Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([O:25][CH3:26])=[O:24].C1C=C[NH+]=CC=1.[Br:33][Br-]Br.Br.C(O)(=O)C>C(O)(=O)C>[Br:33][CH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: COC(=O)c1c(CBr)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A mixture of methyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (5 g), pyridinium bromide perbromide (5.6 g) and 25% hydrogen bromide-acetic acid (5 ml) in acetic acid (200 ml) was stirred for 2 hours at room temperature. The reaction mixture was poured into ice water (200 ml) and stirred for 10 minutes. The resulting precipitates were collected and dissolved in a mixture of chloroform (50 ml) and water (50 ml). The separated organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over magnesium sulfate. The solvent was evaporated in vacuo and the residual crystal was recrystallized from ethanol to give methyl 6-bromomethyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (4.07 g).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[Cl:10][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[C:17]([O:18][CH3:19])[CH:16]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: COc1cc(B(O)O)ccc1Cl
Product: COc1cc(-c2cc(F)c(N)c(Cl)c2)ccc1Cl
Yield: 65.1 %

Procedure:
The title compound (82 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 4-chloro-5-methoxyphenylboronic acid (107 mg, 0.62 mmol) as a pale-yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:30])/[C:5](=[N:25]\[O:26][CH2:27][CH:28]=[CH2:29])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[S:7][C:6](/[C:5](=[N:25]/[O:26][CH2:27][CH:28]=[CH2:29])/[C:4]([OH:30])=[O:3])=[CH:10][CH:9]=1
Reactant: C=CCO/N=C(\C(=O)OCC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCO/N=C(\C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 55 °C
Yield: 63.6 %

Procedure:
As in Example 306 a solution of (E)-5-[2-(2-naphthalenyloxy)ethoxy]-alpha-[(2propenyloxy)imino]-2-thiopheneacetic acid ethyl ester (0.064 g) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 4N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 55° C. for 45 minutes. After the normal work up, the product was crystallized from ethyl acetate-hexane to furnish 0.038 g of (E)-5-[2-(2-naphthalenyloxy)ethoxy]-alpha-[(2-propenyloxy)imino]-2-thiopheneacetic acid, mp 106°-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]1[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@@:9]([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)([O:23][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([O:35][CH3:36])[C:26]=3[O:25][CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccc(OC)c(OC)c1OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 2,3,4-trimethoxy-benzoic acid to yield (3aR,4S,7aR)-4-m-tolylethynyl-4-(2,3,4-trimethoxy-benzoyloxy)-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=8.527 min; HPLC Method I
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[F:13][C:2]([F:1])([F:12])[C:3]1[N:4]([CH2:15][C:16](=[O:18])[CH3:17])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: FC(F)(F)c1nc2ccccc2[nH]1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cn1c(C(F)(F)F)nc2ccccc21

Procedure:
4 g of 2-trifluoromethylbenzimidazole, 2.8 g of chloroacetone, 3.4 g of potassium carbonate and 0.32 g of potassium iodide are dissolved in 50 ml of acetone and boiled under reflux for 4 h. After cooling, the precipitate is filtered off, washed with acetone and dried in a vacuum. 1-(2-trifluoromethylbenzimidazol-1-yl)-propanone is thus obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.S(Cl)(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C1C=CC=CC=1.O.C(#N)C>[N:30]1[CH:31]=[CH:32][C:27]([NH:26][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:20])=[CH:8][N:7]=3)=[CH:15][CH:14]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Nc1ccncc1
Solvent: O
Solvent: CC#N
Solvent: c1ccccc1
Product: O=C(Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)Nc1ccncc1
Yield: 11.9 %

Procedure:
3.0 g (10.1 mmol) of 4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetic acid was dissolved in 15 ml of benzene. Then, 1.8 g (15.1 mmol) of thionyl chloride was added thereto, and the mixture was refluxed under heating for 1.5 hours. Then, benzene and thionyl chloride were distilled off under reduced pressure. To the obtained residue, 15 ml of acetonitrile, 0.95 g (10.1 mmol) of 4-aminopyridine and 1.2 g (11.8 mmol) of triethylamine were added, and the mixture was refluxed under heating for 8 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 0.45 g of the desired product as a milky white powder (melting point: 167.0° to 170.0° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([O:11][C:12]2[C:17]([C:18](OCC)=[O:19])=[C:16]([C:23](=[O:25])[CH3:24])[C:15]([OH:26])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[BH4-].[Li+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]([OH:26])=[C:16]([CH:23]([OH:25])[CH3:24])[C:17]=2[CH2:18][OH:19])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: CCOC(=O)c1c(Oc2c(C)cc(N)c3c2CCC3)ccc(O)c1C(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(N)c2c(c1Oc1ccc(O)c(C(C)O)c1CO)CCC2
Temperature: 60 °C
Reaction time: 96 h
Yield: 34.8 %

Procedure:
To a solution of ethyl 6-(7-amino-5-methylindan-4-yloxy)-2-acetyl-3-hydroxybenzoate (213 mg) in tetrahydrofuran (15 mL) were added lithium borohydride (390 mg) and ethanol (5 mL). The mixture was stirred at 60° C. for 4 days. To the reaction mixture was added water (10 mL). The mixture was acidified with an 10% aqueous solution of citric acid. To the mixture was added ethyl acetate (20 mL). The reaction mixture was stirred for 1 hour, and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/1) to give the title compound (66 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][C:18]2[C:13]([CH3:12])=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ncccc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: Cc1ncccc1NS(=O)(=O)c1ccc(Br)cc1
Yield: 62.7 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (4.73 g, 18.5 mmol) and 2-methyl-3-aminopyridine (2.04 g, 18.9 mmol) in pyridine (36 ml) according to the method of intermediate 1, to give the title compound as a white solid (3.81 g, 11.6 mmol, 63%). δH (CDCl3, 300K) 8.36 (1H, dd J 4.8 Hz 1.5 Hz), 7.70 (1H, dd J 8.1 Hz 1.5 Hz), 7.63 (2H, dd J 6.6 Hz 2.3 Hz), 7.60 (2H, dd J 6.6 Hz 2.3 Hz), 7.17 (1H, dd J 8.1 Hz 4.8 Hz), 6.89 (1H, s), 2.25 (3H, s). m/z (ES+, 70V) 329.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1Br
Temperature: 85 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
Into a round-bottom flask, was placed a solution of 2-bromo-4-fluorobenzoic acid (21.8 g, 99.5 mmol, 1.00 equiv) in a solvent mixture of sulfuric acid (20 mL) and methanol (20 mL). The resulting solution was stirred for 5 h at 85° C., then cooled and cooled and concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL) and washed with brine (200 mL) then aqueous NaHCO3 (100 mL. Note: gas evolution), dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a light yellow oil (22.0 g, 95%).
Reaction SMILES: [C:1]([CH:9]1[CH:14]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:12]=[CH:11][CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(O)(=O)C>[C:2]1([C:1]2[N:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]3[C:9]=2[CH2:10][CH:11]=[CH:12][CH2:13]3)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(c1ccccc1)C1CC=CCC1C(=O)c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Cn1c(-c2ccccc2)c2c(c1-c1ccccc1)CC=CC2

Procedure:
The procedure is as in Example 6, using as substrate 4,5-dibenzoylcyclohexene (Preparation 2) and as the reagent tert-butyl 2-aminoacetate in the presence of acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.CCOCC>C(O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:6][CH2:7]1
Reactant: O=C(O)CCCCCCc1ccc(O)cc1
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)CCCCCC[C@H]1CC[C@H](O)CC1
Yield: 34.1 %

Procedure:
7-(4-Hydroxyphenyl)heptanoic acid (20 g) is subjected to similar catalytic reduction as Reference Example 5 in 80% ethanol. Ether is added to the crude product to give crystals. Recrystallization from ethanol-water and then from i-propanol-ether give trans-7-(4-hydroxycyclohexyl)heptanoic acid (7 g) as colorless needles, m.p. 123°-128° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C(#N)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: COc1ccccc1-c1ccnc(F)c1
Solvent: CC#N
Solvent: O
Product: COc1ccccc1-c1ccnc(Nc2ccccc2)c1
Temperature: 150 °C

Procedure:
A mixture of A3 (80 mg, 0.39 mmol) and aniline (102 mg, 1.1 mmol) was heated for 20 minutes at 150° C. in a microwave oven. The title compound B1 was obtained from the residue by preparative HPLC (water/ACN gradient) as an amorphous solid (20 mg, 19%). MS (ES) C18H16N2O requires: 276. found: 277 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:5]2[C:4](=[O:20])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO.[I-].[Na+]>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][N:12]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:5]2[C:4](=[O:20])[N:3]=1
Reactant: ClCc1ccccc1
Reactant: NC1=NC(=O)C2=C(CNCc3ccccc3)C=NC2=N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: NC1=NC(=O)C2=C(CN(Cc3ccccc3)Cc3ccccc3)C=NC2=N1
Temperature: 60 °C
Reaction time: 4 h
Yield: 24.9 %

Procedure:
In 30 ml of methanol was dissolved 172 mg of 2-amino-5-benzylaminomethylpyrrolo[2,3-d]pyrimidin-4-one (the compound of Example 4), followed by addition of 90 mg of anhydrous potassium carbonate, 2 mg of sodium iodide and 81 mg of benzyl chloride. The mixture was stirred on a water bath at 60° C. for 4 hrs. The solvent was then distilled off and the residue was purified by silica gel column chromatography to give 57 mg of the desired compound.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:1]([O:9][CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(C(=O)CCl)c(N(C)C=O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)COC(=O)c2ccccc2)c(N(C)C=O)c1
Temperature: 25 °C

Procedure:
A solution of benzoic acid (30.3 g) and triethylamine (50.1 ml) in dichloromethane (150 ml) was added dropwise at 0° over a period of 15 minutes to the solution of 2'-(2-chloroacetyl)-5'-methyl-N-methylformanilide obtained above. The resultant solution was allowed to warm to ambient temperature and then heated under reflux overnight. After cooling the reaction mixture was washed with water (2×200 ml), dried over magnesium sulphate and evaporated to give crude 2-[4-methyl-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:27])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[NH:14][C:13]1=[O:23])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:23])[C:12]2=[CH:11][C:10]1[NH:9][CH:8]=[C:7]([CH3:27])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: COc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(c1)C(=Cc1[nH]cc(C)c1CCC(=O)O)C(=O)N2
Temperature: 90 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (240 mg) suspended in ethylene glycol (2 mL) was held in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (1 pellet) was added. It was then stirred at 90° C. for 30 minutes. The reaction mixture was cooled, poured into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 30.5 mg (14%) of 3-[2-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][NH:7][C:8](=[NH:10])[NH2:9])=O>O>[C:2]1([CH3:1])[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]1[N:9]=[C:8]([NH2:10])[NH:7][N:6]=1
Reactant: Cc1ccccc1C(=O)NNC(=N)N
Solvent: O
Product: Cc1ccccc1-c1n[nH]c(N)n1
Yield: 66.2 %

Procedure:
A solution of 2-(2-methylbenzoyl)hydrazinecarboximidamide (5 g) in water (40 mL) was stirred overnight at 100° C. The reaction mixture was diluted with H2O (20 mL) and the solid was collected by filtration and washed with water (20 mL) to afford 3-o-tolyl-1H-1,2,4-triazol-5-amine (3 g, 66% yield) as a white solid.
Reaction SMILES: B.[O:2]1[C:10]2[C:9]([C:11](O)=[O:12])=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1>O1CCCC1>[O:2]1[C:10]2[C:9]([CH2:11][OH:12])=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)c1cncc2ccoc12
Agent: B
Solvent: C1CCOC1
Product: OCc1cncc2ccoc12
Reaction time: 1 h

Procedure:
Add Borane (1.0 M in tetrahydrofuran, 0.61 mL, 0.61 mmol) to a solution of furo[3,2-c]pyridine-7-carboxylic acid (0.100 g, 0.61 mmol) in tetrahydrofuran (2 mL) and stir for 1 hour. Add additional borane (0.61 mL) stir for 30 minutes, add additional borane (0.61 ml), quench with 1N HCl (10 mL) and stir for 15 minutes. Add aqueous ammonium hydroxide (28-30%, 3 mL), extract with diethyl ether, dry over magnesium sulfate, filter and concentrate to give the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=1)[CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
0.384 g (12 mmol) of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 2.26 g.(11.7 mmol) of 5-fluoro-3-methoxycarbonyl-1H-indole in 60 cm3 of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.5 hour, 1.98 g (12 mmol) of 4-chloroquinoline are added. After stirring at a temperature in the region of 120° C. for 6 hours, the reaction mixture is poured into 200 cm3 of water and extracted with 200 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 3.5 g of a brown solid which is purified by silica gel chromatography (eluent: dichloromethane). After concentrating the fractions under reduced pressure, 1.6 g of 5-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid melting at 172° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:23]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(CCc4cccc(N(S(C)(=O)=O)S(C)(=O)=O)c4)CC3)cccc2n1
Reaction time: 18 h

Procedure:
To a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (370 mg) and triethylamine (178 μL) in DCM (3 mL) was added methanesulfonyl chloride (33 □L). The mixture was stirred for 18 h, then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic layer was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography [SiO2; DCM-MeOH, (20:0)→(20:1)] to give the title compound (342 mg).
Reaction SMILES: CS(O)(=O)=O.[H][H].[CH3:8][C:9]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH3:10]>[Pt]>[CH3:10][C:9]([O:16][O:17][C:18]([CH3:19])([CH3:21])[CH3:20])([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[CH3:8]
Reactant: CC(=O)CCC(C)(C)OOC(C)(C)C
Reactant: [H][H]
Agent: [Pt]
Agent: CS(=O)(=O)O
Product: CC(O)CCC(C)(C)OOC(C)(C)C

Procedure:
The catalytic hydrogenation of the carbonyl group in 2-methyl-2-(t-butylperoxy)-5-hexanone was carried out by shaking 5.0 g. (0.025 mole) of the ketone in a Parr Hydrogenation Apparatus with 25 ml. of 10% methanesulfonic acid solution and 1.0 g. of 5% platinum on carbon catalyst at 0° C. for 2 1/2 hours with a hydrogen pressure of 60 p.s.i.g. At the end of the reaction time, the catalyst was separated by filtration, the product taken up in 50 ml. of pentane, the pentane solution washed to neutrality with water, dried over anhydrous magnesium sulfate and the pentane removed under reduced pressure. The recovered product weighed 3.3 g. (65% recovery). An infrared spectrum showed the presence of a hydroxyl band and the absorption band at 880 cm-1 typical of the t-butylperoxy group.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([NH:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23])=[O:19])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and (2S)-2-amino-N,3,3-trimethyl-butanamide, (CAN 89226-12-0) as starting materials, MS (EI): m/e=390.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-(4-Chlorophenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1.[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:20][CH:19]=[CH2:18])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(C)c1C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(-n2nc(C)c(C)c2C)c(F)cc1Cl
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A mixture of 1-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,4,5-trimethylpyrazole (25.5 g), allyl bromide (13.3 g), anhydrous potassium carbonate (14.5 g) and acetonitrile (150 ml) was heated under reflux, with stirring for 3 hours. After cooling, the reaction mixture was filtered through a filter to remove the inorganic salts therefrom and the filtrate was concentrated to a small volume under reduced pressure, affording the titled compound (28.7 g) as a pale brown crystalline solid. Recrystallization of this solid from cyclohexane yielded a white crystalline solid. m.p. 97°-99° C.