Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[N:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:28](=[O:29])[C:27]([CH3:32])([CH3:31])[CH3:26])=[CH:15][CH:14]=3)=[O:10])=[CH:20][CH:21]=[CH:22][N:23]=2)=[CH:24][CH:25]=1
Reactant: O=C(NCc1ccc(O)cc1)c1cccnc1Oc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Yield: 68.8 %

Procedure:
A solution 2-(4-Fluoro-phenoxy)-N-(4-hydroxy-benzyl)-nicotinamide (0.050 grams, 0.148 mmole), trimethylacetyl chloride (0.019 grams, 0.163 mmole) and triethyl amine (0.022 grams, 0.222 mmole) in methylene chloride (5 ml) was stirred for 30 minutes. The mixture was diluted with 50 ml 1N sodium hydroxide and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 40% ethyl acetate/hexane. Recrystalization from ethyl acetate/hexane gave a solid (0.043 g). M.P. 91-93° C.; Anal. calcd. for C24H23N2O4F: C, 68.24; H, 5.49; N, 6.63. Found: C, 66.07; H, 5.24; N, 6.42.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:39](=[O:38])[CH2:40][OH:41])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[OH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(O)C>C1(C)C=CC=CC=1.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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:21]2[CH:22]=[C:17]([CH2:16][OH:15])[CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:10]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cn1
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: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccc(CO)c2)cn1
Temperature: 80 °C
Yield: 86.2 %

Procedure:
2.0 g of tetrakis(triphenylphosphine)palladium and 75 ml of a 2M solution of sodium carbonate are added to a round-bottomed flask containing a solution of 5.0 g of 5-bromopyridin-2-ylamine in 140 ml of toluene, 5.7 g of 3-(hydroxymethyl)phenylboronic acid and 70 ml of ethanol degassed beforehand. The mixture is heated at 80° C. for 16 h. After cooling, the reaction mixture is concentrated under reduced pressure. The residue is taken up between water and ethyl acetate. The organic phase is separated, dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 4.99 g of compound are obtained.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[C:4]([CH2:18][CH3:19])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:34])[CH:33]=1>C1(C)C=CC=CC=1.C(O)C.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>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:3](=[O:20])[C:4]([CH2:18][CH3:19])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1cc(F)cc(F)c1
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: Cc1ccccc1
Solvent: CCO
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cc(F)cc(F)c2)C1=O
Temperature: 95 °C
Reaction time: 12 h
Yield: 36.6 %

Procedure:
To a stirred solution of 4-bromo-2-ethyl-2-methy-5-{4-(methylsulfonyl)-phenyl}-3(2H)-furanone (200 mg) in 15 ml toluene and 5 ml ethanol, were added 34 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate solution, and 110 mg of 3,5-difluorobenzeneboronic acid. Then the reaction solution was stirred at 95° C. for 12 hours. The reaction solvent was evaporated off under reduced pressure and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo. The resulting crude product mixture was purified by column chromatography (hexane/ethylacetate=2:1) to obtain 80 mg of 4-(3,5-difluorophenyl)-2-ethyl-2-methyl-5{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 122-124° C. NMR: δ0.95 (t, J=7.5 Hz, 3H), 1.54 (s, 3H), 1.97 (m, 2H), 3.10 (s, 3H), 6.81 (m, 3H), 7.84 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H). IR (cm−1): 2975, 2928, 1698, 1627, 1321, 1150, 990, 769, 552.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=C=O.[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>>[C:12]([OH:15])(=[O:14])[CH:13]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccccc1
Agent: C=C=O
Agent: [Na+]
Product: O=C(O)C=Cc1ccccc1
Yield: 40 %

Procedure:
The reaction of benzaldehyde with ketene at 60° C. with the addition of sodium acetate and subsequent heating of the reaction product to the boiling point is known from Ind. Chem. 41, 768 (1949). Cinnamic acid is thereby obtained in a yield of 40%.
Reaction SMILES: C(C[C:4]1[S:8][C:7]([C:9]2[N:14]=[N:13][C:12]([N:15]([CH2:23][C:24]3([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:27][CH2:26][CH2:25]3)C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[N:6][CH:5]=1)#N.Cl.CN.C1C=CC2N(O)N=[N:44][C:42]=2C=1.C(Cl)CCl.[C:52]([O:55]CC)(=O)[CH3:53]>Cl.CN(C=O)C>[F:34][C:33]1[C:28]([C:24]2([CH2:23][NH:15][C:12]3[N:13]=[N:14][C:9]([C:7]4[S:8][C:4]([CH2:53][C:52]([NH:44][CH3:42])=[O:55])=[CH:5][N:6]=4)=[CH:10][CH:11]=3)[CH2:25][CH2:26][CH2:27]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CC#N)s2)nn1
Reactant: CCOC(C)=O
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)Cc1cnc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)s1
Reaction time: 0.25 h

Procedure:
A solution of t-butyl 6-(5-(cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1 g, 2 mmol) in HCl (30 mL, conc) was heated to 105° C. in a microwave reactor and stirred for 15 min. The reaction was concentrated to give 900 mg (2.3 mmol) of a crude reddish solid. To this solid was added methylamine hydrochloride (183 mg, 2.7 mmol), HOBt (365 mg, 2.7 mmol), EDC (516 mg, 2.7 mmol), DMF (30 mL), and TEA (1.3 mL, 9 mmol). The reaction was stirred at rt overnight. The reaction was then poured into ethyl acetate (200 mL), washed with water (3×100 mL), and the organic layer was separated, dried over Na2SO4, filtered, concentrated, and recrystallized from EtOAc to give 408 mg of 2-(2-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)-N-methylacetamide as a white solid (M+H=413.3).
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([OH:27])=O)[CH:20]=[C:21]([CH3:23])[CH:22]=1.[NH2:28][C@H:29]([C:37]([OH:39])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:23][C:21]1[CH:20]=[C:19]([CH2:24][C:25]([NH:28][CH:29]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]([O:39][CH3:1])=[O:38])=[O:27])[CH:18]=[C:17]([CH3:16])[CH:22]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)NC(=O)Cc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DMAP (4-dimethylaminopyridine) (17.0 mg, 1.40 mmol) and DCC (1,3-dicyclohexylcarbodiimide)(86.2 mg, 4.19 mmol) were added to a solution of 3,5-dimethylphenylacetic acid (500 mg, 2.79 mmol) in dry THF (50 ml) were added. The mixture was stirred at rt for 30 min and then methyl ester of L-Phenylalanine (461 mg, 2.79 mmol) was added. After 48 h at rt. the crude mixture was filtered over celite and the solvent was removed under reduced pressure. The product was purified by flash chromatography (hexane/ethyl acetate 2:1) to afford (S) methyl 2-[2-(3,5-dimethylphenyl)acetamido]-3-phenyl-propanoate as white solid (70% c.y.).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.CC(C)=O.[C:41]([OH:50])(=[O:49])[CH:42]([CH:44]([C:46]([OH:48])=[O:47])[OH:45])[OH:43]>CCCCCC>[CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.[C:46]([C@H:44]([C@@H:42]([C:41]([O-:50])=[O:49])[OH:43])[OH:45])([O-:48])=[O:47]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
Ticagrelor (0.5 g) and acetone (10 mL) were charged into a round bottom flask and the mixture was stirred at about 30° C. for about 15 minutes for clear solution. Then D (−)-tartaric acid (0.16 g) was added to the above reaction mixture at about 30° C. and mixture was stirred for overnight. To the clear solution, n-hexane (35 mL) was added and stirred for about 1 hour at 25-30° C. for solid separation. The solid was filtered, washed with n-hexane (5 mL) and dried to afford the title compound in about 93% yield having chiral HPLC purity of about 98%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][O:6][C:7](=[O:9])[CH3:8])=[O:3].[C:10]([O:15][CH2:16][CH2:17][OH:18])(=[O:14])[C:11]([CH3:13])=[CH2:12].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[O:4][CH2:5][O:6][C:7](=[O:9])[CH3:8]
Reactant: CC(=O)OCOC(=O)Cl
Reactant: C=C(C)C(=O)OCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(=O)OCOC(C)=O
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of acetoxymethyl chloroformate (1.00 g, 0.0066 mol) and 2-hydroxyethyl methacrylate (0.86 g, 0.0066 mol) in methylene chloride (30 ml), pyridine (0.52 g, 0.0066 mol) was added at 0° C. After 10 min at 0° C. and 18 hours at 25° C. the reaction mixture was washed with aqueous hydrochloric acid (100 ml), aqueous saturated sodium hydrogen carbonate (100 ml) and water (100 ml). The solvent was removed under reduced pressure after drying (MgSO4). Flash chromatography (silicagel, hexane/ethyl acetate (3:2)) gave 1.05 g (65%) of the title product.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[I-:13].O>N1C=CC=CC=1>[OH:1][C:2]1[C:12]([I:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: [I-]
Reactant: CCOC(=O)c1ccc(O)nc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(O)c(I)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Ethyl 6-hydroxynicotinate (2.0 g, 12.0 mmol) was dissolved in pyridine (60 mL), which was then added with iodide (6.07 g, 23.9 mmol) and stirred at 60° C. overnight. The reaction solution was then added with water at room temperature and extracted with ethyl acetate. Subsequently, the organic layer was washed with a saturated aqueous solution of sodium sulfite and brine, and dried over sodium sulfate. The obtained residue was purified using column chromatography (chloroform/methanol) and concentrated in vacuo. Ethyl 6-hydroxy-5-iodonicotinate (2.9 g, yield 83%) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1.[BH4-].[Na+].O.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[O:10][C:9]([CH2:11][OH:12])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2cccc(F)c2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(Oc2cccc(F)c2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(3-fluoro-phenoxy)-furan-2-carbaldehyde described in Preparation Example 50 (1.5 g, 7.3 mmol) in tetrahydrofuran (20 mL) was added sodium borohydride (280 mg, 7.3 mmol), and the solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice, and the organic layer was filtered through a glass filter lined with silica gel. The solvent was evaporated in vacuo, and the title compound (1.5 g, 7.2 mmol) was obtained as a pale yellow oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)CCC>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Brc1ccncc1
Agent: Br
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 58 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (10.0 g, 69.9 mmol, 1 eq) and 4-bromopyridine HBr (16.2 g, 83.7 mmol, 1.2 eq) were dissolved in n-butanol (120 ml) and DIPEA (23 ml, 139.8 mmol, 2.0 eq) and refluxed for 14 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure. After purification by column chromatography (silica gel, 3% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 58% (9.0 g, 40.9 mmol).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1[C:36]2[C:31](=[CH:32][C:33]([C:37](O)=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[N:27]=[CH:28][CH:29]=[CH:30]4)=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc2ncccc2c1

Procedure:
The title compound, yellow solid (106 mg, 88%), MS (ISP) m/z=482.4 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and quinoline-6-carboxylic acid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3].C(O)CCC.C(=O)([O-])[O-].[K+].[K+].Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1>O>[CH2:1]([NH:4][C:5]1[N:6]=[C:7]([N:28]2[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]2)[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3]
Reactant: OC1CCNCC1
Reactant: CCCNc1nc(Cl)c2ccn(C)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CCCNc1nc(N2CCC(O)CC2)c2ccn(C)c2n1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
2-(n-Propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXIV) (1.6 g, 7.1 mmol) was added to n-butanol (10 mL) followed by potassium carbonate (4.9 g, 35.5 mmol) and piperidin-4-ol hydrochloride (632 mg, 10.7 mmol). The mixture was stirred in an autoclave equipped with a stirrer at 130° C. for 16 h. After cooling to room temperature, water was added (20 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution, and dried over anhydrous Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (pet ether/EtOAc=3/1) to yield 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolo[2,3-d]pyrimidine (1.2 g, 75%) as a yellow solid. LCMS (ESI) m/z=290 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH3:24][S:25]([O-:27])=[O:26].[Na+]>CN(C=O)C.C(Cl)Cl.CO>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[CH:7]=[C:2]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:3]=[CH:4][C:5]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ccc2[N+](=O)[O-])CC1
Temperature: 100 °C

Procedure:
To a solution of cis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide (0.100 g, 0.309 mmol) in DMF (0.55 mL) was added sodium methanesulfinate (0.045 g, 0.371 mmol), and the reaction mixture was heated at 100° C. for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by flash chromatography, eluting with 0-70% 9:1 DCM/MeOH to cis-N-isopropyl-4-(5-(methylsulfonyl)-2-nitrophenylamino)cyclohexanecarboxamide as a bright orange solid (0.124 g, 105% yield). MS (ESI pos. ion) m/z: 384.0 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1)=[O:4].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CNCc2ccc(Cl)cc2)cc1
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a solution of 4-formyl benzoic acid methyl (10.0 g) in chloroform (300 ml), 4-chlorobenzylamine (11.2 g) was added, and the mixed solution was stirred for 15 min. Then, to the resulting solution, sodium triacetoxyborohydride (16.8 g) was added, and the mixed solution was stirred at room temperature for two hours. To the resulting solution, acetic acid (10.5 ml) was added, and the solution was stirred for four hours. Saturated sodium bicarbonate water was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate/n-hexane=15 to 50%) to give methyl 4-{[(4-chlorobenzyl)amino]methyl}benzoate (13.8 g).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]([C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1)CCO.Cl[CH2:25][CH2:26][Cl:27]>>[Cl:27][CH2:26][CH2:25][N:8]([C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1)[CH2:7][CH2:6][Cl:3]
Reactant: ClCCCl
Reactant: COC(=O)COc1ccc(N(CCO)CCO)cc1
Reactant: O=S(Cl)Cl
Product: COC(=O)COc1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (3.17 g; 26.6 mmol) was added dropwise under ice cooling to a solution of 2.39 g (8.87 mmol) of methyl 4-[N,N-bis(2-hydroxyethyl)amino]phenoxyacetate in 72 ml of 1,2-dichloroethane. The thus-obtained mixture was stirred at room temperature for 4 hours and then concentrated. The resulting residue was purified by flush chromatography (chloroform/methanol=200/3), whereby 2.0 g of the title compound were obtained as brown crystals (yield: 74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][C:23]=1[C:30]([F:33])([F:32])[F:31]>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[C:23]([C:30]([F:33])([F:31])[F:32])[CH:24]=1)[C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(NC(=O)OC(C)(C)C)sc2ccccc12
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)C(=O)OC(C)(C)C)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 6-B (2.0 g, 7.59 mmol) in DMF (20 mL), cooled to 0° C., was added 60% NaH (0.334 g, 8.35 mmol) and the reaction mixture was stirred for 15 minutes. 4-Fluoro-3-trifluoromethyl benzyl bromide (1.26 mL, 8.35 mmol) was added drop-wise at 0° C. and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into ice water, extracted with ethyl acetate, the organic phase washed with H2O, brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. The crude oil was purified by flash column chromatography (SiO2) eluting with a 0% EtOAc-heptane to 25% EtOAc-heptane gradient to afford compound 6-C as a clear oil. Compound 6-C was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[OH:23][CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=1[CH3:37])=[O:28].N1CCCCC1>C(O)C>[OH:23][CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32](/[CH:35]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:31][C:30]=1[CH3:37])=[O:28]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCO
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCO

Procedure:
A mixture of 5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (150 mg, 0.42 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-ethyl)-amide (88 mg, 1 eq. 0 and piperidine (18 mg, 0.5 eq.) in ethanol (2 mL) was stirred at rt for 5 days. The reaction was concentrated and triturated with ethanol to give the titled compound as a pale yellow solid.