Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[C:5]2[OH:16].[OH-].[Na+:18].O.O.O.C([O-])(=O)C.[Na+].[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>O>[Na+:18].[OH:16][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:36]([C:33]3[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=3)(=[O:37])=[O:38])[CH:3]=2)[CH:8]=[C:7]([S:12]([O-:15])(=[O:13])=[O:14])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3cc(S(=O)(=O)[O-])cc(O)c3c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 11.95 g of 6-amino-4-hydroxy-2-naphthalenesulfonic acid in 200 ml of water was adjusted to pH 8.0 with aqueous 5N sodium hydroxide, then 12.17 g of sodium acetate trihydrate was added to the stirred mixture followed by 15.06 g of p-nitrobenzenesulfonyl chloride. The mixture was stirred vigorously under nitrogen at room temperature for 16 hours producing a yellow solid. The mixture was filtered and the solid was washed with water, ethanol and then ether and dried in vacuo and gave 12.07 g of 4-hydroxy-6-p-nitrobenzenesulfonamido-2-naphthalenesulfonic acid sodium salt as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:56][N:57]1[CH2:61][CH2:60][CH2:59][C@H:58]1[CH:62]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:62]/[C@@H:58]4[CH2:59][CH2:60][CH2:61][N:57]4[CH3:56])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN1CCC[C@H]1C=O
Reactant: CCOP(=O)(CC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1CCC[C@H]1/C=C/C(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 4f (277 mg, 0.50 mmol) was dissolved in 2.5 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (750 μL, 0.75 mmol). After stirring for 45 minutes, the reaction mixture was added with (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (113 mg, 2 mmol), and stirred for 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]quinazolin-6-yl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamide 4 (85 mg, yield 33.0%) as a yellow solid.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH2:6][CH2:5][C:4]2=[O:8])[CH2:2]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>[OH-].[Na+]>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[C:5]2[CH2:6][CH2:7][C:3]3([CH2:2][CH2:1]3)[C:4]2=[O:8])=[CH:12][CH:11]=1
Reactant: O=C1CCCC12CC2
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1C(=Cc2ccc(Cl)cc2)CCC12CC2

Procedure:
It is known that spiro-[2.4]-heptan-4-one can be reacted with 4-chlorobenzaldehyde in methanolic sodium hydoxide solution to give 5-(4-chlorobenzylidene)spiro[2.4]-heptan-4-one (see DE-A 43 20 498, Example 1). A disadvantage is the extremely long reaction time required, of 50 hours.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([NH2:23])=[O:22]>>[N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([NH2:23])=[O:22])=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ncccc12
Reactant: NC(=O)c1sccc1N
Product: NC(=O)c1sccc1NC(=O)Cc1cccc2ncccc12

Procedure:
The title compound was prepared from 2-(quinolin-5-yl)acetic acid and 3-aminothiophene-2-carboxamide using protocol B. Method[1], MS (ESI) 312.1 [M+H], Retention time=0.351 min.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35](O)[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:41]2)=[CH:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:49])[CH3:50])[CH2:41]2)=[CH:28]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: Cc1ccc(OC(C(=O)O[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O4)[C@H]32)c2ccccc2)cc1
Yield: 48.9 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.32 g of (2RS)-2-(4-methylphenoxy)-2-phenylacetic acid and 0.61g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 0.42 g of the title compound as a colorless foam.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][NH2:4].N1C=CN=C1.[Si:11](OS(C(F)(F)F)(=O)=O)([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13].O>C1COCC1>[CH2:12]([Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[O:5][CH:2]([CH3:1])[CH2:3][NH2:4])[CH3:13]
Reactant: CC(O)CN
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)OC(C)CN
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a 50 mL round bottomed flask, 1-methyl-2-aminoethanol (500.0 mg, 6.66 mmol) and imidazole (498.8 mg, 7.326 mmol, 1.1 equiv.) were dissolved in THF (3 mL). The mixture was cooled down to −78° C. and then TESOTf (1.76 g, 6.66 mmol, 1.0 equiv.) was added at the same temperature. The mixture was allowed to warm to room temperature. After stirring for 1 h, water (30 mL) was added to the mixture and the whole was extracted with EtOAc (30 mL×3). Combined organic layers were washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the O-silylated aminoalcohol as a colorless oil (2-(triethylsilyloxy)propan-1-amine, 2.34 g). Obtained product was immediately used for the subsequent step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.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>[CH3:19][NH:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=[C:2]([C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]([F:31])([F:43])[F:44])=[CH:39][CH:38]=3)[N:7]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCC3)cc(Cl)n2)cc1
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: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCC3)cc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 34 %

Procedure:
To a solution of 4-(6-chloro-4-pyrrolidin-1-yl-pyridin-2-ylamino)-N-methyl-benzenesulfonamide (100 mg, 0.27 mmol) in 1,4-dioxane (8 mL) was added 1N sodium carbonate solution (0.3 mL) and tetrakis(triphenylphosphine)palladium(0) (15.8 mg, 0.013 mmol), followed by 4-trifluoromethoxyphenyl boronic acid (67.2 mg, 0.32 mmol). The resulting reaction mixture was refluxed for 8 hours, after which time water was added (100 mL) to the reaction mixture, and the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel (20:80 acetone:petroleum ether) to afford the desired compound pale yellow solid (46 mg, yield 34%.).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH3:3].[H][H].Cl>[C].[Pd].C(O)(=O)C>[CH3:3][CH:2]([CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH3:1]
Reactant: CC(C)C(CCC(=O)O)C(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)C(CCC(=O)O)Cc1ccccc1
Yield: 86.7 %

Procedure:
4-(2-Propyl)-5-oxo-5-phenylpentanoic acid (5.50 g, 23.5 mmol) was subjected to hydrogen catalytic reduction at room temperature by the use of 10% palladium-carbon (0.6 g) as catalyst in a mixed solvent of acetic acid (60 ml) and 35% hydrochloric acid (3 ml). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 4.49 g of 4-(2-propyl)-5-phenylpentanoic acid.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][C:3]2=[O:17].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)(=O)C>[OH:17][CH2:3][C:2]1([CH3:1])[CH2:12][CH:11]1[C:10]1[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:4]
Reactant: COCOc1cccc2c1C1CC1(C)C(=O)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1cccc(O)c1C1CC1(C)CO
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
To a solution of 1a-methyl-7-{[(methyloxy)methyl]oxy}-1a,7b-dihydrocyclopropa[c]chromen-2(1H)-one (Intermediate 122, 360 mg) in dry tetrahydrofuran (15 ml) stirred under nitrogen at 0° C. was added a solution of lithium aluminium hydride (1.0M in THF, 1.537 ml, 1.537 mmol) and the reaction mixture was stirred at that temperature for 20 minutes. The reaction was then diluted with THF (20 ml) and quenched with the addition of Na2SO4.10H2O (10 eq) leaving the mixture under stirring for 30 minutes. The reaction was diluted with ethyl acetate, dried over Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, with a gradient from cyclohexane/ethyl acetate 5/1 to cyclohexane/ethyl acetate 1/1) to give the title compound as a white solid (307 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][N:22]=3)[NH:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](I)[CH3:25].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][N:22]=3)[N:17]([CH2:24][CH3:25])[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: c1ccc(COc2ccc(-c3n[nH]c4nccnc34)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(OCc3ccccc3)cc2)c2nccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3-[4-(benzyloxy)phenyl]-1H-pyrazolo[3,4-b]pyrazine (0.58 g), EtI (0.18 ml), and K2CO3 (0.39 g) in DMF (5 mL) was stirred for 3 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (0.61 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19].C(=O)([O-])[O-].[K+].[K+]>CO.Cl[Pd]Cl>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(F)c(F)c2)c1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
A mixture of methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 3,4-difluorophenylboronic acid (5.06 g, 32.05 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (1.066 g, 1.46 mmol) was stirred in methanol (30 mL) and heated in a single-node microwave reactor at 100° C. for 30 min. The solvent was evaporated in vacuo. DCM (400 mL) and 8% NaHCO3 (aq) (400 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (400 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on three Biotage® KP-SIL 100 g columns. A gradient from 5% EtOAc in heptane over 2 CV followed by 5% to 20% of EtOAc in heptane over 9 CV was used as mobile phase. Methyl 2-(3,4-difluorophenyl)isonicotinate (5.82 g, 80%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 4.00 (s, 3H), 7.23-7.33 (m, 1H), 7.76-7.84 (m, 2H), 7.90-8.00 (m, 1H), 8.21-8.27 (m, 1H), 8.82 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[OH:14][C@H:15]1[CH2:19][N:18]([C:20]2[N:21]=[C:22]([NH:29][C:30]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[NH:32][N:31]=3)[C:23]3[CH2:28][CH2:27][CH2:26][C:24]=3[N:25]=2)[C@H:17]([C:38](OC)=[O:39])[CH2:16]1>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:38]([C@@H:17]2[CH2:16][C@@H:15]([OH:14])[CH2:19][N:18]2[C:20]2[N:21]=[C:22]([NH:29][C:30]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[NH:32][N:31]=3)[C:23]3[CH2:28][CH2:27][CH2:26][C:24]=3[N:25]=2)=[O:39])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Reactant: Nc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3C[C@H](O)C[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.6 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (4.64 mg, 4.14 mmol) in dry THF (5 mL) was added 2 M solution of isopropylmagnesium chloride (1.98 mL, 3.96 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of (2S,4R)-methyl 4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (400 mg, 1.04 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at 25° C. for 4 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and diluted with water (25 mL). The product was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (2×100 mL) followed by brine (100 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue which was purified by reverse phase HPLC to afford 66 mg of (2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CDCl3, freebase) δ (ppm): 0.99-1.30 (m, 6H), 2.10-2.30 (m, 4H), 2.65-2.74 (m, 2H), 2.78-2.98 (m, 4H), 3.78-3.05 (m, 1H), 3.91-3.99 (m, 1H), 4.70-4.78 (m, 1H), 4.92-4.98 (m, 1H), 6.34 (s, 1H), 6.77 (s, 1H), 6.82 (dd, 1H), 7.93 (s, 1H), 8.08-8.18 (m, 1H). The other diasteromers are prepared using appropriate chiral starting materials.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:19]([CH3:36])[C:20]([C:34]#[N:35])=[C:21]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[C:28](=[O:33])[CH2:27]1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:19]([CH3:36])[C:20]([C:34]#[N:35])=[C:21]3[C:25]=2[O:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[C:28](=[O:33])[CH2:27]2)=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCN(C)C(=O)C3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCN(C)C(=O)C3)nc2c1C#N
Temperature: 130 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (67.9 μl, 0.535 mmol) and triethylamine (86.1 μl, 0.618 mmol) were added to a dimethyl sulfoxide (5 ml) solution of 7-fluoro-5-methyl-2-(4-methyl-3-oxopiperazin-1-yl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-188) (150 mg, 0.412 mmol), followed by stirring in an oil bath at 130° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (50 ml), washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1) to obtain the entitled compound (109 mg, 54.5%) as a colorless foamy substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:12][CH3:13])=[N:9][C:10]=2I)[CH:7]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:12][CH3:13])=[N:9][C:10]=2[Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CSc1nc(I)c2ccc(F)cn12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc(SC)n2cc(F)ccc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask, 6-fluoro-1-iodo-3-methylsulfanyl-imidazo[1,5-a]pyridine (109 mg, 0.35 mmol) was dissolved in THF (3 ml). The light brown solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.21 ml, 0.42 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (0.11 ml, 0.40 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h then quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 6-fluoro-3-methylsulfanyl-1-tributylstannanyl-imidazo[1,5-a]pyridine as a brown oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1.CS(O)(=O)=O.[C:25](=O)(O)[O-:26].[Na+]>CO>[CH3:1][O:2][CH:3]([O:26][CH3:25])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][CH:10]=1
Reactant: CCCCCCCCOc1ccc(C=COC)cc1
Reactant: O=C([O-])O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCOc1ccc(CC(OC)OC)cc1

Procedure:
A solution of 1-(2-methoxyethenyl)-4-(octyloxy)benzene (3.67 g) and methanesulfonic acid (0.5 ml) in methanol (30 ml) is refluxed for 30 min, cooled, and neutralized with 1.0N aqueous sodium bicarbonate (10 ml). The mixture is evaporated in vacuo, and the residue dissolved in ether, dried with sodium sulfate, filtered, and evaporated to leave 1-(2,2-dimethoxyethyl)-4-(octyloxy)benzene as a colorless oil. This acetal may be used directly in step C below (as in example 2). Alternatively, the acetal is dissolved in a 1:1 mixture of THF and 3N hydrochloric acid, refluxed for one hour, and cooled. The mixture is extracted with dichloromethane, and without drying the dichloromethane extracts are concentrated to provide crude 4-(octyloxy)phenylacetaldehyde as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[CH:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][C:19]=1[CH:28]([NH:35][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:15])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Reactant: NC(c1ccccc1)c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccccc1)c1cc(C(F)(F)F)ccc1Cl

Procedure:
Prepared in analogy to example 1.1 from (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and rac-C-(2-Chloro-5-trifluoromethyl-phenyl)-C-phenyl-methylamine hydrochloride (CA [13954-13-7]).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][O:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[CH3:18][O:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: COc1cccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)c1OC
Yield: 96.6 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 16.4 mg (0.09 mMol) 2,3-dimethoxybenzoic acid, 11.4 mg (97%) of the title compound were recovered.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[CH:37][N:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[O:17]=[C:16]1[C:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]2[N:36]=[CH:37][N:38]=[C:12]2[N:11]1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (20 g), 6N hydrochloric acid (150 mL) and tetrahydrofuran (200 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (14 g, 77%).