Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:23][CH:24]([CH3:28])[CH2:25][CH2:26][OH:27])=[N:5][C:6]([CH2:21][CH3:22])=[C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)[N:8]=1)[CH3:2].N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([O:27][CH2:26][CH2:25][CH:24]([NH:23][C:4]1[C:3]([CH2:1][CH3:2])=[N:8][C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[C:6]([CH2:21][CH3:22])[N:5]=1)[CH3:28])(=[O:37])[CH3:36]
Reactant: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1NC(C)CCO
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1NC(C)CCOC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A 25 mL dry round bottom flask equipped with a magnetic stir bar was charged with a solution of 3-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}butan-1-ol (Example 39, 192 mg, 0.5 mmol) in CH2Cl2 (5 mL). The reaction was cooled with an ice bath and then treated with pyridine (0.044 mL, 0.55 mmol) followed by acetyl chloride (0.039 mL, 0.55 mmol). The solution turned from clear to a light yellow. The ice bath was removed and the reaction was stirred at ambient temperature for 2 hours. The reaction was diluted with CH2Cl2, washed twice with water, once with brine, dried with MgSO4, filtered and concentrated to give 217 mg of a crude oil. This material was purified by Biotage MPLC (40 g column, 20% ethyl acetate in heptane) to give 208 mg (97%) of 3-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}butyl acetate as a clear oil. Rf 0.15 (5% acetone in toluene). OAMS supporting ions at: ESI+ 426.1.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]2[C:8](=[O:12])[CH:9]=[CH:10][O:11][C:6]=2[C:5]=1[CH2:15][CH:16]=[CH2:17].[CH3:18][O:19][C:20](=[O:44])[CH2:21][CH2:22][C:23]1[C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]I.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20](=[O:44])[CH2:21][CH2:22][C:23]1[C:24]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:3][C:4]2[CH:14]=[CH:13][C:7]3[C:8](=[O:12])[CH:9]=[CH:10][O:11][C:6]=3[C:5]=2[CH2:15][CH:16]=[CH2:17])=[CH:25][CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: C=CCc1c(O)ccc2c(=O)ccoc12
Reactant: COC(=O)CCCOc1cccc(CCCCCCI)c1CCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1c(OCCCCCCc2cccc(OCCCC(=O)OC)c2CCC(=O)OC)ccc2c(=O)ccoc12
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 79 %

Procedure:
To a slurry of 202 mg(5.05 mmol) of 60% sodium hydride-mineral oil dispersion (pre-washed with penlane) in 3 mL of anhydrous N,N-dimethylformamide was added a solution of 0.77 g (3.81 mmol) of 7-hydroxy-8-(2-propenyl)-4H-1-benzopyran-4-one in 12 mL of anhydrous N,N-dimethylformamide, over a 1 min period. The mixture was stirred at room temperature for 15 min whereupon a solution of 2.1 g (4.29 mmol) of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (example 17) in 15 mL of anhydrous N,N-dimethylformamide was added over a 1 min period. The resulting mixture was stirred at room temperature for 3 hr before being treated with ice-water, and worked-up with ethyl acetate in the usual manner. The oily product was chromatographed on silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 1.7 g (79.1%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C

Procedure:
2,6-Dichloro-9H-purine (20 g, 0.11 mol) and 4-toluenesulphonic acid monohydrate (0.2 g) were dissolved in ethyl acetate (300 ml), the mixture was heated to 50° C. and a solution of 2,3-dihydropyran (12.6 ml, 0.14 mol) in ethyl acetate (50 ml) was added slowly over 30 minutes. The reaction mixture was then cooled to room temperature, water (100 ml) was added and the pH of the solution was adjusted to 7 with a saturated aqueous solution of sodium hydrogen carbonate. The layers were separated and the organic layer was washed sequentially with water and brine, dried (anhydrous magnesium sulphate), filtered and evaporated under reduced pressure. The residue was twice azeotroped from pentane to afford the title compound as a slightly impure white solid (30.9 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:32][C:33](=[O:44])[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)[CH3:35])[CH2:30]C>>[CH2:29]([O:32][C:33](=[O:44])[CH:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:42][O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:40][CH:41]=1)[CH3:35])[CH3:30]
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCCOC(=O)C(C)c1ccc(CBr)cc1
Product: CCOC(=O)C(C)c1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 2-(4-Bromomethyl-phenyl)-propionic acid propyl ester as in the procedure of Example 43. MS m/z 570;
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C(OCC)C>[OH:13][CH2:12][C:11]1[CH:10]=[C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-benzoylbenzoic acid (6.26 g, 27.7 mmol) was carefully added in several portions to borane-N,N-diethylaniline complex (7.38 mL, 41.5 mmol) in anhydrous THF (60 mL) at ambient temperature. After 15 minutes, the reaction mixture was heated at reflux for 5 hours and then cooled to ambient temperature. The reaction mixture was diluted with diethyl ether, quenched with 1N HCl and the separated aqueous phase was extracted with diethyl ether. The organic layers were combined, washed with 1N HCl, brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40% ethyl acetate/hexanes) to provide a mixture of the title compound and the diol, [3-(hydroxymethyl)phenyl](phenyl)methanol, as a colorless oil (3.59 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>ClCCl.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][C:14]=1[N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(F)cc2)cc1N1CCN(C)CC1
Yield: 88.9 %

Procedure:
4-Fluorobenzoyl chloride (0.23 ml, 1.95 mmol) with 4-methoxy-3-(4-methyl-1-piperazinyl)phenylamine (400 mg, 1.95 mmol) in dry dichloromethane (40 ml) and triethylamine (1 ml) was stirred for 1 h. The solution was partitioned between dichloromethane (40 ml) and saturated aqueous potassium carbonate (40 ml), the organic solution dried (sodium sulphate) and evaporated to dryness under reduced pressure to afford an oil, which was purified by column chromatography (silica, chloroform,/methanol 5%) to afford the tide compound (595 mg, 89%) which was crystallised from methanol/diethyl ether as the oxalate salt.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:14]1([CH2:20][CH2:21][C:22](Cl)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=P(Cl)(Cl)Cl>>[CH2:21]([C:22]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1)[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), phenylpropionylchloride (185 mg, 0.163 ml, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.031 mg (10.7%); MS m/z: 291.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.09 (t, 2H, 3J=7.7 Hz); 3.25 (t, 2H, 3J=7.5 Hz); 7.15-7.19 (m, 1H); 7.23-7.27 (m, 4H); 7.84 (d, 1H, 3J=8.7 Hz); 7.92 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.20 (br s, 1H); 8.87 (s, 1H); HPLC (METHOD [A]): rt 11.82 min (100%)
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1(C)C=CC=CC=1>[C:46]1([C:2]2[N:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5]3=[N:4][C:3]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4n(c3Br)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4n(c3-c3ccccc3)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a suspension of tert-butyl (1-(4-(3-bromo-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.213 g, 1 eq.) in a mixture of toluene (5 mL), ethanol (5 mL), and saturated sodium bicarbonate (1 mL) was added phenyl boronic acid (0.07 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.025 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl (1-(4-(3-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.084 g, 40%) as a yellow solid. 1H NMR (DMSO-d6) 400 MHz δ 8.55 (s, 1 H), 8.06 (dd, JA=4.8 Hz, JB=2.4 Hz, 1H), 7.95 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), 7.78 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.58-7.50 (m, 1H), 7.44-7.36 (m, 4H), 7.35-7.31 (m, 2H), 7.30-7.18 (m, 4H), 7.14-7.09 (m, 1H), 6.89 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), 6.73 (dd, JA=7.6 Hz, JB=4.8 Hz, 1H), 2.45-2.28 (m, 4H), 2.04-1.92 (m, 1H), 1.83-1.70 (m, 1H), 1.33 (br. s, 9H); LCMS: 556 [M+H].
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:21]=[C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH2:19][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Oc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Cn2c(=O)sc3ccccc32)cc1
Yield: 67 %

Procedure:
To a solution of 2-hydroxybenzothiazole (1.17 g, 7.58 mmol) in THF (10 mL) was added Et3N (1.1 mL, 7.89 mmol). A solution of 2-bromo-4′-methylacetophenone (1.67 g, 7.06 mmol) in THf (10 mL) was added dropwise. Another equivalent of Et3N was added after 24 hours. Purification by flash chromatography on silicagel (CH2Cl2) gave a white powder in 67% yield: mp 168-170° C.; 1H-NMR (DMSO-d6) 2.43 (s, 3H), 5.62 (s, 2H), 7.21 (t, 1H), 7.27 (d, 1H) 7.32 (t, 1H), 7.42 (d, 2H), 7.70 (d, 1H), 8.01 (d, 2H); Anal. (C16H13NO2S) C, H, N.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[S:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17](O)(=[O:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[S:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)(=[O:19])[CH3:18]
Reactant: OCc1cc2c3ccccc3[nH]c(=S)n2n1
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc2c3ccccc3[nH]c(=S)n2n1

Procedure:
3.23 g (0.014 mole) of the product of Example 5 [2-(hydroxymethyl)pyrazolo[1,5-c]quinazoline-5(6H)-thione] is refluxed with 250 ml of glacial acetic acid for 20 hours under nitrogen. The solution is cooled and stripped to a solid residue which is dissolved in a mixture of ethyl acetate-absolute ethanol. The volume of solution is reduced and the concentrated solution set aside at 5°. The precipitate is filtered off to give the product. Recrystallization from ethyl acetate-absolute ethanol gives the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[C:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH2:24][S:23][CH:22]2[C:26](Cl)=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1>O.C1COCC1>[C:12]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH2:24][S:23][CH:22]2[C:26]([NH:1][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: NC(C(=O)O)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Intermediate VIII (Scheme 3), e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (1.747 g, 5 mmol) was dissolved in DCM (20 mL). The resulting solution was cooled down to −10° C. and oxalyl chloride (0.645 mL, 7.5 mmol) was added slowly. DMF (0.1 mL) was added carefully. The reaction mixture was allowed to warm to RT over 1 h and stirred an additional hour at RT. As the reaction was complete, the solvents were evaporated. Toluene was added and evaporated to remove residual oxalyl chloride. This process was repeated twice, affording intermediate XXX, e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride as a yellow solid (1.839 g, quantitative yield). α-Aminophenylacetic acid (831 mg, 5.5 mmol) was dissolved in water (20 mL). TEA (2.77 mL, 20 mmol) was added carefully. THF (25 mL) was added to reaction mixture. The reaction mixture was cooled to 0° C. Acid chloride previously prepared XXX, e.g. 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride dissolved in THF (25 mL) was added dropwise. The reaction mixture was stirred 15 min at 0° C. and overnight at RT. Solvents were concentrated and the resulting aqueous fraction was acidified with HCl 5N and extracted with 3 portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated. The crude product was recrystallized in acetone/Et2O mixture, affording carboxylic acid Ia, e.g., ({[3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)(phenyl)acetic acid in 97% purity by HPLC (943 mg, 39% yield).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: C[C@H]1CNCCN1
Reactant: Brc1ccccn1
Product: C[C@H]1CN(c2ccccn2)CCN1
Temperature: 120 °C
Yield: 67.7 %

Procedure:
(S)-(+)-2-Methylpiperazine (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120° C. for 14 hours. The reaction mixture was allowed to cool to 23° C. and partitioned between ethyl acetate and water. The layers were separated, and the water layer extracted twice with ethyl acetate. The aqueous phase was brought to pH ˜11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with ethyl acetate (2×) and dichloromethane (2×). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.6 g (67% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[CH2:13]([O:20][CH2:21][CH2:22][SH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:13]([O:20][CH2:21][CH2:22][S:23][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: SCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CSCCOCc1ccccc1)c1ccc(F)cc1F
Yield: 80.1 %

Procedure:
Using 2-chloro-2',4'-difluoroacetophenone (4.5 g, 0.024 mol), 2-benzyloxyethanethiol (4.2 g, 0.025 mol), potassium carbonate (4.0 g, 0.029 mol) and methanol (50 ml), 2-(2-benzyloxyethyl)thio-2',4'-difluoroacetophenone (6.2 g, yield: 80.8%) was obtained as a colorless oil by similar procedures to Example 1.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].N.Cl[P:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:13]([P:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[O:3][CH2:1][CH3:2])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCO
Reactant: CCCCCCP(Cl)c1ccccc1
Agent: N
Product: CCCCCCP(OCC)c1ccccc1
Yield: 79.2 %

Procedure:
135 g (2.94 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 7.4 g (0,435 mol) of ammonia are then introduced at this temperature with constant stirring. 86 g (0.376 mol) of chloro-(n-hexyl)phenyl-phosphine are then added dropwise at this temperature in 40 minutes, then the mixture is allowed to come to room temperature with stirring, is filtered by suction and washed with ethanol. The filtrate is freed from ethanol and any ammonia present in vacuo. The remaining residue is distilled. 71 g of ethyl n-hexyl(phenyl)phosphinite are obtained at 1.1 mbar and an overhead temperature of 110° C. This corresponds to a yield of 79% of theory.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(CC)C.Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:11][CH2:12][CH2:13][CH2:14][S:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: c1ccc(CCCC2SCCCS2)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: c1ccc(CCCC2(CCCc3ccccc3)SCCCS2)cc1
Temperature: -25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.0 g (4.2 mmol) of 2-(3-phenylpropyl)-1,3-dithiane in 25 ml of dry tetrahydrofuran was cooled to -78° C., and treated with 3.23 ml (4.2 mmol) of secbutyllithium. The resulting solution was stirred at -25° C. for 20 min, recooled to -78° C., and treated with 0.64 ml (4.2 mmol) of 1-bromo-3-phenylpropane. After being stirred at -78° C. for 15 min, the solution was allowed to stir overnight at ambient temperature. The solution was partitioned between ether and aqueous ammonium chloride, and the organic layer was washed sequentially with water, 1 M sodium bisulfite, and saturated brine, dried over MgSO4, and concentrated in vacuo to give the desired compound. 1H NMR (CDCl3) δ 65-1.9 (m, 9H), 2.18 (m, 1H), 2.55-2.75 (m, 6H), 2.78 (t, J=8 Hz, 1H), 3.40 (t, J=6 Hz, 1H), 7.1-7.35 (m, 10H). Mass spectrum (M+H)+ =357.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, diethylamine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.59 minutes; C20H20Cl2N4O2 (419.31); mass spectrum: (M+H)+=419.2.
Reaction SMILES: S(=O)(=O)(O)O.O[CH:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[O:9][CH2:8]1.O>C1C=CC=CC=1>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]2[CH:7]=[CH:8][O:9][C:10]=2[CH:15]=1
Reactant: Cc1ccc2c(c1)OCC2O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc2ccoc2c1
Reaction time: 3 h

Procedure:
Sulfuric acid (0.2 ml) and 10.0 g of 3-hydroxy6-methyl-2,3-dihydrobenzofuran were dissolved in 200 ml of benzene and heated at reflux with the azeotropic removal of water. After 3 hours, the reaction mixture was added to water (500 ml) and extracted with ether. The combined ether extracts were washed with water and saturated aqueous sodium bicarbonate, dried with sodium sulfate and the solvent evaporated to give 6-methylbenzofuran.
Reaction SMILES: Cl.[C:2]1(=[O:13])[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>CN(C=O)C>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:29]=[CH:30][C:21]=1[N:10]1[CH2:11][CH2:12][C:7]2([C:2](=[O:13])[NH:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][CH2:9]1
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C1NCCCC12CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 60 °C
Yield: 78.3 %

Procedure:
To the stirred solution of 2,9-diazaspiro[5.5]undecan-1-one hydrochloride (2.2 g, 10.78 mmol) in DMF (15 mL) was added K2CO3 (4.45 g, 32.24 mmol) and 2-chloro quinoxaline (1.94 g, 11.82 mmol). The mixture was heated at 60° C. for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude mixture water was added and extracted with ethyl acetate. The organic layer was dried over anhydride sodium sulfate, filtered and concentrated to obtain a yellow solid which was triturated with n-pentane to yield a yellow solid (2.5 g, 78%). [1H-NMR (DMSO-d6, 300 MHz): δ 8.91 (s, 1H), 7.81 (d, 1H), 7.62-7.55 (m, 2H), 7.42-7.33 (m, 2H), 4.33-4.19 (m, 2H), 3.52-3.33 (m, 2H), 3.20-3.05 (m, 2H), 2.12-1.98 (m, 2H), 1.95-1.64 (m, 4H), 1.59-1.48 (m, 2H); HPLC RtA=3.665 min (97%); LCMS RtA=0.377, [M+H]+=297.1].