 5-[4-(methoxymethyl)phenyl]-3-(methylsulfonyl)-1,2,4-triazine (3.40 g, 12.2 mmol) in THF (35 mL) and treated with NH3 gas by purging for 30 minutes, similarly to the general procedure of Preparation 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6].[ClH:26]>O1CCCC1>[ClH:26].[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CCNCC2)c1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into a 25-mL three-neck flask equipped with a thermowell with a thermocouple, a reflux condenser, a stopper, and a magnetic stir bar was placed 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) (1.1 g, 3.0 mmol) and 9.7 g of tetrahydrofuran. After 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) had dissolved, 6.3 g of 3N aqueous hydrochloric acid was added in one portion. The reaction was stirred to 18 hours at ambient temperature and then heated to 60° C. for 4 hours to give 4-(2,3-dimethoxybenzoyl)piperidine hydrochloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F.O>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: OCc1nccs1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2nccs2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
2-(2-Chloro-4-nitro-phenoxymethyl)-thiazole is prepared by adding thiazol-2-yl-methanol (2.74 g, 23.76 mmol) to a slurry of sodium hydride (1.21 g of a 60% dispersion in oil, 30.2 mmol) in DMF (10 ml) at 0° C. After several minutes, 2-chloro-1-fluoro-4-nitro-benzene (3.79 g, 21.60 mmol) is added and the reaction mixture warmed to room temperature. The reaction mixture is stirred at room temperature for 3 h, and 60° C. for 16 h. After cooling to room temperature, the reaction mixture is poured into 200 ml water. The resulting precipitate is collected by filtration, washed with water, and dried in vacuo to give 2-(2-chloro-4-nitro-phenoxymethyl)-thiazole (5.80 g, 99%) which is used without further purification.