Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15](I)=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:44][N:45](C=O)C>CO.O>[C:44]([C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])[C:2]=3[F:1])[CH:8]=2)[NH:13][CH:14]=1)#[N:45]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)c1F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C#N)c3c2)c1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
2,6-Difluoro-N-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.025 g, 0.0379 mmol) and Cu(I)CN (0.0678 g, 0.758 mmol) were taken up in DMF (0.5 mL) and heated to 100° C. overnight. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil, N-(3-cyano-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide. The oil (0.021 g, 0.038 mmol) was dissolved in MeOH (1.0 mL) and water (0.3 mL). K2CO3 (0.053 g, 0.38 mmol) was added, and the mixture stirred for 1 hour at room temperature. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (5% MeOH/DCM) giving N-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (2.9 mg, 18%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.57-8.58 (m, 1H), 8.52-8.53 (m, 1H), 8.47 (s, 1H), 7.53-7.59 (m, 1H), 7.25-7.29 (m, 1H), 3.09-3.13 (m, 2H), 1.74-1.80 (m, 2H), 0.98-1.01 (m, 3H); m/z (APCI-neg) M−1=418.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16][C@:17]([NH:28][S@](C(C)(C)C)=O)([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=[CH2:20])[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[NH2:28][C@@:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)([CH2:18][CH:19]=[CH2:20])[CH2:16][CH2:15][N:10]([C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:9])[C:11](=[O:14])[O:12][CH3:13]
Reactant: C=CC[C@@](CCN(C(=O)OC)[C@@H](C)c1ccc(Br)cc1)(N[S@@](=O)C(C)(C)C)c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C=CC[C@](N)(CCN(C(=O)OC)[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1

Procedure:
A 50-mL round-bottomed flask was charged with methyl (S)-1-(4-bromophenyl)ethyl((S)-3-((S)-1,1-dimethylethylsulfinamido)-3-(4-fluorophenyl)hex-5-enyl)carbamate (96 mg, 0.17 mmol) and 4 M HCl in dioxane (10 mL, 40 mmol) while cooling in an ice-water bath. The reaction mixture was concentrated to give crude methyl (S)-3-amino-3-(4-fluorophenyl)hex-5-enyl((S)-1-(4-bromophenyl)ethyl)carbamate, which was used to the next step without purification.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](O)=[O:5].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:29][CH2:30][CH2:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[S:49][C:48]3[C:43](=[N:44][CH:45]=[CH:46][C:47]=3[O:50][C:51]3[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=3[F:58])[CH:42]=2)=[CH:37][CH:36]=1)[CH3:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:29][CH2:30][CH2:31][N:32]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[S:49][C:48]3[C:43](=[N:44][CH:45]=[CH:46][C:47]=3[O:50][C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:4](=[O:5])[CH2:3][C:2]([NH:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:1])=[CH:53][C:52]=3[F:58])[CH:42]=2)=[CH:39][CH:40]=1)[CH3:33]
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a solution of the acid 1 (142 mg, 2 eq, 1.58 mmol) in dry DCM (10 ml), at 0° C., was added, BOPCl (502 mg, 2 eq, 0.826 mmol) and the reaction mixture was stirred for 10 minutes. A solution of the amine 87 (348 mg, 0.79 mmol) and iPr2NEt (610 mg, 6 eq, 4.72 mmol) in dry DCM (7 ml) was then added and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness and partitioned between EtOAc and satd NaHCO3 soln, the organic phase was washed twice with saturated NaHCO3 then collected, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude was purified by column chromatography (EtOAc) to afford the desired product 88 as an off-white solid (102 mg, 21% yield). 1H NMR (DMSO-d6) δ (ppm): 10.58 (s, 1H), 10.22 (s, 1H), 8.48 (d, J=5.28 Hz, 1H), 8.03 (s, 1H), 7.85 (m, 3H), 7.59 (m, 2H), 7.43 (m, 4H), 7.32 (m, 2H), 7.05 (t, J=7.43 Hz, 1H), 6.61 (m, 1H), 3.70 (t, J=6.65 Hz, 2H), 3.59 (s, 2H), 3.50 (s, 2H), 2.69 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]([C:16]3[CH:33]=[CH:32][C:19]([O:20][C:21]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:22]=4[CH2:23][CH2:24][CH2:25][C:26]5=[O:31])=[CH:18][CH:17]=3)=[C:14]3[C:9]([C:10]([C:34]([F:37])([F:36])[F:35])=[CH:11][CH:12]=[CH:13]3)=[N:8]2)=[C:4]([F:40])[CH:3]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]([C:16]3[CH:33]=[CH:32][C:19]([O:20][C:21]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:22]=4[CH2:23][CH2:24][CH2:25][CH:26]5[OH:31])=[CH:18][CH:17]=3)=[C:14]3[C:9]([C:10]([C:34]([F:36])([F:37])[F:35])=[CH:11][CH:12]=[CH:13]3)=[N:8]2)=[C:4]([F:40])[CH:3]=1
Reactant: O=C1CCCc2c(Oc3ccc(-c4c5cccc(C(F)(F)F)c5nn4Cc4ccc(Cl)cc4F)cc3)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCCc2c(Oc3ccc(-c4c5cccc(C(F)(F)F)c5nn4Cc4ccc(Cl)cc4F)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-{4-[2-(4-chloro-2-fluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}-3,4-dihydronaphthalen-1(2H)-one (330 mg, 0.58 mmol) dissolved in 10 mL of EtOH was added to a slurry of NaBH4 in EtOH and stirred at room temperature overnight. The reaction mixture was quenched with H2O and stirred for 15 min. Filtration of the mixture was followed by extraction with CH2Cl2. The combined organic phases were dried, evaporated and the crude material was purified by HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford a racemic mixture. Separation of the two enatiomers afforded the analytically pure products of this Example 903 and Example 936.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[C:7]=2[CH:8]=1)#[N:13]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)c2ncoc2-c2ccccc2)[C@@H]1O

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 5-phenyl-4-oxazolecarboxylic acid by the same method as described for the title compound of Example 2 to afford an off-white solid, m.p. 196°-197° C. [α]D =-179.8° (c=0.40, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:40]([C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1)#[N:41]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([C:5]1[N:6]=[CH:7][N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)[CH2:46][C:45]1[CH:48]=[CH:49][C:42]([C:40]#[N:41])=[CH:43][CH:44]=1
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(C#N)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (977 mg, 2.55 mmol) in THF (25 ml) was cooled to -78° C. Lithium hexamethyldisilazide (2.68 ml, 2.68 mmol) was added dropwise and the reaction stirred 30 min at -78° C. 4-Cyanobenzyl bromide (500.7 mg, 2.68 mmol) was added and the reaction stirred a furthur 4 hrs at -78° C. and then at -20° C. for 12 hr. The reaction was quenched with water (10 ml) and saturated NaHCO3 solutuon (10 ml) and extracted with EtOAc. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, 3% MeOH in CH2Cl2) afforded the product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:21]1[O:35][C@H:34]([C:36](C)(C)[O:37]C(C)(C)C)[C@@H:28]([O:29]C(C)(C)C)[C@H:22]1[O:23]C(C)(C)C.[F-].[NH4+]>CO>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:9]2[N:10]=[C:2]([NH2:1])[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=2)[C@@H:21]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:28]([OH:29])[C@H:22]2[OH:23])=[CH:19][CH:18]=1
Reactant: CC(C)(C)O[C@@H]1[C@H](OC(C)(C)C)[C@@H](C(C)(C)OC(C)(C)C)O[C@H]1n1cnc2c(N)nc(OCCc3ccc(Cl)cc3)nc21
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of 3438.4 g (4.51 mol) of 6-amino-2-[2-(4-chlorophenyl)ethoxy]-9-(2,3,5-tri-O-tert-butyldimethyl-β-D-ribofuranosyl)purine in 48.4 L of methanol was added 1.679 g (45.32 mol) of ammonium fluoride. The solution was heated to reflux and monitored by HPLC to determine completion. The reaction was allowed to cool to room temperature and the solvent was concentrated under reduced pressure. The reaction mixture was partitioned between water (17.3 L) and ethyl acetate (17.3 L). The aqueous layer was washed again with ethyl acetate (17.4 L). The combined organic layers were dried over magnesium sulfate (1000 g), filtered and removed under reduced pressure. The resultant solid was recrystallized from ethanol (9.87 L) to yield an off-white solid (1139 g, 59.8% yield).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:26][CH2:27][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:29][CH2:30]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(NC(=O)OC(C)(C)C)CC3)n2n1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
In a 100 mL round-bottomed flask were placed N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 0.5 g, 1.450 mmol) and tert-butyl piperidin-4-ylcarbamate (0.305 g, 1.523 mmol) in N-methyl-2-pyrrolidinone (Volume: 14.50 ml). Diisopropylethylamine (0.253 ml, 1.450 mmol) was added. The reaction was heated overnight at 100° C. The reaction mixture was partitioned between ethyl acetate and brine. The organic was dried MgSO4, filtered and concentrated in vacuo. The compound was chromatographed on silica using 30-50% EtOAc/Hexane silica column to give tert-butyl 1-(5-(4-(2-hydroxypropan-2-yl)benzamido)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)piperidin-4-ylcarbamate (6A, 0.576 mg, 78%) as a yellow solid. 1H NMR (METHANOL-d4) δ: 7.79-8.02 (m, 2H), 7.60-7.73 (m, 2H), 7.33 (s, 1H), 6.83 (br. s., 1H), 6.13 (s, 1H), 4.39 (d, J=12.6 Hz, 2H), 3.57-3.78 (m, 1H), 3.11-3.23 (m, 2H), 2.43 (s, 3H), 1.73 (d, J=8.8 Hz, 2H), 1.56 (s, 6H), 1.46 (s, 9H); resonances of the three piperidine peaks are obscured by diisopropylethylamine. ESI-MS: m/z 509.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:15])[C@@H:12]([CH3:14])[NH2:13])[CH3:9].C(N)C1C=CC=CC=1.[CH2:24]([O:34][CH2:35][CH2:36][C:37](Cl)=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].COCCCCCCCCCCCC(Cl)=O>>[CH2:24]([O:34][CH2:35][CH2:36][C:37]([NH:13][C@@H:12]([C:11]([O:10][CH2:8][CH3:9])=[O:15])[CH3:14])=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)[C@@H](C)N
Reactant: CCCCCCCCCCOCCC(=O)Cl
Agent: COCCCCCCCCCCCC(=O)Cl
Solvent: NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCOCCC(=O)N[C@H](C)C(=O)OCC

Procedure:
The title compound is prepared by the method of Example 14 using an equivalent amount of D-alanine ethyl ester trifluoroacetate [the title product of Example 33] as a reactant instead of benzylamine, and using 3-decyloxypropanoyl chloride [the title product of Example 98] as a reactant instead of 12-methoxy-1-dodecanoyl chloride [the title product of Example 11].
Reaction SMILES: O(CC([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([OH:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.C1(NC2CCCCC2)CCCCC1.C(NC(C)C)(C)C.Cl[Si](Cl)(C)C.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:19][C:16]1[CH2:17][S:18][C@@H:13]2[C@H:12]([NH2:11])[C:23](=[O:24])[N:14]2[C:15]=1[C:20]([OH:22])=[O:21]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: C[Si](C)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: -45 °C

Procedure:
7-(Phenoxyacetamido)-3-methyl-3-cephem-4-carboxylic acid (11.38 mmoles) is dissolved in 80 ml of methylene chloride. Dicyclohexylamine or diisopropylamine (13 mmoles) is added with stirring and 1.75 ml of dichlorodimethylsilane is added. After stirring for 30 minutes, the mixture is cooled to -45° C and an additional 27.77 mmoles of the same amine as used above is added followed by 3 g of finely powdered PCl5.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[N:9][C:10]([NH:13][NH2:14])=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:15]([CH2:18][C:19](=O)[CH3:20])(=O)[CH3:16]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[N:9][C:10]([N:13]3[C:19]([CH3:20])=[CH:18][C:15]([CH3:16])=[N:14]3)=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)CC(C)=O
Reactant: NNc1ccc(N2CCOCC2)nn1
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(N3CCOCC3)nn2)n1

Procedure:
A mixture of 1.95 g (0.01 moles) of 3-morpholino-6-pyridazinylhydrazine, 1.0 g (0.01 moles) of acetylacetone and 20 ml of ethanol is heated to reflux for 3 hours. After cooling the separated crystals are filtered, washed with ethanol and dried. Yield: 1.65 g (64.5%); m.p. 119°-121° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)(=[O:21])=[O:22])[CH3:34])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
To a solution of [(R)-5-(3-chloro-4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (example 2-2, method D, 2nd step) (400 mg, 0.85 mmol) in acetonitrile (15 mL) was added methyl iodide (182 mg, 1.28 mmol) and potassium carbonate (350 mg, 2.53 mmol). The reaction mixture was stirred at 70° C. for 5 hours, then cooled to room temperature and filtered through a glass funnel. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (gradient elution, 0-10% methanol in dichloromethane) to afford {(R)-5-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (365 mg, 89%) as a yellow oil. MS cald. for C23H27ClFNO5S 483, obsd. 484 (ESI+) [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O1CCCC1.Cl>O1CCCC1>[CH:19]1([CH:7]([C:6]2[CH:5]=[C:4]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:13][CH:14]=3)[S:3][C:2]=2[CH3:1])[OH:8])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 2-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-3-carbaldehyde (2.33 g) synthesized above in tetrahydrofuran (50 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (12.9 mL) at 0° C., and the mixture was stirred for 1 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane), and then purified by NH-silica gel column chromatography (ethyl acetate) to give the title compound (1.98 g, 65%) as a white solid.
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:6]([O:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)[O:23][N:22]=2)=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
To a tetrahydrofuran (7.00 mL) solution of (2-benzyloxy-pyridin-5-yl)acetohydroximoyl chloride (191 mg, 0.690 mmol) described in Manufacturing Example 12-1-5 and 5-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 28-1-3 was added triethylamine (142 μL, 1.02 mmol) under nitrogen atmosphere at room temperature, which was stirred for 3 hours at 60° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1→2:1) to obtain the title compound (15.7 mg, 12.9%).
Reaction SMILES: [Cl-].[CH:2](=[N:9][CH:10]1[C:53](=[O:54])[N:12]2[C:13]([C:37]([O:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])=[C:14]([CH2:17][P+:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][S:16][C@H:11]12)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:2](=[N:9][CH:10]1[C:53](=[O:54])[N:12]2[C:13]([C:37]([O:39][CH:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:38])=[C:14]([CH:17]=[P:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][S:16][C@H:11]12)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=P(c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
A mixture of XV (322 g, 0.42 mole) and 5N Na2CO3 (252 ml) in CH2Cl2 (1.6 L) was stirred vigorously for 15 minutes at room temperature. The organic layer was separated, dried over MgSO4 and concentrated to about 500 ml of volume. The concentrate was added to acetone (1 L), with stirring, to give a light yellow crystalline powder which was collected by filtration to yield 237 g (78%) of XVI, melting at 195°-198° C. (dec.).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22][C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=O)[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO.C(Cl)Cl>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:14]([C@H:23]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][N:18]4[CH2:19][CH2:20][CH2:21][C@H:17]43)=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CN1CCCC1c1cccc(OCCCN2CCCCC2)c1)c1cccs1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: c1csc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 85 %

Procedure:
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thiophen-2-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.24 g (85%) of the desired product as an oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C24H32N2O2S, 412.2; m/z found, 413.6 [M+H]+. 1H NMR (MeOH-d4): 7.75 (m, 2H) 7.18 (t, J=8.0, 1H), 7.09 (dd, J=4.0, 5.0, 1H), 7.0 (m, 1H), 6.94 (d, J=7.6, 1H), 6.77 (m, 1H), 4.88 (s, 1H), 3.96 (m, 2H), 3.88 (d, J=16.4, 1H), 3.47 (d, J=8.8, 1H), 3.42 (d, J=16.0, 1H), 3.37 (m, 1H), 3.34 (s, 2H), 2.43 (m, 7H), 2.18 (m, 1H), 1.94 (m, 3H), 1.86 (m, 1H), 1.76 (m, 1H), 1.59 (m, 4H), 1.45 (br m, 2H).