Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][OH:23]>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][OH:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Nc1ccccc1CO
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1CO
Yield: 53.1 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (2.64 g, 10 mmol) was dissolved in I,4-dioxan (10 ml), 2-aminobenzyl alcohol (1.85 g, I5 mmol) added, and the mixture heated to reflux for 5 minutes. The dioxan was evaporated, water added, and the product extracted into dichloromethane. Chromatography (silica gel, ethyl acetate) and recrystallisation from ethyl acetate gave 3-butyryl-4-(2-(hydroxymethyl)phenylamino)-8-methoxyquinoline (1.86 g, 53%), m.p. 159°-161°.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(#N)C.O1CCOCC1>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)ccc1N1CCCNCC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.4 %

Procedure:
To a solution of 4-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.100 g, 0.215 mmol) in acetonitrile (5 mL) is added 2.0 mL of hydrogen chloride as a 4.0 M solution in 1,4-dioxane. The mixture is stirred at room temperature for 48 h during which time a solid precipitates from solution. The off-white solid is collected by filtration, washed with methylene chloride and dried on the filter pad to provide 0.070 g of 3-chloro-N-(5-chloro-2-[1,4]diazepan-1-yl-phenyl)-benzamide.
Reaction SMILES: ClC1C(C2C=CC=CC=2)=N[N:5]=[C:4]2N(C)N=C(C3C=CC(C#N)=CC=3)C=12.[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH3:49])[N:40]=[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44](I)[CH:43]=3)[C:28]=12.ClC1C(C2C=CC=CC=2)=NN=C2N(C)N=C(C3C=CC(I)=CC=3)C=12>>[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH3:49])[N:40]=[C:41]([C:42]3[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=3)[C:4]#[N:5])[C:28]=12
Reactant: Cn1nc(-c2ccc(C#N)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: Cn1nc(-c2cccc(I)c2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: Cn1nc(-c2ccc(I)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Product: Cn1nc(-c2cccc(C#N)c2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 34 was synthesised following similar procedures outlined in Example 35 (Compound 24), using 4-chloro-3-(3-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 3, Example 30) as the starting material instead of 4-chloro-3-(4-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 43, Example 23).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](OCC)(=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Li])CCC>CCCCCC.C1CCCCC1>[O:12]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=O)OCC
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CCOC(=O)C(=O)c1nccs1

Procedure:
Prepared from thiazole and diethyl oxalate using Method KE-A. In this case the temperature was held at −35° C. and n-butyllithium in hexane was used in place of sec-butyllithium in cyclohexane.
Reaction SMILES: [N:1]([N:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6])=O>[Zn].C(O)(=O)C>[NH2:1][N:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6]
Reactant: O=NN1CCC[C@H]1C(=O)O
Agent: [Zn]
Solvent: CC(=O)O
Product: NN1CCC[C@H]1C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of 10 g. of N-nitroso-L-proline in 500 ml. of 50% acetic acid is cooled in an ice bath and 40 g. of zinc dust is added gradually, with vigorous stirring, at a rate that the temperature of the reaction mixture is maintained below 10°. The addition requires about 15 minutes. The unreacted zinc dust is removed by filtration and the filtrate treated with hydrogen sulfide to precipitate the zinc as zinc sulfide. The precipitated zinc sulfide is removed by filtration and the filtrate evaporate to dryness. The residue is dissolved in 30 ml. of absolute ethanol and the solution allowed to remain overnight at 5°. The N-amino-L-proline, a yellow crystalline solid, is removed by filtration and melts at 153°-154° after drying.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.Cl.[C:19]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:19]1([N:29]2[CH2:34][CH2:33][N:32]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2[nH]1
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a mixture of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (175 mg, 0.754 mmol) and 1-naphthalen-1-yl-piperazine hydrochloride (206 mg, 0.829 mmol) in DCE (4 mL) was added Et3N (0.23 mL, 1.66 mmol). The mixture was stirred for 10 min and NaBH(OAc)3 (224 mg, 1.06 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to give a white foam. Purification by liquid chromatography (5% MeOH/CH2Cl2) gave the title compound as a white foam (260 mg, 0.607 mmol, 80%). The foam was dissolved in a minimal amount of CH2Cl2 and Et2O was added. 1M HCl in Et2O (0.6 mL) was added and a white precipitate formed. The solid was collected by filtration, washed with Et2O and dried to give a white fluffy solid (257 mg). MS: APCI: M+1: 429.2 (Exact Mass: 428.22).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[N:6][CH:7]=1.C([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH3:35])[CH:33]=2)[CH:28]=[C:27]1B(O)O)(OC(C)(C)C)=O>>[CH3:35][C:32]1[CH:33]=[C:34]2[C:29]([CH:28]=[C:27]([C:2]3[CH:3]=[C:4]([N:8]4[C:16](=[O:17])[C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:9]4=[O:18])[CH:5]=[N:6][CH:7]=3)[NH:26]2)=[CH:30][CH:31]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cncc(Br)c1
Reactant: Cc1ccc2cc(B(O)O)n(C(=O)OC(C)(C)C)c2c1
Product: Cc1ccc2cc(-c3cncc(N4C(=O)c5ccccc5C4=O)c3)[nH]c2c1

Procedure:
2-(5-Bromo-pyridin-3-yl)-isoindole-1,3-dione and N-Boc-6-methyl-indoleboronic acid are processed according to the procedure described in Example 103 to give 2-[5-(6-methyl-1H-indol-2-yl)-pyridin-3-yl]-isoindole-1,3-dione. MS (ESI) m/z 354.1 (M+H)+
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]([Cl:21])([Cl:20])[C@@H:11]1[N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13](=[O:19])[O:12]1.[CH3:22][N+:23]([CH3:25])=[CH2:24].[I-].O>C1COCC1>[CH3:22][N:23]([CH2:25][C@@:14]12[CH2:18][CH2:17][CH2:16][N:15]1[C@@H:11]([C:10]([Cl:9])([Cl:20])[Cl:21])[O:12][C:13]2=[O:19])[CH3:24]
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Reactant: C=[N+](C)C
Agent: CC(C)[N-]C(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1M of solution of lithium diisopropylamide in a 3:5 mixture of hexanes/THF (8.25 ml) is added dropwise to (3R,7aS)-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (1.51 g, prepared as described by Wang and Germanas Synlett 1999, 33-36.) in THF (5 ml) at −78° C. After stirring 30 minutes at −78° C. Eschenmoser's salt (2.78 g) is added. The reaction mixture is then allowed to warm to −40° C. with vigorous stirring over 1 hour and maintained for 2 hours at −40° C. Water is then added and the aqueous layer extracted with dichloromethane, the combined organic layers dried over sodium sulphate and evaporated. The residue is then purified by mormal phase chromatography eluting with a gradient from dichloromethane to 20% ethyl acetate in dichloromethane to give the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].C[O-].[Na+].[CH3:13][O:14][C:15](=[O:22])/[CH:16]=[C:17](/[O:20][CH3:21])\[CH2:18]Cl>CN(C=O)C>[CH3:13][O:14][C:15](=[O:22])/[CH:16]=[C:17](/[O:20][CH3:21])\[CH2:18][CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:2][CH3:1])=[O:9]
Reactant: COC(=O)/C=C(\CCl)OC
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\CC(C(=O)OC)C(=O)OC)OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
66 g (0.5 mol) of malonic acid dimethyl ester was placed in 250 ml of N,N'-dimethylformamide. 27.8 g (0.5 mol) of sodium methylate was added at 20°C.; 10 minutes later 41.6 g (0.25 mol) of 4-chloro-3-methoxy-2E-butenoic acid methyl ester was added within 5 minutes. It was stirred for 2 hours at 20° C. Then 10.8 g (0.2 mol) of sodium methylate was added once more. After stirring for 15 hours at 20° C. it was distilled off. After working up according to Example (a) 53.8 g (81 percent) of the title compound, with a purity of 98 percent (GC), was obtained. Data for the title compound was:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(CC)CC)C.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH2:29]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CCCCCCCCCCCCBr
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCNCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 33.4 %

Procedure:
In a 100-ml round-bottomed flask were placed 2,4-dichlorobenzylamine (3.5 g (20 mmol)), triethylamine (4.0 g (40 mmol)), and chloroform (10 ml) under nitrogen. While stirring, laurylbromide (4.9 g (20 mmol)) in chloroform (5 ml) was added dropwise at 50°-60° C. The mixture was stirred for 6 hours. The reaction mixture was cooled to room temperature and concentrated. The resultant concentrate was dissolved in ethyl acetate, washed with water, and purified via silica gel column chromatography (chloroform:methanol=10:1), thereby obtaining 2.3 g of N-lauryl-2,4-dichlorobenzylamine as pale yellow crystals (yield: 34%).
Reaction SMILES: [CH3:1][C:2](O)([CH3:5])[CH2:3][NH2:4].O=S(Cl)Cl.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[S:21]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]1[NH:4][CH2:3][C:2]([CH3:5])([CH3:1])[S:21]1
Reactant: CC(C)(O)CN
Reactant: S=C=Nc1cccc(Cl)c1Cl
Solvent: O=S(Cl)Cl
Product: CC1(C)CNC(=Nc2cccc(Cl)c2Cl)S1

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C1a to afford 2-(2,3-dichlorophenylimino)-5,5dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2-(2,3-dichlorophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([NH2:8])=[O:7])#[N:4].[C:9]([O:13][C:14](=[O:39])[NH:15][C:16]1([C:20]2[CH:25]=[CH:24][C:23]([C:26](=O)/[C:27](/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28]/N(C)C)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C=O)C.CO.O>[C:9]([O:13][C:14](=[O:39])[NH:15][C:16]1([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:28][C:5]([C:3]#[N:4])=[C:6]([OH:7])[N:8]=3)=[CH:24][CH:25]=2)[CH2:17][CH2:18][CH2:19]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: N#CCC(N)=O
Reactant: CN(C)/C=C(/C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(C#N)cc3-c3ccccc3)cc2)CCC1
Temperature: 40 °C
Yield: 92.6 %

Procedure:
To a suspension of sodium hydride (3.58 g, 0.089 mol) in DMF (150 ml) at 0° C. was added a solution of 2-cyanoacetamide (3.48 g, 0.041 mol) and (E)-tert-butyl(1-(4-(3-(dimethylamino)-2-phenylacryloyl)phenyl)cyclobutyl)carbamate (15 g, 0.0357 mol) in methanol (5.5 ml) and DMF (150 ml). The resulting mixture was heated at 40° C. for 16 h. After cooled down to room temperature, the mixture was added to a solution of acetic (50 ml) in water (300 ml) slowly. The resulting precipitate was filtered and the filter cake was partitioned between water (250 ml) and dichloromethane (150 ml). The layers were separated and the aqueous phase extracted into dichloromethane (150 ml). The combined organic phases were washed with water (200 ml) and brine (150 ml), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give the title compound as a yellow solid (14.6 g, 93%). LCMS (Method A): RT=6.59 min, M+1=442. 1H NMR (500 MHz, CDCl3): 7.89 (1H, s), 7.37-7.32 (2H, m), 7.22-7.16 (5H, m), 7.03-6.98 (2H, m), 2.50-2.37 (4H, m), 2.06-1.97 (1H, m), 1.82-1.77 (1H, m), 1.45-1.05 (9H, br).
Reaction SMILES: Cl.[CH:2]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[C:17]([NH:19][CH3:20])[CH:16]=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.O=C(Cl)[O:23][C:24](Cl)(Cl)Cl.CCN(CC)CC.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[CH:2]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[C:17]([N:19]([CH3:20])[C:24]([N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[O:23])[CH:16]=[CH:15][N:14]=3)[CH2:11][CH2:12]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNc1ccnc(N2CCN(C3CCCC3)CC2)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)N1CCCCC1)c1ccnc(N2CCN(C3CCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
A mixture of 20 mg (0.08 mmol) [2-(4-cyclopentyl-piperazin-1-yl)-pyridin-4-yl]-methyl-amine hydrochloride (intermediate 10), 46 mg (0.08 mmol) diphosgene and 31 mg (0.3 mmol) NEt3 in 1 ml THF was treated with 43 mg (0.5 mmol) piperidine (commercially available) and stirred for 30 min at room temperature. After evaporation of all volatiles the residue was taken up in methanol/DMF and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 15 mg (52%) of the title compound as white solid. MS (m/e): 372.1 (MH+; 100%).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C.C1COCC1.[H][H]>[Pt].C(OCC)(=O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(O)cc2)cc1
Yield: 96.2 %

Procedure:
1-(4-Hydroxyphenoxy)-4-nitrobenzene X (8.93 g, 38.62 mmol), 0.5% platinum catalyst on activated charcoal (1.5 g), THF (100 mL), and ethyl acetate (20 mL) were charged into a 250 mL hydrogenation vessel. Hydrogenation was carried out under 60 psi of hydrogen at room temperature for 16 hr. The reaction mixture was filtered and the organic solvents were removed under reduced pressure at 40° C. to give 4-(4-aminophenoxy)phenol XI (8.10 g, 96.2% yield), mp 130°-4° C. The IR and 1H-NMR spectra agreed with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[NH2:5].N1C=CC=CC=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:30](=[O:31])[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3F)CC2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 4 (0.32 g, 1 mmol) and pyridine (0.12 mL, 1.5 mmol) in acetonitrile (4 mL, 0.25M), phenyl chloroformate (0.16 mL, 1.2 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for overnight. Then water was added and the mixture was stirred for 30 min. The precipitated white solid was filtered and the solid was washed with acetonitrile and then dried under vacuum to obtain compound 5 (0.35 g, 83%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:2]1.Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:13]([O:12][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:2]=1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of benzyl indole-3-carboxylate, ethyl 4-bromobutyrate and potassium t-butoxide in N,N-dimethylformamide was stirred at 50° C. for 4 hours. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate, and washed with diluted hydrochloric acid and water, dried over magnesium sulfate and concentrated. The concentrate was chromatographed on a silica gel column to give the object compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCc1cccs1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1c(NCCc2cccs2)ccnc1Cl

Procedure:
A mixture of 2,4-dichloro-3-nitropyridine (1.5 g), 2-aminoethylthiophene (1 g) and triethylamine (5 mL) is heated to reflux in EtOH (60 mL). The reaction mixture is cooled, the solvent evaporated and the residue chromatographed on silica gel (10% hexane/CH2Cl2) to yield the desired addition product.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O:21]C)=[O:20])[C:13]=2[CH:12]=[CH:11]1>>[OH:9][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:1][N:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=[O:20])[C:13]=2[CH:12]=[CH:11]1
Reactant: c1ccc(C2CO2)cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Product: O=C(O)c1cccc2c1ccn2CC(O)c1ccccc1
Yield: 56.9 %

Procedure:
The same procedures used in Example 1 were repeated except for using 4.53 g of styrene oxide and 6.00 g of methyl indole-4-carboxylate as a starting material to give 5.48 g of 1-(2-hydroxy-2-phenylethyl) indole-4-carboxylic acid as a yellow amorphous substance. The yield thereof was found to be 57%.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[CH:7]=1)(=[O:4])=[O:3].C([N:19]([CH2:22][CH3:23])CC)C>C(O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][N:12]([CH2:10][CH2:9][C:8]3[CH:14]=[CH:23][C:22]([NH:19][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[CH2:13][CH2:14][C:8]=2[CH:7]=1)(=[O:3])=[O:4]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCNCC2
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(CCN2CCc3ccc(NS(C)(=O)=O)cc3CC2)cc1

Procedure:
7-Methanesulphonamido-1,2,4,5-tetrahydro-3H-3-benzazepine (0.21 g), 4-[2-(methanesulphonyloxy)ethyl]methanesulphonanilide (0.26 g) (see EP-A-0245997, Preparation 7) and triethylamine (0.12 ml) were heated at reflux temperature in ethanol for 24 hours. The solvent was removed in vacuo and the residue taken up in methylene chloride, washed with aqueous sodium bicarbonate, brine and then water. The organic layer was dried (Na2SO4), evaporated in vacuo and the residue purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 5%). The product-containing fractions were combined and evaporated to give a solid which was recrystallised to give the title compound, yield 0.05 g, m.p. 190°-193°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(OCC)C>C(O)CCC.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N#CCC#N
Solvent: CCCCO
Solvent: CCOCC
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 2,4-dichlorobenzaldehyde (30.00 g, 171 mmol) and malononitrile (13.59 g, 206 mmol) were suspended in 1-butanol (350 ml). After stirring for 15 min, 8 drops of piperidine were added at room temperature. After stirring for an additional 3 h, diethyl ether was added. The precipitate was filtered and washed with diethyl ether and hexane to give the title compound, MS: m/e=222.8 (M+), as a colorless solid (35.34 g, 92%).
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1>C(OCC)(=O)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)[O-])ccc1O

Procedure:
Sitagliptin free base (0.25 gms) and ferulic acid (0.12 gms) were dissolved in ethyl acetate (2 ml) at 60° C. and the resultant solution was left for slow solvent evaporation at room temperature for 30 hours. Precipitated solids were filtered off and suck dried to obtain the title compound. Yield: 0.31 gms.