Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH:37]1[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:39]2[CH2:40][CH2:41][CH:36]([CH3:35])[CH:37]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38]2)=[O:13])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1CCNCC1NC(=O)OC(C)(C)C
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)CNc2cc(Cl)cc(Cl)c2)CC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)acetic acid (153 mg, 0.69 mmol) in DMF (5 mL) was added HOBt (141 mg, 1.0 mmol), EDCI (201 mg, 1.0 mmol), tert-butyl 4-methylpiperidin-3-ylcarbamate (150 mg, 0.69 mmol), and DIEA (0.18 mL, 1.3 mmol) at 0° C. Then the reaction mixture was stirred at rt for 5 h, partitioned between EtOAc and water. The organic phase was separated and washed with brine, and concentrated in vacuo to yield the crude product, which was purified by column chromatography using 0-2% MeOH: DCM solvent mixture to yield the titled intermediate (160 mg, 54%) as a thick liquid. 1H NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.49 (s, 1H), 6.38 (s, 1H), 6.29 (s, 1H), 5.22-5.15 (m, 1H), 4.65-4.56 (m, 1H), 4.35-4.16 (m, 2H), 3.25-2.89 (m, 2H), 2.85-2.69 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.45 (m, 1H), 1.22 and 1.14 (2s, 9H), 1.05 and 0.95 (2d, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=416.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][N:8]([CH2:30][C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=1)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9][C:10]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20]COCC[Si](C)(C)C)=[CH:16][C:15]=1[Cl:29])[CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:1]([O:5][C:6](=[O:44])[CH2:7][N:8]([CH2:30][C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=1)[C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:9][C:10]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[Cl:29])[CH3:13])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)CN(CC(=O)OC(C)(C)C)Cc1cccc(C(=O)OC(C)(C)C)c1)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)CN(CC(=O)OC(C)(C)C)Cc1cccc(C(=O)OC(C)(C)C)c1)c1ccc(O)cc1Cl
Temperature: 50 °C
Reaction time: 96 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl){2-[(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)(methyl)amino]-2-oxoethyl}amino]methyl}benzoate (805 mg) in tetrahydrofuran (16.1 mL) was added a 1 M solution of tetra-n-butylammonium in tetrahydrofuran (3.72 mL), followed by stirring at 50° C. for 4 days. To a reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl){2-[(2-chloro-4-hydroxyphenyl)(methyl)amino]-2-oxoethyl}amino]methyl}benzoate (583 mg).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([OH:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:13][C:8]1[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]2[O:3][C:2]([CH3:1])([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[CH2:6][C:5]=2[C:7]=1[CH3:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)CC(C)(CN1CCN(c3ccccc3)CC1)O2
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(C)(CN1CCN(c3ccccc3)CC1)O2
Yield: 48 %

Procedure:
Using 2,4,6,7-tetramethyl-2-(4-phenyl-1-piperazinyl)methyl-2,3-dihydrobenzofuran-5-ol and benzyl bromide, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][C@H:15]2[C:38]([N:40]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]=[CH2:55])[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])=[O:13])[CH2:8][C@H:7]1C=C)=[O:5])[CH3:2]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C@@:6]12[CH2:8][C@H:7]1[CH:55]=[CH:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][N:40]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[C:38](=[O:39])[C@H:15]1[C@@H:14]([CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Solvent: ClCCl
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2

Procedure:
A solution of 48 (158 mg, 0.209 mmol) in dry DCM (25 mL) was bubbled with argon for 5 min. To the stirred solution under argon atmosphere was then added a solution of Hoveyda-Grubbs catalyst 2nd generation (11 mg, 0.018 mmol) in dry DCM (5 mL).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[CH:4][CH:3]=1.FC1C=C([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[CH3:31][C:26]1([CH3:32])[C:27]([CH3:30])([CH3:29])[O:28][B:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]4[CH:16]=3)=[CH:4][CH:3]=2)[O:25]1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: Brc1ccc(-c2cn3ccccc3n2)cc1
Product: CC1(C)OB(c2ccc(-c3cn4ccccc4n3)cc2)OC1(C)C

Procedure:
2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazo[1,2-a]pyridine was prepared from 2-(4-bromophenyl)imidazo[1,2-a]pyridine (0.273 g, 1.00 mmol) in a manner similar to that used for the preparation of N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as a white solid (0.250 g, 78%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt=11.35 min, 87%; m/z 321 (MH+).
Reaction SMILES: ClC(O[CH2:5][CH:6](C)C)=O.[C:9]([O:13][C:14]([NH:16][CH2:17][P:18]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:20])[OH:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)C.C(N(CC)CC)C>C(Cl)Cl>[C:9]([O:13][C:14]([NH:16][CH2:17][P:18]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])[O:20][CH2:5][CH3:6])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCP(=O)(O)CNC(=O)OC(C)(C)C
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
Isobutyl chloroformate (1.50 ml, 11.48 mmol) is added dropwise with stirring at 0° C. to a solution of the phosphinic acid 1 (3.200 g, 9.88 mmol) in a mixture of methylene chloride (50 ml), ethanol (3.00 ml, 51.59 mmol), triethylamine (1.40 ml, 10.06 mmol) and N,N-dimethylpyridine (10 mg). After 90 minutes, the reaction solution is extracted with saturated aqueous ammonium chloride solution (30 ml) and saturated aqueous KHCO3 solution (30 ml). The organic phase is dried over Na2SO4 and concentrated under reduced pressure. After purification by column chromatography on silica gel (ethyl acetate/heptane=3:2), the phosphinic acid ester 3 (1.840 g, 53% of theory) is obtained. See above spectroscopic data.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COCc3ccc4ccccc4c3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxymethyl-phenyl)-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(naphthalen-2-ylmethoxymethyl)-phenyl]-piperidine-1-carboxylate as a colourless oil, Rf : 0.31 (SiO2, hexane:ethyl acetate=2:1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:34][CH:26]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NC1CCCCCCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclooctanamine as a brown solid (46%). MS 456 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:11][CH:10]=2)[C:25]#[N:26])=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)C#N
Reactant: CSc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Product: CSc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methylthiobenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a yellow powder (yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][C:28]1([CH2:33][OH:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][C:28]4([CH2:33][OH:34])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NC1(CO)CCCC1
Product: Cn1c(=O)c(C(=O)NC2(CO)CCCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 47 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (18 mg, 0.050 mmol) described in example 92 and (1-aminocyclopentyl)methanol (76 mg, 0.66 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[1-(hydroxymethyl)cyclopentyl]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide(10 mg, 48% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.56 (br s, 1H), 8.55 (s, 1 H), 7.37 (s, 1 H), 7.17-7.14 (m, 2 H), 7.04-6.99 (m, 2 H), 4.12 (s, 2 H), 3.78 (s, 2 H), 3.56 (s, 3 H), 1.98-1.68 (m, 8 H); MS m/z 424 (M−1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:32])[CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)[CH2:7][CH3:8].[OH-].[Li+].Cl>O1CCOCC1.O>[C:26]1([S:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH:6]([CH2:7][CH3:8])[C:5]([OH:32])=[O:4])=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(Cc1ccc(OCCc2ccc(Sc3ccccc3)cc2)cc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(Cc1ccc(OCCc2ccc(Sc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
Sodium hydroxide (3 ml, 1M) was slowly added to a solution of 2-{4-[2-(4-phenylsulfanylphenyl)ethoxy]benzyl}butanoic acid methyl ester (described in Example 79) (0.59 g, 1.4 mmole) in dioxan (12 ml). The reaction mixture was stirred at room temperature for 12 hours, then at 50° C. for 4 hours. Lithium hydroxide (50 mg) was added and the mixture was stirred at 70° C. for 24 hours. The reaction mixture was acidified with hydrochloric acid (6 M), water (20 ml) was added and the product was extracted with ethyl acetate (2×25 ml), washed with water (25 ml), dried (sodium sulfate) and the solvent was evaporated in vacuo to give 0.53 g (yield 93%) of the desired product.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([C@@H:26]2[C@H:30]([CH2:31][CH3:32])[CH2:29][C@H:28]([NH:33][S:34]([CH:37]3[CH2:39][CH2:38]3)(=[O:36])=[O:35])[CH2:27]2)[N:7]2[C:12]3[CH:13]=[CH:14][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]=3[N:10]=[CH:9][C:8]=12)[CH:2]=[CH2:3].B.CSC.[OH:44]O.[OH-].[Na+]>C1COCC1.O.CCOC(C)=O>[CH2:31]([C@H:30]1[C@@H:26]([C:6]2[N:7]3[C:12]4[CH:13]=[CH:14][NH:15][C:11]=4[N:10]=[CH:9][C:8]3=[C:4]([CH2:1][CH2:2][CH2:3][OH:44])[N:5]=2)[CH2:27][C@@H:28]([NH:33][S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:35])=[O:36])[CH2:29]1)[CH3:32]
Reactant: OO
Reactant: C=CCc1nc([C@H]2C[C@@H](NS(=O)(=O)C3CC3)C[C@H]2CC)n2c1cnc1c2ccn1S(=O)(=O)c1ccc(C)cc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CSC
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nc(CCCO)c2cnc3[nH]ccc3n12
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a solution of N-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.090 g, 0.16 mmol, prepared using H with Preparation #12, Preparation #Z.1, HATU and DIEA, and Q with Lawesson's reagent and mercury (II) trifluoroacetate) in THF (3 mL) at about 0° C. was added BH3•DMS (2 M in THF, 0.040 mL, 0.079 mmol). After about 2 h, additional BH3•DMS (2 M in THF, 0.040 mL, 0.079 mmol) was added to the reaction mixture. After about 6 h total, a premixed solution of H2O2 (30% aqueous, 0.324 mL, 3.17 mmol) and NaOH (2 N aqueous, 0.793 mL, 1.58 mmol) was added to the reaction mixture. After stirring for about 15 h, EtOAc (20 mL) and water (20 mL) were added to the reaction mixture. The organic layer was separated, washed with brine (20 mL), and concd in vacuo. The crude residue was purified by chromatography on silica gel (12 g) eluting with EtOAc to provide N-((1S,3R,4S)-3-ethyl-4-(3-(3-hydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.025 g, 37%) as a white solid: LC/MS (Table 1, Method a) Rt=1.70 min; MS m/z: 432 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[CH2:7]2.[CH3:13][N:14](C=O)C>[Pd].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.[C-]#N.[Zn+2].[C-]#N>[O:12]=[C:6]1[CH2:5][CH2:4][C:3]2[CH:2]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=2[CH2:7]1
Reactant: O=C1CCc2c(Br)cccc2C1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Product: N#Cc1ccc2c(c1)CCC(=O)C2

Procedure:
To a 20 mL microwave tube was added 5-bromo-2-tetralone (2.0 g, 8.9 mmol) and Palladium(0) Tetrakis (0.616 g, 0.533 mmol), zinc cyanide (1.0 g, 8.9 mmol), and DMF (8 mL). The tube was sealed, degassed and microwaved at 80° C. for 1.0 hour. TLC showed no starting material left. The mixture was diluted with ethyl acetate, washed with ammonium hydroxide (2M, 2 x), dried with sodium sulfate, filtered and evaporated under reduced pressure. The product was purified by silica gel chromatography with isocratic 30% ethyl acetate-hexane to furnish the title compound. 1H-NMR (500 MHz, CDCl3) δ ppm 7.57 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 3.67 (s, 2H), 3.14 (t, J=7.0 Hz, 2H), 2.60 (t, J=7.0 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=[N:12][CH:13]=2)[CH:7]=1.[CH3:26][C:27]1(C)[C:31](C)(C)OB(C(C)=C)O1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:24]([C:5]1[CH:4]=[CH:3][C:2]([C:27]([CH3:31])=[CH2:26])=[CH:7][C:6]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=[N:12][CH:13]=1)=[O:25]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)c1ccc(C=O)c(-c2ccc(C(=O)NCCC(=O)OCC)nc2)c1
Temperature: 90 °C

Procedure:
Ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (180 mg, 0.50 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (126 mg, 0.75 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), S-PHOS (41 mg, 0.10) K3PO3 (318 mg, 1.50 mmol) were dissolved in toluene (2 mL) and the resulting mixture was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[C:28]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:18](=[O:20])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:12]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 2.5 g (E)-3-[1-(4-Iodo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid is dissolved in 140 ml DMF. To this mixture are added 0.949 g HOBtxH2O, and 6.27 g Et3N. After 30 min 3.57 g EDCxHCl are added and the resulting mixture is stirred for 30 min. Now 1.29 g of N-boc-o-phenylenediamine are added and the reaction mixture is stirred overnight. The solvent is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is dried and evaporated and the crude product is purified by silica gel flash chromatography.
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[CH2:3][C:4]1[C:5]([CH3:14])=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7]2.N1C=CN=C1.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.C(Cl)Cl>[Si:26]([O:16][CH2:15][CH:2]([OH:1])[CH2:3][C:4]1[C:5]([CH3:14])=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7]2)([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: Cc1c(CC(O)CO)ccc2c1COC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(CC(O)CO[Si](C)(C)C(C)(C)C)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-(2,3-dihydroxypropyl)-4-methylisobenzofuran-1(3H)-one (2.00 g, 9.0 mmol) in dry DMF (20 mL) was added imidazole (1.20 g, 18.0 mmol) and TBSCl (1.50 g, 9.9 mmol). After stirring at 25° C. for 2.5 h, the reaction mixture was diluted with CH2Cl2 (50 mL) and washed with H2O (3×20 mL) and saturated NaHCO3 (3×20 mL). The combined aqueous layers were extracted five times with CH2Cl2 (20 mL). The combined organic layers were washed with brine (3×30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0-60% ethyl acetate in petroleum ether) to give the title compound.
Reaction SMILES: CC1C=CC([O:8][S:9]([C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([NH:32][C:33]([NH:35][C:36]5[CH:45]=[C:44]6[C:39]([CH:40]=[CH:41][C:42]([S:46]([NH:49][C:50]7[CH:51]=[C:52]([S:56]([O:59]C8C=CC(C)=CC=8)(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=7)(=[O:48])=[O:47])=[CH:43]6)=[CH:38][CH:37]=5)=[O:34])=[CH:29]4)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=CC=1.C[O-].[Na+:69].C1COCC1.Cl>CO.O>[Na+:69].[Na+:69].[S:56]([C:52]1[CH:51]=[C:50]([NH:49][S:46]([C:42]2[CH:43]=[C:44]3[C:39]([CH:38]=[CH:37][C:36]([NH:35][C:33]([NH:32][C:28]4[CH:29]=[C:30]5[C:25]([CH:24]=[CH:23][C:22]([S:19]([NH:18][C:14]6[CH:13]=[C:12]([S:9]([O-:11])(=[O:8])=[O:10])[CH:17]=[CH:16][CH:15]=6)(=[O:21])=[O:20])=[CH:31]5)=[CH:26][CH:27]=4)=[O:34])=[CH:45]3)=[CH:40][CH:41]=2)(=[O:48])=[O:47])[CH:55]=[CH:54][CH:53]=1)([OH:59])(=[O:57])=[O:58].[S:56]([C:52]1[CH:51]=[C:50]([NH:49][S:46]([C:42]2[CH:43]=[C:44]3[C:39]([CH:38]=[CH:37][C:36]([NH:35][C:33]([NH:32][C:28]4[CH:29]=[C:30]5[C:25]([CH:24]=[CH:23][C:22]([S:19]([NH:18][C:14]6[CH:13]=[C:12]([S:9]([O-:11])(=[O:8])=[O:10])[CH:17]=[CH:16][CH:15]=6)(=[O:21])=[O:20])=[CH:31]5)=[CH:26][CH:27]=4)=[O:34])=[CH:45]3)=[CH:40][CH:41]=2)(=[O:48])=[O:47])[CH:55]=[CH:54][CH:53]=1)([OH:59])(=[O:57])=[O:58]
Reactant: Cc1ccc(OS(=O)(=O)c2cccc(NS(=O)(=O)c3ccc4ccc(NC(=O)Nc5ccc6ccc(S(=O)(=O)Nc7cccc(S(=O)(=O)Oc8ccc(C)cc8)c7)cc6c5)cc4c3)c2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc2ccc(S(=O)(=O)Nc3cccc(S(=O)(=O)[O-])c3)cc2c1)Nc1ccc2ccc(S(=O)(=O)Nc3cccc(S(=O)(=O)O)c3)cc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 20 mg (0.02 mole) of compound 112 was added 1.5 mL of 1.37 M sodium methoxide in methanol, 1 mL of water, and 0.5 mL of THF. The resulting solution was allowed to stir at ambient temperature for 2 days. The reaction was acidified with 1 N HCl (aqueous) and the organic volatiles removed in vacuo. The solid precipitate was collected by vacuum filtration to afford 15 mg of compound 114.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.[C:6]([C:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[CH:9][C:10](Cl)=[O:11])#[N:7]>O1CCOCC1>[C:6]([C:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[CH:9][C:10]([N:1]=[N+:2]=[N-:3])=[O:11])#[N:7]
Reactant: N#CC(=CC(=O)Cl)c1cccs1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CC(=CC(=O)N=[N+]=[N-])c1cccs1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a vigorously stirring suspension of NaN3 (55 g, 0.85 mol) in 1:1; dioxane:H2O (200 mL) cooled to 0° C. was added dropwise over 20 min a solution of 3-cyano-3-thiophen-2-yl-acryloyl chloride 22 (84.3 g, 0.428 mol) in dioxane (150 mL). After stirring at 0° C. for 20 min, the reaction was warmed to room temperature and stirred for 1 h. To the reaction solution was added 600 mL H2O, thus producing a precipitate which was filtered, washed with H2O and dried under vacuum to provide pure 85 g of 23.