Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C(OCC)(=O)C>[CH2:1]([C:3]1([C:13]2[N:14]=[CH:15][N:16]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH:17]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCC1(c2c[nH]cn2)Cc2ccccc2C1=O
Solvent: CCOC(C)=O
Product: CCC1(c2cn(Cc3ccc(Cl)cc3)cn2)Cc2ccccc2C1=O
Yield: 74 %

Procedure:
2-ethyl-2-(1H-imidazol-4-yl)-1-indanone and 4-chlorobenzyl chloride were reacted at 60° C. as described in example 5. The yield was 74%. The hydrochloride was prepared in ethyl acetate, m.p. 150°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:18])[CH3:17]>C(N(CC)CC)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:16](=[O:18])[CH3:17])[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Clc1ccc(NCc2cccnc2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
N-[(3-pyridyl)methyl]-N-(4-chlorophenyl)acetamide was prepared by reacting 5.0 g. of N-(4-chlorophenyl)-[(3-pyridyl)methyl]amine with 2.0 g. of acetyl chloride in 250 ml. containing 3.0 g. of triethylamine according to the method of Example 11. Weight 1.1 g. M.P. 64°-65° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[N:6]=[CH:5]2.[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:19]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:12]([C:7]4[N:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=5)[N:8]=4)=[O:14])[CH2:25]3)[C:19]=12
Reactant: Cc1ccc2nc(C(=O)O)ncc2c1
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(C(=O)N[C@H]3CCN(c4nccn5ccnc45)C3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 6-methylquinazoline-2-carboxylic acid (0.040 g, 0.21 mmol, 1.2 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.49 g, 0.18 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.10 mL, 0.7 mmol, 4 eq) and HATU (0.075 g, 0.20 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-6-methylquinazoline-2-carboxamide (0.057 g, 0.15 mmol, 86%). 1H NMR (400 MHz, CD3OD) δ 9.48 (s, 1 H), 8.02 (d, J=1.6 Hz, 2 H), 7.98-7.88 (m, 3 H), 7.78 (s, 1 H), 7.17 (d, J=5.8 Hz, 1 H), 5.00-3.80 (br, 4 H), 2.60 (s, 3H), 2.65-2.40 (br, 2 H); MS: (ES) m/z calculated for C20H19N7O [M+H]+ 374.2, found 374.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.CON(C)[C:23]([CH:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:24]>C1COCC1>[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:23]([CH:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:24]
Reactant: CON(C)C(=O)C1CCOC1
Reactant: Fc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(c1ccncc1F)C1CCOC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
Diisopropylamine (605 μL, 4.30 mmol) was dissolved in THF (8 mL) and cooled to −78° C. nBuLi (1.72 mL, 2.5 M in hexanes, 4.30 mmol) was added and the resulting solution was stirred for 10 min, warmed to room temperature for 30 min and re-cooled to −78° C. 3-Fluoro-pyridine (370 μL, 4.30 mmol) was added drop-wise and the reaction mixture was stirred for 2 h. A solution of N-methoxy-N-methyloxolane-3-carboxamide (685 mg, 4.30 mmol) in THF (4.2 mL) was added drop-wise and the reaction mixture was warmed to room temperature and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAc (5 mL), diluted with EtOAc (50 mL), washed with water (2×25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound as a yellow gum (61.0 mg, 10%). LCMS (ES+): 196.0 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][S:6][C:7](=[S:17])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)#[N:2].Cl.[OH2:19]>>[C:1]([CH2:3][CH2:4][CH2:5][S:6][C:7](=[S:17])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:19])[NH2:2]
Reactant: O
Reactant: N#CCCCSC(=S)NCc1ccc(Cl)cc1
Agent: Cl
Product: NC(=O)CCCSC(=S)NCc1ccc(Cl)cc1

Procedure:
29.2 G. of 3-cyanopropyl(p-chlorobenzyl)dithiocarbamate were suspended in 150 ml. of concentrated hydrochloric acid and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. After washing, drying and concentration of the ethyl acetate phases, 18.1 g. of 3-carbamoylpropyl)p-chlorobenzyl)dithiocarbamate were crystallized from ethyl acetate/diisopropyl ether; melting point 123°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21].[BH4-].[Na+]>CO>[CH2:20]([CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1)[CH3:21]
Reactant: CCC(CC)CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 3-ethylpentylamine (Example 733, Part B) (0.317 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.516 g, 58%): TOF MS ES+ 360.2 (M+H)+, HRMS calcd for C20H27N3O2F 360.2087 (M+H)+, found 360.2086, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.3 min, 100% purity.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([Cl:22])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:21].[ClH:21].[Cl:22][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:20]=[C:19]([Cl:21])[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc(Cl)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Clc1cc(NC2CCNCC2)nc(Cl)n1

Procedure:
A solution of 4-(2,6-dichloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 8.93 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (70 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 247.3 [M+H]+.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:19]([N:21]1CCOC[CH2:22]1)C.C(OC(Cl)=O)C(C)C.O>CN(C)C=O>[CH3:19][N:21]([CH3:22])[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:7][CH2:8][CH3:9])=[CH:18][CH:17]=1
Reactant: CCCC(c1ccc(C(=O)O)cc1)n1ccnc1
Reactant: CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(c1ccc(C(=O)N(C)C)cc1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.2 g of 4-[1-(1-imidazolyl)-butyl]-benzoic acid is dissolved in 10 ml of dimethylformamide, mixed at 0° C. with 1 ml of N-ethylmorpholine and 1 ml of chloroformic acid isobutyl ester. It is stirred for 30 minutes at 0° C., 2 ml of dimethylamino solution is instilled and stirred for 2 hours at 0° C. It is stirred into 500 ml of water, extracted with ethyl acetate and the organic phase is concentrated by evaporation in a vacuum. The remaining residue is distilled on a bulb tube. Boiling point: 260° C./0.03 mbar. 0.9 g of 4-[1-(1-imidazolyl)butyl]-benzoic acid dimethylamide is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O.[NH2:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:10]=2[C:11]([NH:28][NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.40 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.08 ml of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The reaction mixture was poured into water and then filtered. The resulting filter cake was washed with water and methyl tert-butyl ether. The filter cake was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.35 g of 3-bromo-N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: C(Cl)(=O)C.[N+:5]([C:8]([CH3:38])([CH3:37])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:13][C:12]=1[C:30]1[N:31]([CH3:36])[N:32]=[CH:33][C:34]=1[Cl:35])([O-])=O>CO.[Zn]>[NH2:5][C:8]([CH3:38])([CH3:37])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)=[CH:13][C:12]=1[C:30]1[N:31]([CH3:36])[N:32]=[CH:33][C:34]=1[Cl:35]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)Cl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)N
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (388 μl, 5.44 mmol) was added dropwise to a solution of N-(4-(2-nitro-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide (270 mg, 0.544 mmol) in methanol (5.0 mL). Zinc dust (356 mg, 5.44 mmol) was added, and the mixture was stirred at 23° C. After 1 hour, the mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in ammonium hydroxide (35%), diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness to afford the title compound as a colorless foam which was used without further purification. LCMS m/z (%) 469.4 (M+H, 37Cl 46.9), 467.2 (M+H, 35Cl 86.1), 452.2 (51.6%), 450.1 (100.0%).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Cl:12][C:13]1[C:20]([Cl:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:14]=1[CH:15]=[O:16].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][N:7]1[C:11]([CH:15]([OH:16])[C:14]2[CH:17]=[C:18]([O:24][CH3:25])[C:19]([O:22][CH3:23])=[C:20]([Cl:21])[C:13]=2[Cl:12])=[CH:10][CH:9]=[N:8]1
Reactant: Cn1cccn1
Reactant: COc1cc(C=O)c(Cl)c(Cl)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C(O)c2ccnn2C)c(Cl)c(Cl)c1OC
Reaction time: 1 h
Yield: 90.5 %

Procedure:
18 ml of 1.6M n-butyl lithium in n-hexane is added dropwise to a solution of 2.26 g of 1-methyl-pyrazole in tetrahydrofuran at -60° C. under argon gas atmosphere and the mixture is stirred at the same temperature for 1 hour. A solution of 5.88 g of 2,3-dichloro-4,5-dimethoxybenzaldehyde in tetrahydrofuran is added dropwise to the mixture at -60° to -50° C. and the mixture is stirred at -50° C. to room temperature for 1 hour. An aqueous ammonium chloride solution is added to the reaction mixture and the mixture is concentrated to remove organic solvent. The residue is extracted with ethyl acetate, and the extract is washed, dried and evaporated to remove solvent. The residue is crystallized from isopropyl ether to give 7.18 g of α-(1-methylpyrazol-5-yl)-2,3-dichloro-4,5-dimethoxybenzylalcohol.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][CH:7]=1)[CH3:2].[N+:25]([O-])([OH:27])=[O:26].O>C(Cl)(Cl)Cl>[CH2:19]([CH:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26])[CH3:20]
Reactant: O=[N+]([O-])O
Reactant: CCCCC(CC)COc1ccc(OCC(CC)CCCC)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCC(CC)COc1ccc(OCC(CC)CCCC)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
1,4-Bis(2-ethylhexyloxy)benzene (50.2 g, 0.150 mol) is dissolved in chloroform (150 ml) and cooled to 0° C. Nitric acid (70%, 17.0 g, 0.190 mol) is added dropwise at 0-3° C. and the reaction stirred whilst monitoring progress by HPLC. After 60 minutes, water (50 ml) is added and the organic layer separated, dried (MgSO4) and evaporated to give the title compound as a yellow oil (56.9 g, 100%). The material is used without further purification.
Reaction SMILES: [ClH:1].[N:2]1([CH:6]2[CH2:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12](C(OCCCC)=O)[CH2:11][CH2:10]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1>CO>[ClH:1].[ClH:1].[N:2]1([CH:6]2[CH2:7][CH2:8][C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:22][CH2:23]2)[CH2:3][CH2:4][CH2:5]1
Reactant: CCCCOC(=O)N1CCC2(CCC(N3CCC3)CC2)CC1
Agent: Cl
Solvent: CO
Product: C1CN(C2CCC3(CCNCC3)CC2)C1

Procedure:
Hydrogen chloride in methanol (1.25 mol/l, 15.5 ml) was added to tent-butyl 9-(azetidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1 g, 3.24 mmol) and the mixture was refluxed for 45 min. The solvent was removed in vacuo and the residue was dissolved in a small amount of ethanol. A solid was then precipitated out by addition of acetone, and finally diethyl ether was added and the precipitate formed was filtered out with suction. Yield: 0.87 g (95%)
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:24]([C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([OH:26])=[O:25]>CO>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[CH3:13][O:25][C:24]([C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]1)=[O:26]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1
Yield: 453.8 %

Procedure:
1 g of para-toluenesulfonic acid monohydrate is added to a solution of 10 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 300 ml of MeOH and the mixture is refluxed for 3 days. The reaction mixture is concentrated under vacuum, the residue taken up in acetone and ether is added until precipitation occurs. After spinning the precipitate formed, 9.34 g of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[C:10]([CH3:11])[C:2]=1[NH2:1]
Reactant: COc1ccc(C(=O)O)c(N)c1C
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of 2-amino-4-methoxy-3-methyl benzoic acid (3.1 g, 17.1 mmol) in dry DMF (40 ml) was added potassium carbonate (2.4 g, 17.1 mmol) and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (3.1 g, 22 mmol) was added and the mixture was stirred for three hours at room temperature. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (2.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][O:24][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCO)CC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O

Procedure:
In analogy to the procedure described in example 5C, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(3-hydroxy-propyl)-[1,4]diazepan-5-one and methanesulfonyl chloride gave the crude title compound as white foam and as a mixture of mainly mesylate and some chloride.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1cccc(OCCCCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Methyl 3-(3-chloro-propoxy)-phenylacetate (12.7 g, 52.3 mmol) was dissolved in dioxane (25 mL) and 1N NaOH (53 mL) was added. The mixture was stirred at room temperature for 45 minutes then acidified by addition of 1N hydrochloric acid (60 mL). A white precipitae formed which was filtered, washed with 1N HCl, water and dried. 3-(3-Chloro-propoxy)-phenylacetic acid (11.7 g, 98%). 1H NMR (500 MHz, CDCl3) δ 7.25 (1H, dd), 6.93–6.85 (3H, m), 4.11 (2H, t), 3.79 (2H, t), 3.70 (2H, s), 2.25 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][OH:12].O=O>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: NCCCO
Reactant: Clc1ccccn1
Agent: O=O
Solvent: O
Product: OCCCNc1ccccn1
Temperature: 150 °C
Reaction time: 14.5 h

Procedure:
Charge 2-chloropyridine (1.0 equiv) and 3-aminopropan-1-ol (2.2 equiv, 1.5 volumes, 1.5 wt equiv) and mix thoroughly. Purge oxygen from the system by applying vacuum (ca −10 psi) to the system and backfilling with nitrogen three times. Heat the solution to 150° C. and hold for 13-16 h under a nitrogen atmosphere. The light yellow to yellow reaction mixture is then cooled to 18-23° C. and water (1.0 volume, 1.0 wt equiv) is added. Extract the mixture three times with i-PrOAc (3×5.0 volumes, 3×4.4 wt equiv). Combine the organic extracts and wash with water (0.5 volumes, 0.5 wt equiv). Concentrate the i-PrOAc solution in vacuo to minimum stir. Tert-butyl methyl ether (5.0 volumes, 3.7 wt equiv) is used to dissolve the residual oil. Add seed crystals (0.1 wt %) of the pure product and hold at 18-23 for 5 h. Cool the mixture to 0-5° C. and hold for 1-2 h. Isolate the crystalline product by filtration and wash twice with tent-butyl methyl ether (2×2 volumes, 2×1.5 wt equiv) at 5-10° C. Dry 3-(2-pyridinylamino)-1-propanol at 25-30° C. under reduced pressure. Percent yield range observed: 60-70%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:8][Cl:9])=[O:7])(=[O:3])[CH3:2].C[Si](C)(C)[O:12][CH2:13][CH2:14]O[Si](C)(C)C.C(=O)=O.CC(C)=O>C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[C:1]([O:4][CH2:5][C:6]1([CH2:8][Cl:9])[O:12][CH2:13][CH2:14][O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)CCl
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)OCC1(CCl)OCCO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 73.6 %

Procedure:
A solution of 1-acetoxy-3-chloroacetone (20.0 g, 133 mmol, TCI America) and 1,2-bis(trimethylsilyloxy)ethane (30.2 g, 146 mmol, Aldrich) in anhydrous CH2Cl2 and under N2 atmosphere was cooled (−78° C., dry ice/acetone) and trimethylsilyl trifluoromethanesulfonate (1.2 mL, 6.6 mmol, Aldrich) was added. The reaction was warmed to room temperature and stirred for 5 days, with monitoring by 1H-NMR. The crude reaction solution was separated by silica gel column, and eluted with CH2Cl2, then 5% Et2O in CH2Cl2. Product fractions were pooled and concentrated in-vacuo giving the title compound (19.05 g) as a yellow oil, contaminated with 1-acetoxy-3-chloroacetone (2.93 g) and CH2Cl2 (1.0 g): 1H NMR (500 MHz, CDCl3) δ ppm 4.17 (2H, s), 4.03-4.11 (4H, m), 3.60 (2H, s), 2.09 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][N:13]=[C:12]3[N:19]2[CH2:30][CH2:29][CH2:28][C@H:20]2[C:21]([O:23]C(C)(C)C)=[O:22])[S:3]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][N:13]=[C:12]3[N:19]2[CH2:30][CH2:29][CH2:28][CH:20]2[C:21]([OH:23])=[O:22])[S:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ncnc2ccc(C=C3SC(=O)NC3=O)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(=Cc2ccc3ncnc(N4CCCC4C(=O)O)c3c2)S1
Yield: 80.6 %

Procedure:
10 mg of tert-butyl 1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}-L-prolinate (example 27) was stirred in a 25% (TFA/DCM) solution for 12 h at rt. The solvents were evaporated under vacuo and expected compound was precipitated with diethyl ether to give pure 1-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-pyrrolidine-2-carboxylic acid (7 mg, 81%).
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.[CH3:12][C:13](=[C:21]([CH3:23])[CH3:22])[CH2:14][CH2:15][C:16]([O:18]CC)=O.[Cl-].[NH4+]>C(OCC)C>[CH3:12][C:13](=[C:21]([CH3:22])[CH3:23])[CH2:14][CH2:15][C:16]1([OH:18])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: BrCCCCBr
Reactant: CCOC(=O)CCC(C)=C(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: BrCCBr
Product: CC(C)=C(C)CCC1(O)CCCC1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
Magnesium turnings (9.53 g, 0.39 mol) were covered with dry diethyl ether (50 ml) at room temperature under nitrogen. 1,2-Dibromoethane (0.5 ml) was added in one portion. As soon as a visible reaction had started (bubbling), magnetic stirring was switched on and a solution of 1,4-dibromobutane (50 g, 0.225 mol) in dry diethyl ether (360 ml) was added at a rate such as to maintain a constant reflux (1 hour). The reaction was further refluxed for 1 hour before cooling in an ice-water bath. Ethyl 4,5-dimethyl-4-hexenoate (26.5 g, 0.156 mol) in dry diethyl ether (30 ml) was added dropwise. Then the reaction was warmed up to room temperature and the reaction was refluxed for 1 hour. It was recooled in an ice-water bath before adding a saturated aqueous ammonium chloride solution (250 ml, slowly). After warming up to room temperature and shaking vigorously, the phases were separated. The organic phase was washed with aqueous saturated bicarbonate (250 ml) and water (500 ml). Each aqueous phase was re-extracted with diethyl ether (250 ml). Combined extracts were dried over anhydrous sodium sulfate. The product was purified by column chromatography on silica gel (eluting with heptanes/ethyl acetate 11:1 to 3:1) followed by bulb-to-bulb distillation (110° C./1 mbar). 22.62 g of the title compound (99.6% pure, 0.122 mol, 78%) were obtained.