Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][O:18][CH3:19])[C@H:12]([CH2:20][OH:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:22]([C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][C:31]=1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1)[CH2:23][CH2:24][CH3:25].CO>C1COCC1.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][O:18][CH3:19])[C@H:12]([CH2:20][O:21][C:29]2[N:28]=[N:27][C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[C:31]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:36][CH:37]=3)[CH:30]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: COCO[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2OCOC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a stirred solution of (±)-cis-4-methoxymethoxy-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (1.98 mmol, 0.5 g) in ether (5 mL) at 0° C. was added LAH powder (50 mg) in one lot and continued stirring at 0° C. for additional 20 min followed 10 min at room temperature. TLC analysis of an aliquot of the reaction mixture showed complete consumption of starting material. The reaction mixture was diluted with ether (5 mL), cooled to 0° C., added ethyl acetate drop-wise followed by saturated sodium sulfate. The organic layer was separated, dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 50% ethyl acetate in hexanes to provide (±)-cis-3-hydroxymethyl-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.506 g, 93%) as an oil. To a stirred suspension of sodium hydride (4.16 mmol, 0.1 g) in THF (8 mL) at room temperature was added (±)-cis-3-hydroxymethyl-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (1.84 mmol, 0.506 g) followed 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 1.74 mmol, 0.6 g). The resultant reaction mixture was kept stirring at 50-60° C. for 2 h. The reaction mixture was cooled to room temperature and excess NaH was decomposed by addition of methanol drop-wise. This was diluted with ethyl acetate (20 mL), washed with water (5 mL), separated the organic layer, dried, filtered and concentrated under reduced pressure. The resultant residue was purified by flash silica gel chromatography by eluting with 40% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.93 g, 82% yield) as a light yellow oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:9])=[O:8].C([Li])CCC.[CH3:34][C:35]([CH3:37])=[O:36].FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[OH:36][C:35]([CH3:37])([CH3:34])[CH:10]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:15][CH:16]=1)[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(N3CCOCC3)cc2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(O)C(c1ccc(N2CCOCC2)cc1)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
Under inert gas, 0.264 g of N-(2,4-dimethoxybenzyl)-C-(4-morpholin-4-ylphenyl)methanesulfonamide was initially charged in 3 ml of THF and then, at −78° C., 0.85 ml of a 1.6 N butyllithium solution in hexane was added dropwise. The reaction mixture was stirred for 10 minutes and then 0.22 ml of acetone was added dropwise. The mixture was stirred at constant temperature for 30 minutes, 0.102 ml of trifluoroacetic acid was added and the mixture was allowed to come to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 4 ml of dichloromethane, and 1.2 ml of trifluoroacetic acid was added. After stirring at room temperature for 16 h, the crude product was purified in a purification laboratory by means of preparative HPLC. This gave the product with a molecular weight of 428.43 g/mol (C14H22N2O4S).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=O)=O>>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[CH2:18][CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)OCCc1cccs1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2CCc1cccs1
Yield: 39.1 %

Procedure:
The same procedures used in Example 1 were repeated except for using 435 mg of indole-4-carbaldehyde and 680 mg of 2-(thien-2-yl)ethyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 299 mg of 1-[2-(thien-2-yl)ethyl]indole-4-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 39%.
Reaction SMILES: [C:1]1([P:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([C:18]2[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:34]O>C(Cl)Cl>[C:28]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([C:18]2[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13]3)=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C1=CC(c2cccc3ccccc23)Nc2c1cccc2P(c1ccccc1)c1ccccc1
Reactant: OO
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1cccc2c1NC(c1cccc3ccccc13)C=C2
Yield: 90.7 %

Procedure:
Following the procedure described for the synthesis of compound 5,8-diphenylphosphino-2-naphthale-1-yl-1,2-dihydroquinoline (11) (8.8 g, 20 mmol) in CH2Cl2 (60 mL) was oxidised with H2O2 (4.15 mL, 30% w/w in H2O, 40 mmol) to give compound 12 (8.3 g) in 91% yield. 1H NMR (400.13 MHz, CDCl3) δ 8.00 (d, 1H, J=8.4 Hz, C5′—H), 7.83 (dd, 1H, J=7.6, 2.0 Hz, C8′—H), 7.7-7.6 (m, 3H, C2′—H/Ph-H), 7.6-7.5 (m, 3H, Ph-H), 7.5-7.4 (m, 5H, C6′/7′—H/Ph-H), 7.4-7.3 (m, 2H, Ph-H), 7.29 (d, 1H, J=8.0 Hz, C4′—H), 7.19 (t, 1H, J=8.0 Hz, C3′—H), 6.96 (d, 1H, J=7.2 Hz, C5—H), 6.64 (ddd, 1H, J=13.6, 7.6, 1.2 Hz, C7—H), 6.44 (td, 1H, J=7.2, 2.8 Hz, C6—H), 6.34 (dt, 1H, J=10.0, 1.6 Hz, C4—H), 6.32 (t, 1H, J=1.6 Hz, C2—H), 5.78 (dd, 1H, J=10.0, 4.0 Hz, C3—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 148.3, 148.2, 139.2, 132.9, 131.9 (d, J=11.1 Hz), 131.8 (d, J=12.1 Hz), 131.2 (d, J=10.1 Hz), 130.9 (d, J=9.1 Hz), 130.7, 129.8, 128.4, 127.8, 127.5 (d, J=12.1), 127.3 (d J=12.1), 126.6, 125.3, 124.7, 124.5, 123.8, 123.7, 123.4, 121.5, 121.5, 118.9, 114.2, 114.0, 108.9, 107.8, 52.6 ppm; 31P NMR (161.97 MHz, CDCl3) δ+35.2 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9].F[B-](F)(F)F.[CH2:22]([O+](CC)CC)[CH3:23]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH:12]([O:16][CH2:22][CH3:23])[CH2:11]1)=[O:9]
Reactant: O=C1CN(C(=O)c2ccccc2Cl)CCN1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1CN(C(=O)c2ccccc2Cl)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[(2-chlorophenyl)carbonyl]-2-piperazinone (I4) (676 mg, 2.83 mmol) was dissolved in dichloromethane (DCM) (10 mL) and was treated with triethyloxonium tetrafluoroborate (628 mg, 3.31 mmol). The solution was stirred at 25° C. for 16 hr and the solution partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (3×25 mL), combined extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated to a crude oil in 816 mg that was used in the subsequent step without further purification. Compound was not characterised but used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20].COC(=O)CC(=O)C(Br)C.C(C1C=CC(C(N)=S)=CC=1)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:24]=[CH:23][C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=3)[S:29][C:30]=2[CH3:36])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: Cc1sc(-c2ccc(C(C)C)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CC(C)c1ccc(C(N)=S)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)C)cc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-isopropyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-isopropyl-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-isopropyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-isopropyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15]C.ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH3:15]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2 S)-1-{[5-(2,4-dichlorophenyl)-3-ethyl-6-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: MS (ESI+) for C24H25Cl2N3O m/z 443 (M+H)+.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][O:30]COC)=[CH:24][CH:23]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[O:1]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][OH:30])=[CH:26][CH:27]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COCOCCc1ccc(Cc2ccc(OC)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2ccc(CCO)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
To a solution of 5-methoxy-2-(4-[2-(methoxymethyloxy)ethyl]benzyl)phenyl β-D-glucopyranoside (0.053 g) in methanol (2.3 mL) was added p-toluenesulfonic acid monohydrate (0.032 g), and the mixture was stirred at 50° C. for 3 hours. After cooling to room temperature, to the reaction mixture was added triethylamine (0.5 mL), and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give 2-[4-(2-hydroxyethyl)-benzyl]-5-methoxyphenyl β-D-glucopyranoside (0.023 g).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][NH2:15])[CH2:9][CH2:8][CH2:7]2.[C:16](OC(=O)CC)(=O)[CH2:17][CH3:18]>>[ClH:1].[CH2:16]([NH:15][CH2:14][CH:10]1[C:11]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][CH2:9]1)[CH2:17][CH3:18]
Reactant: COc1ccc2c(c1)CCCC2CN
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Product: CCCNCC1CCCc2cc(OC)ccc21

Procedure:
The product from Example 2 was reacted as in Example 15 but replacing acetic anhydride with propionic anhydride and gave the desired product.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:24])[CH2:10][CH2:11][CH:12]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][C:15]([OH:17])=O.[Cl-].[NH4+]>O1CCCC1>[CH3:7][O:8][C:9]([CH:10]1[CH2:11][CH:12]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14][C:15]1=[O:17])=[O:24]
Reactant: COC(=O)CCC(CCC(=O)O)c1ccncc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1CC(c2ccncc2)CCC1=O
Reaction time: 2 h
Yield: 39.8 %

Procedure:
To 100 ml of tetrahydrofuran, there was added 13 g of potassium t-butoxide. A solution of 26 g of 4-(4-pyridyl)pimelic acid methyl ester in 50 ml of tetrahydrofuran was added at 20° to 40° C. and the mixture was stirred for 2 hours. After the reaction was completed, the mixture was treated with saturated aqueous solution of ammonium chloride and then extracted with ether. The ether solution was washed with water and dried. Ether was distilled off and the residue was recrystallized from ether. There was obtained 9.6 g of 2-methoxycarbonyl-4-(4-pyridyl)cyclohexanone: m.p. 82°-83° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:16][C@H:17]([C:25](O)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:9]([NH:16][C@H:17]([C:25]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1
Yield: 87.5 %

Procedure:
In substantially the same manner as Working Example 2, benzylamine (3.53 g) was condensed with Boc-L-phenylalanine (7.96 g) to give N-(Boc-L-phenylalanyl)benzylamine (9.30 g) (yield 87%). The compound thus obtained (7.08 g) was dissolved in ethyl acetate (100 ml), to which was added 4N hydrochloric acid/ethyl acetate solution (80 ml, manufactured by Kokusan Chemical Works, Ltd.), and the mixture was left standing for a half hour at room temperature. The reaction mixture was treated with ethylether to give N-(L-phenylalanyl)benzylamine hydrochloride (3.51 g) (yield 60%). The compound thus obtained (0.96 g) was condensed, in substantially the same manner as Working Example 8, with monoethyl ester of (2S,3S)-N-methylaziridine-2,3-dicarboxylic acid (0.52 g) obtained in Working Example 42 to give the above-titled compound (Compound 91; 0.86 g) as white crystals (yield 71%).
Reaction SMILES: [ClH:1].F[C:3]1[CH:8]=[C:7]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=2)[CH:22]=1)=[O:17].C(OC(N1CCO[C@@H](C2C=CC(N)=CC=2[F:53])C1)=O)(C)(C)C>>[ClH:1].[F:53][C:6]1[CH:5]=[C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]([C:23]3[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[N:24]=3)[CH:22]=2)=[O:17])[CH:3]=[CH:8][C:7]=1[C@@H:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2F)C1
Reactant: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Agent: Cl
Product: O=C(Nc1ccc([C@H]2CNCCO2)c(F)c1)c1cnn(-c2cncc(C(F)(F)F)n2)c1

Procedure:
In analogy to example 83, step a) using 1-(6-Trifluoromethyl-pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (prepared as described in example 125) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 83) instead of (+)—(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.CN([C:16]([O:20][N:21]1N=NC2C=CC=N[C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CONC.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([N:21]([O:20][CH3:16])[CH3:22])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1F
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Cl)c(Cl)cc1F
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
4,5-Dichloro-2-fluoro-benzoic acid (50 mg, 0.24 mmol), HATU (100.0 mg, 0.26 mmol) and N-methoxymethanamine (hydrochloric acid) (23.33 mg, 0.24 mmol) were combined in DMF (1.0 mL) and treated with DIEA (83.33 μL, 0.48 mmol). After 10 min, the reaction was complete. The reaction was diluted with diethyl ether and washed with 50% sat. NaHCO3 (2×) and brine, dried over Na2SO4, filtered and concentrated. Silica gel chromatography using a gradient of ethyl acetate/hexanes from 0 to 30% provided 4,5-dichloro-2-fluoro-N-methoxy-N-methyl-benzamide (50 mg, 83%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=6.3 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 3.56 (s, 3H), 3.35 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].O.C(Cl)Cl>O1CCOCC1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]3[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=3)[CH:11]=[O:12])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=Cc1cccc(-c2ccc3[nH]ccc3c2)c1
Temperature: 100 °C
Yield: 57 %

Procedure:
A mixture of 5-bromo-indole (8.7 g, 44.4 mmol), 3-formylbenzeneboronic acid (10 g, 66.7 mmol), cesium carbonate in water (2M, 88.8 mL, 178 mmol) in 450 mL of dioxane was degassed (evacuate in vacuo and pressurize with nitrogen, 3 times) PdCl2(dppf).DCM (1.1 g, 1.3 mmol) was added and the mixture degassed one more time as described above. The resulting mixture was heated at 100° C. for 3 h, then it was allowed to cool to room temperature and partitioned between diethyl ether and water. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with water, brine, dried over MgSO4, filtered and evaporated to give the crude product. Chromatography on silica gel (elution with ethyl acetate/heptane) afforded 5.6 g of the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1C
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccccc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH3:15])=[O:12])=[CH:10][C:2]=2[Cl:1])=[O:5])[CH2:29]1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: NCC1CCCNC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC(CN)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-3-aminomethylpiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.81 minutes; C23H25C12N5O2 (474.39); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:23])=[C:5]([C:19]([O:21][CH3:22])=[O:20])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:7]=1[C:8](O)=[O:9].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[CH2:38][OH:39])=[CH:32][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:23])=[C:5]([C:19]([O:21][CH3:22])=[O:20])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:7]=1[C:8]([O:39][CH2:38]/[CH:37]=[CH:36]/[C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:25]2[NH:24][CH:28]=[CH:27][N:26]=2)=[CH:31][CH:32]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc(Cl)c1Cl
Reactant: OC/C=C/c1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
356 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2,3-dichlorophenyl)pyridine-3-carboxylic acid together with 215 mg (1 mM) of (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexyl-carbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylamino-pyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 481 mg (87%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:12]4[CH:24]=[CH:23][S:22][C:13]=4[C:14](=[O:21])[NH:15][C:16]=3[CH:17]=[CH:18][C:19]=2[OH:20])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[OH:20][C:19]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:21])[C:13]3[S:22][CH:23]=[CH:24][C:12]=3[C:11]=2[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([C@@H:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH3:3])=[CH:9][CH:8]=1
Reactant: C[C@H](N)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Reactant: CS(=O)(=O)Cl
Product: C[C@H](NS(C)(=O)=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 56.3 %

Procedure:
Following the procedure outlined for Example 301, (S)-9-[4-(1-aminoethyl)phenyl]-8-hydroxythieno[2,3-c]quinolin-4(5H)-one (100 mg, 0.30 mmol) was reacted with methanesulfonyl chloride (100 mg, 0.89 mmol) to afford the desired product (70 mg, 56%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 5.89-7.55 (m, 2H), 7.52 (d, J=5.4 Hz, 1H), 7.38 (d J=8.9 Hz, 1H), 7.30-7.28 (m, 2H), 7.15 (d, J=8.9 Hz, 1H), 6.00 (d, J=5.4 Hz, 1H), 4.71 (q, J=7.1 Hz, 1H), 2.82 (s, 3H), 1.61 (d, J=7.0 Hz, 3H); ESI MS m/z 415 [C20H18N2O4S2+H]+; HPLC >99% (AUC), tR=12.43 min.