Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH:12]1([CH2:18]O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10]
Reactant: O=C(O)Cc1ccccn1
Reactant: OCC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Cc1ccccn1)OCC1CCCCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 422 mg of 2-pyridylacetic acid hydrochloride and 596 μl of cyclohexylmethanol in 5 ml of dry pyridine was added 651 mg of 1,3-dicyclohexylcarbodiimide, and the mixture was stirred for 10 hours at room temperature. The precipitates were filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in 20 ml of a 1N-hydrochloric acid, acidic solution was washed twice with 25 ml of diethyl ether. A 2N-aqueous sodium hydroxide was added to the solution to a pH of 11. A separated oil was extracted with 50 ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 525 mg of cyclohexylmethyl 2-pyridylacetate as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[OH:23])[CH:18]=O)[CH3:13]>CO>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:20]=[CH:21][C:22]=1[OH:23])[CH3:13]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CCOc1cc(C=O)ccc1O
Solvent: CO
Product: CCOc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1O
Temperature: 25 °C
Yield: 59.9 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-ethoxy-4-hydroxybenzaldehyde 1.22 g were dissolved in methanol 75 ml, concentrated -hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.19 g.
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]([OH:8])[CH:6]([OH:9])[CH:5]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].N1C=CN=C1.[Si:39](Cl)([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>C(Cl)Cl>[Si:39]([O:8][CH:7]1[CH:6]([OH:9])[CH:5]([O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][C:3](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]1=[CH2:1])([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(O)C1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Ethyl (2-methylene-3,4-dihydroxy-5-(tert-butyldiphenylsilyloxy)cyclohexylidene)acetate (0.466 g) was dissolved in 5 ml of methylene chloride, and 0.204 g of imidazole and 0.30 g of tert-butyldiphenylsilyl chloride were added, followed by stirring the mixture at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.664 g of ethyl (3,5-bis-(tert-butyldiphenylsilyloxy)-4-hydroxy-2-methylene-cyclohexylidene)acetate having the following property.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>C1COCC1>[CH3:15][O:16][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)cnc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc2cc([N+](=O)[O-])ccc2n1
Yield: 68.3 %

Procedure:
Into 10 ml of THF was dissolved 1.16 g of 2-chloro-6-nitroquinoxaline, and then 1.0 g of sodium methoxide was added thereto, followed by heating under refluxing for 30 minutes. Then, the solvent was removed by evaporation. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline. After the solvent was removed by evaporation, the residue was crystallized from diethyl ether-hexane to obtain 776 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[S:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][C:30]=3Cl)[CH:25]=2)=[O:23])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[S:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][C:30]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:25]=2)=[O:23])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(NCCCN1CCOCC1)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCCN5CCOCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (3-morpholin-4-yl-propyl)-amide by a procedure analogous to Example 1C. MS: 450 (MH+); HPLC Rf: 3.48 min.; HPLC purity 96%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21](=O)[CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[NH2:37][NH2:38].CC(O)=O>CCO>[Cl:1][C:2]1[C:3]([C:21](=[N:37][NH2:38])[CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cnc21
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CC(=NN)c2c(Cl)cnc3[nH]ccc23)CC1
Yield: 44.2 %

Procedure:
To a suspension of tert-butyl 4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxoethyl)piperidine-1-carboxylate (1.00 g, 1.87 mmol) in EtOH (6.4 mL) were added anhydrous hydrazine (2.94 mL, 94.0 mmol) and AcOH (0.536 mL, 9.36 mmol). The reaction mixture was stirred at reflux for about 16 h. The solvent was removed under reduced pressure and the crude material was taken up in DCM and dried over anhydrous MgSO4. The solvent was removed and DCM (3 mL) was added. The solid was removed by filtration and the filtrate was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford tert-butyl 4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydrazonoethyl)piperidine-1-carboxylate (0.324 g, 44%) as a white solid consisting of a 1/1 mixture of E/Z isomers: LC/MS (Table 1, Method r) Rt=1.46 and 1.53 min; MS m/z: 392/394 and 392/394 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:13][CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][S:25]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=[O:27])=[O:26]>>[CH2:6]([N:13]([CH2:14][CH3:15])[C:3](=[O:4])[CH2:2][N:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16])[S:25]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=[O:27])=[O:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCNCc1ccccc1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C(Br)CBr
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccc2ccccc2c1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and naphthalene-2-sulfonic acid (2-methoxy-phenyl)-amide
Reaction SMILES: [C:1](=[O:3])=[O:2].C1COCC1.[Li][C:10]1[S:20][C:13]2[C:14]3[CH:19]=[CH:18][S:17][C:15]=3[S:16][C:12]=2[CH:11]=1>O>[S:20]1[C:13]2[C:14]3[CH:19]=[CH:18][S:17][C:15]=3[S:16][C:12]=2[CH:11]=[C:10]1[C:1]([OH:3])=[O:2]
Reactant: O=C=O
Reactant: [Li]c1cc2sc3sccc3c2s1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2sc3sccc3c2s1
Temperature: -78 °C
Yield: 61 %

Procedure:
Carbon dioxide was added in small lumps to a flask against a fast flow of nitrogen. The flask was then sealed under a nitrogen bubbler and cooled to the −78° C. THF was added to cover the CO2 and the mixture stirred. The cooled lithiodithienothiophene was added dropwise via syringe and a violent reaction was observed resulting in the formation of a yellow suspension. Once addition was complete the mixture was allowed to warm to r.t. during which time the mixture turned to an off white colour. After stirring for a further 30 min. water (30 cm3) was added and the mixture turned to a light green/brown solution. This was washed with ether (2×20 cm3) and the organics discarded. The aqueous layer was acidified by the addition of HCl (10 cm3, 5 M) which precipitated out a fine yellow solid. Recrystallisation was attempted in 33% acetic acid. A fine, insoluble suspension remained after heating and this was left to further crystallise overnight to give the title compound as a fine yellow/green powder (286 mg, 61%); δH 7.31, (1H, d, J5.1), 7.56 (2H, d, J5.1), 7.94 (1H, s); v max/cm−1 (KBr) 3090 m, 2823 m, 2559 m, 1652 s, 1504 s, 1470 w, 1428 s, 1311 s, 1265 m, 1164 m, 928 s, 750 s, 716 s and 602 s; m.p. 276° C. (sublimes) m.p.(lit.reference 29) 275-277° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[C:29](=[O:46])[N:30]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]([CH3:37])=[N:32]2>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[C:29](=[O:46])[N:30]([CH:38]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]([CH3:37])=[N:32]3)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(Cl)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a stirred solution of (4-chloro-phenyl)-acetic acid (0.31 g, 1.8 mmol) in DMF in a 40° C. oil bath (8 mL), was added 1.1′-carbonyldiimidazole (0.33 g, 2.0 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.62 g, 1.8 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as an off-white solid (580 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.10 min (98.5%); mp, 285° C. (decomposed); 1HNMR (DMSO-d6) 2.14-2.19 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 3.54 (s, 2H, ArCH2), 4.74-4.78 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.26-7.72 (m, 7H, Ar), 8.39 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.28, 30.59, 41.49, 41.72, 56.48, 117.68, 124.72, 125.59, 128.13, 130.92, 131.08, 133.82, 135.32, 140.64, 148.44, 154.80, 160.90, 169.50, 169.88, 172.59. LCMS MH=453, 455; Anal Calcd For C23H21N4O4Cl+0.15H2O+0.06 CH2Cl2: C, 60.12; H, 4.69; N, 12.16; Cl, 8.62. Found: C, 59.78; H, 4.60; N, 12.22; Cl, 9.00.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C@@H:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29][OH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][OH:30])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(N[C@H](CO)c1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (S)-2-amino-2-phenylethanol via Procedure G. The crude product was purified on reverse phase HPLC to yield (S)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxy-1-phenylethyl)terephthalamide. MS (Q1) 506 (M)+.
Reaction SMILES: [NH4+].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9])#[N:3].Cl>>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:3]
Reactant: N#CCCCCC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Product: N#CCCCCC(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
A 200-mL portion of the filtrate of the product mixture described above, containing the 5-cyanopentanoic acid ammonium salt (1.13M), was adjusted to pH 2.5 with 6N HCl, then saturated with sodium chloride and extracted with 4×200 mL of ethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered, and the solvent removed by rotary evaporation at reduced pressure. Remaining ether was removed by stirring the colorless liquid at room temperature under high vacuum (60 millitorr), for 5 h to yield 27.32 g (95% isolated yield) of 5-cyanopentanoic acid. The 5-cyanopentanoic acid was then distilled under vacuum (75 millitorr) at 110-112° C. without decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24](Cl)=[CH:23][N:22]=1)COCC[Si](C)(C)C)(=[O:11])=[O:10].[CH2:30]([CH2:32][NH2:33])[OH:31].[H-].[Na+]>COCCOC>[NH2:33][CH2:32][CH2:30][O:31][C:24]1[N:25]=[C:26]([O:27][CH3:28])[C:21]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:10])=[O:11])=[N:22][CH:23]=1
Reactant: NCCO
Reactant: COc1nc(Cl)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nc(OCCN)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
2,3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 115a) (0.25 g) was added to a mixture of ethanolamine (0.05 mL) and sodium hydride (0.035 g of a 60% dispersion in oil) in 1,2-dimethoxyethane (15 mL) at room temperature. After 2 h, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. Chromatography on silica gel eluting with methanol/dichloromethane mixtures gave the title compound containing the SEM ([2-(trimethylsilyl)ethoxy]methyl) protecting group as an oil (0.14 g). Trifluoroacetic acid (1 mL) and dichloromethane (3 mL) were added. After 0.5 h at room temperature, toluene was added and the solution evaporated to dryness. HCl (4M in dioxane) was added and the mixture evaporated to dryness. The product was crystallised from diethyl ether (0.075 g).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][OH:16]>C(OCC)C>[CH3:7][C:8]1[CH2:13][CH2:12][CH2:11][C:15](=[O:16])[C:9]=1[CH2:10][C:1]([O:2][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CO
Reactant: BrCc1ccccc1
Agent: [Cs+]
Solvent: CCOCC
Product: CC1=C(CC(=O)OCc2ccccc2)C(=O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of the acid (Org. Proc. Research & Dev 1997, p. 222) (2.0 g, 11.9 mmol) in MeOH (20 mL) was stirred with caesium carbonate (1.93 g, 5.94 mmol) for 1 h and the solvents were removed in vacuo. The residue was taken up in DMF (20 mL) and benzyl bromide (1.84 mL, 15.5 mmol) was added. The solution was stirred overnight at room temperature. The solution was diluted with diethylether (100 mL) and the precipitate was removed by filtration. The filtrate was washed with brine (3*50 mL), dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl actetate (9/1 to 4/1) to give the desired compound as a colourless oil (2.8 g, 90%); 1H NMR (400 MHz, CHLOROFORM-d) 7.31-7.41 (5H, m), 5.12 (2H, s), 3.43 (2H, s), 2.42 (4H, s), 1.99 (2H, quin, J=6.2 Hz), 1.93 (3H, s).
Reaction SMILES: [CH2:1]([C:4]1[CH:23]=[CH:22][C:7]([N:8]=[CH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].CC1C=CC(NCC2C=C(OC)C(OC)=C(OC)C=2)=CC=1>>[CH2:1]([C:4]1[CH:23]=[CH:22][C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(N=Cc2cc(OC)c(OC)c(OC)c2)cc1
Agent: COc1cc(CNc2ccc(C)cc2)cc(OC)c1OC
Product: CCCc1ccc(NCc2cc(OC)c(OC)c(OC)c2)cc1
Yield: 70.7 %

Procedure:
From 108g (8.5 g, 26.9 mmol), a similar procedure as described for 109a gave 109g (6.0 g, 70.3%) as an oil. 1H NMR (200 MHz, CDCl3) δ7.00 (d, J=8 Hz, 2H), 6.61 (s, 2H), 6.60 (d, J=8 Hz, 2H), 4.23 (s, 2H), 3.84 (s, 9H), 2.84 (t, J=8 Hz, 2H), 1.60 (sextet, J=8 Hz, 2H), 0.92 (t, J=8 Hz, 3H). EIMS m/e 315 (M+, 93).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Br:9][C:10]1[C:15]([OH:16])=[C:14]([N+:17]([O-])=O)[CH:13]=[C:12]([F:20])[CH:11]=1>O.C(O)C>[NH2:17][C:14]1[CH:13]=[C:12]([F:20])[CH:11]=[C:10]([Br:9])[C:15]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(F)cc(Br)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)cc(Br)c1O
Temperature: 25 °C
Yield: 48.9 %

Procedure:
Sodium dithionite (58 g, 335 mmol) was dissolved in warm water (300 mL) and was added slowly to a solution of 6-bromo-4-fluoro-2-nitrophenol (11.8 g, 50 mmol) in 250 mL of ethanol heated on a steam bath. The reaction mixture turned from deep orange to light yellow. The suspension is diluted with water till a clear yellow solution was obtained. Partial concentration on a rotary evaporator induced crystallization. The mixture was then cooled to room temperature and crystals formed. Filtration and drying afforded the title compound as a white solid (5.04 g, 49% yield). MS 207 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH2:13]([S-:15])[CH3:14].[Na+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([S:15][CH2:13][CH3:14])=[N:7][N:6]=[CH:5]2
Reactant: CC[S-]
Reactant: Clc1nncc2cc(Br)ccc12
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSc1nncc2cc(Br)ccc12
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-1-chlorophthalazine (0.22 g, 0.9 mmol) in acetonitile (5 mL) stirred at ambient was added sodium ethanethiolate (0.2 g, 2 mmol), and the mixture was stirred for 1 h. The mixture was diluted with ethyl acetate (100 mL), washed with sat. NH4Cl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by chromatography eluting with 1-5% 2 M ammonia methanol/dichloromethane to give the 6-bromo-1-(ethylthio)phthalazine as pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:21][C:22]([F:35])([F:34])[C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:25][CH:24]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:27][C:23]([C:22]([F:35])([F:21])[F:34])=[CH:24][N:25]=3)[CH2:29][CH2:30]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(SCC(F)(F)F)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(SCC(F)(F)F)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 49 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-ethylsulfanyl)-benzoic acid (Example A24) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a light yellow solid (yield 49%). MS (m/e): 534.0 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[CH:3]=[C:2]([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)[N:7]=[C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=[CH:10][C:5]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (3.1 g, 7.4 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.7 g, 8.7 mmol) and Pd(PPh3)4 (0.428 g, 0.370 mmol) in 1,4-dioxane (20 mL) was purged with argon for 10 min. Then, 2M Na2CO3 (2.8 g, 26.41) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired intermediate (2.8 g, 73.7%).
Reaction SMILES: O1C(C=O)=CN=C1.[Cl:8]C1C=CC(C=O)=CC=1F.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([NH2:28])[CH2:26][CH3:27])=[CH:21][C:20]=1[F:29].ClC1C=CC(C(N)CC)=CC=1F>>[ClH:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([NH2:28])[CH2:26][CH3:27])=[CH:21][C:20]=1[F:29]
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: CCC(N)c1ccc(Cl)c(F)c1
Agent: CC[C@@H](N)c1ccc(Cl)c(F)c1
Agent: O=Cc1cnco1
Product: Cl

Procedure:
(R)-1-(4-chloro-3-fluorophenyl)propan-1-amine hydrochloride (139) was prepared in accord with procedures described in steps 1 and 2 of example 1, except in step 1, oxazole-5-carbaldehyde was replaced with 4-chloro-3-fluorobenzaldehyde. Condensation of (R)-1-(4-chloro-3-fluorophenyl)propan-1-amine and 138 was carried out in accord with step 6 of example 1 except 28 was replaced with 138 and 22 was replaced with 1-(4-chloro-3-fluorophenyl)propan-1-amine. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:40) to afford 0.30 g (75%) of I-38: 1H NMR (400 MHz, d6-DMSO) δ 8.06 (s, 1H), 7.51-7.47 (t, 1H), 7.34 (d, 1H), 7.17 (d, 1H), 6.95 (d, 1H), 6.53 (d, 1H), 4.64-4.55 (m, 2H), 4.38-4.26 (m, 2H), 3.93-3.90 (m, 1H), 3.59-3.55 (m, 2H), 3.46-3.31 (m, 1H), 3.29-3.24 (m, 1H), 2.55-2.50 (m, 2H), 1.76-1.63 (m, 1H), 1.08 (d, 3H), 0.84 (t, 3H); MS m/z (APCI-pos) M+1=422.