Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]([C:37]([O:39][CH3:40])=[O:38])[NH:17][C: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)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:41]([O:43][C:44]1[C:45](=O)[C:46](=[O:51])[C:47]=1[O:48]CC)[CH3:42]>C(Cl)Cl.CCOC(C)=O>[CH2:41]([O:43][C:44]1[C:47](=[O:48])[C:46](=[O:51])[C:45]=1[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C@@H:16]([C:37]([O:39][CH3:40])=[O:38])[NH:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:42]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: COC(=O)[C@H](COc1ccc(-c2cccc(N)c2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1c(Nc2cccc(-c3ccc(OC[C@H](NC(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)OC)cc3)c2)c(=O)c1=O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The compound of Example 3 (1.50 g, 2.8 mmol, 1 equiv) was dissolved in 3,4-diethoxy-3 cyclobutene-1,2-dione (2.1 mL, 14.2 mmol, 5 equiv). The reaction mixture was stirred at 60-70° C. for 1 h. It was then allowed to cool to rt and diluted with CH2Cl2/EtOAc 9:1 (12 mL). The solution was filtered over a pad of silica gel and eluted with CH2Cl2/EtOAc 9:1. Unreacted 3,4-diethoxy-3-cyclobutene-1,2-dion eluted first followed by the title compound. Yield 0.68 g, 36.7%. 1H NMR (CDCl3, 7.72-7.51 (m, 8H); 7.48-7.32 (m, 3H); 7.29-7.03 (m, 10H); 6.94 (d, 2H); 4.94 (q, 2H); 4.29 (dd, 1H); 4.14 (dd, 1H); 3.85-3.69 (m, 1H); 3.23 (s, 3H); 2.90 (d, 1H); 1.55 (t, 3H). MS (ESI) 675 (M+Na), 653 (M+H), 243 (CPh3).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:20][Li]>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]([OH:11])[CH3:20])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]C
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Solvent: C1CCOC1
Product: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole-5-carboxaldehyde (Example 1(ii)) (1.1 g, 3.97 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to -78° C. under argon and a solution of methyl lithium (3.64 ml of 1.2 M in diethyl ether, 4.57 mmol) was added dropwise. The mixture was stirred for 1.5 hours, quenched with ammonium chloride solution, warmed to ambient temperature and extracted with ethyl acetate. The washed, dried, concentrated product was flash chromatographed over silica gel with ethyl acetate to provide 1.07 g (92%) of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy)ethyl-1H-imidazol.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][C:4]=1[CH3:20].[Cl-].[NH+]1C=CC=CC=1>O>[OH:2][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][C:8]=1[CH3:9]
Reactant: COc1c(C)cc(-c2[nH]c3ccccc3c2C)cc1C
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Product: Cc1cc(-c2[nH]c3ccccc3c2C)cc(C)c1O
Yield: 63.8 %

Procedure:
4.3 g of 2-(4-methoxy-3,5-dimethylphenyl)-3-methylindole and 13 g of pyridinium chloride were reacted at 200° C. for 1.5 hours. The reaction mixture was cooled, poured into water, extracted with ethyl acetate, washed with water, and dried. The solvent was evaporated, and the residue was recrystallized from benzene-hexane to give 2.6 g of 2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: [H+].[CH3:2][C@H:3]([NH2:12])[C@H:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[I:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(Cl)Cl.[OH-].[Na+]>[I:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:12][CH:3]([CH3:2])[CH:4]([OH:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:18]
Reactant: O=C(Cl)c1ccccc1I
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [Cl-]
Agent: [H+]
Agent: [Na+]
Solvent: ClCCl
Product: CC(NC(=O)c1ccccc1I)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a ice-cooled mixture of norephedrine hydrochloride (1) (5.2 g, 27.8 mmol) in CH2Cl2 (120 mL) and 5% NaOH aqueous solution (40 mL) was added dropwise a solution of 2-Iodobenzoyl chloride (2a, 7.5 g, 28.1 mmol) in CH2CL2 (15 mL). The resulting mixture was stirred at 0° C. for 4 h. The solvent was removed in vacuo. The residue was washed with H2O, then dried, and recrystallized from EtOH to afford a white solid (9.5 g, 90%). mp 129-130° C. 1H NMR (CDCl3) d 1.06 (d, J=6.9 Hz, 3 H, CH3), 3.58 (bs, 1H, --CHCH3), 4.95 (d, J=2.7 Hz, 1 H, --CHOH), 6.19 (d, J=8.4 Hz, 1 H, NH), 7.01-7.06 (m, 1 H, aromatic), 7.2-7.39 (m, 7 H, aromatic), 7.77 (d, J=7.8 Hz, 1 H, aromatic). 13C NMR (CDCl3) d 13.74 (q, CH3), 51.55 (d, --CHCH3), 75.64 (d, --CHOH), 92.44 (s, =CI--, aromatic), 126.02 (d, aromatic), 126.13 (d, aromatic), 127.45 (d, aromatic), 128.07 (d, aromatic), 128.17 (d, aromatic), 139.70 (d, aromatic), 140.66 (s, aromatic), 141.85 (s, aromatic), 169.57 (s, --CONH--). Anal. Calcd. for C16H16INO2 : C, 50.41; H, 4.23; N, 3.67. Found: C, 50.25; H, 4.18; N, 3.58.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:10]1[S:41][C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:18][C:19]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:20]=3[O:21][C@@H:22]3[CH2:26][N:25]([S:27]([CH3:30])(=[O:29])=[O:28])[C@H:24]([CH2:31][O:32]C(=O)C)[CH2:23]3)[C:12]=2[C:11]=1[CH3:42])(=[O:9])[NH2:8].OS([O-])(=O)=O.[K+]>CO.C1COCC1>[F:40][C:37]1[CH:38]=[CH:39][C:19]([NH:18][C:17]2[C:12]3[C:11]([CH3:42])=[C:10]([C:7]([NH2:8])=[O:9])[S:41][C:13]=3[N:14]=[CH:15][N:16]=2)=[C:20]([O:21][C@H:22]2[CH2:23][C@@H:24]([CH2:31][OH:32])[N:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:26]2)[CH:36]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CN1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(S(C)(=O)=O)C3)c12
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Potassium carbonate (278 mg) was added to a solution of acetic acid (2S,4S)-4-[2-(6-carbamoyl-5-methyl-thieno[2,3-d]pyrimidin-4-ylamino)-5-fluoro-phenoxy]-1-methanesulfonyl-pyrrolidin-2-ylmethyl ester (360 mg) in MeOH (5 ml) and THF (2 ml). The reaction was stirred at room temperature for 90 h. 10% aq. KHSO4 was added and the resultant suspension was filtered. The filter cake was washed with dichloromethan and diethylether.
Reaction SMILES: I[C:2]1[C:3]([CH3:16])=[C:4]2[C:8]3=[C:9]([CH2:11][NH:12][CH2:13][C:14](=[O:15])[N:7]3[CH:6]=[CH:5]2)[CH:10]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([C:2]2[C:3]([CH3:16])=[C:4]3[C:8]4=[C:9]([CH2:11][NH:12][CH2:13][C:14](=[O:15])[N:7]4[CH:6]=[CH:5]3)[CH:10]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(I)cc2c3c1ccn3C(=O)CNC2
Reactant: OB(O)c1ccccc1
Solvent: O
Product: Cc1c(-c2ccccc2)cc2c3c1ccn3C(=O)CNC2
Yield: 70 %

Procedure:
Using a procedure as described in Example 50(b), the title compound was synthesized from 6-iodo-7-methyl-3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 50(a)), and phenylboronic acid to give a white solid in 70% yield: 1H NMR (DMSO-d6) δ 2.23 (s, 3H), 3.46 (bs, 2H), 4.13 (bs, 2H), 7.17 (t, 1H, J=7.5 Hz), 7.45-7.56 (m, 5H), 7.76 (d, 1H, J=7.5 Hz), 7.84 (d, 1H, J=7.5 Hz), 8.29-8.31 (m, 1H). LRMS (M+) 276. Anal. (C18H16N2).0.4 H2O) C, H, N.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].N1C=CC=CC=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].Cl>ClCCl>[O:9]=[C:4]1[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]([O:10][C:19](=[O:20])[CH2:18][Cl:17])=[CH:3]1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Into a 250 ml round bottom flask containing the bicyclo[3.2.1]octane-2,4-dione (10 g, 72 mmol) is added dry dichloromethane (100 ml) and pyridine (6.28 g, 87 mmol). To the stirred mixture is added dropwise over a period of 15 minutes the chloroacetyl chloride (9.82 g, 72 mmol) diluted in dichloromethane (100 ml). The reaction mixture is therefore stirred for 2 hours at room temperature. The reaction mixture is therefore poured into 100 ml of aqueous 2N HCl and extracted with ethyl acetate (2×100 ml). The combined organic extracts are dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an orange oil. The crude product is distilled under reduced pressure to give chloro-acetic acid 4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester (13.4 g).
Reaction SMILES: FC(F)(F)CCC([N:7]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][C:8]21[CH2:10][CH2:9]2)=O.C(N(CC)CC)C.[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35]>C1COCC1>[CH2:33]([S:36]([N:7]1[CH:8]2[CH2:10][CH2:9][CH:14]1[CH2:13][N:12]([C:15]1[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=1)[CH2:11]2)(=[O:38])=[O:37])[CH2:34][CH3:35]
Reactant: CCCS(=O)(=O)Cl
Reactant: O=C(CCC(F)(F)F)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and propane-1-sulfonyl chloride (0.06 mmol) was added. The reaction mixture was left at it for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8](=[O:21])[NH:9][CH2:10][C:11]1[NH:12][C:13]2[C:14]([N:20]=1)=[N:15][CH:16]=[C:17](Br)[CH:18]=2)([CH3:6])([CH3:5])[CH3:4].[CH3:22][C:23]1[C:27](B(O)O)=[C:26]([CH3:31])[O:25][N:24]=1.OC(C(O)(C)C)(C)C>>[C:3]([O:7][C:8](=[O:21])[NH:9][CH2:10][C:11]1[NH:12][C:13]2[C:14]([N:20]=1)=[N:15][CH:16]=[C:17]([C:27]1[C:23]([CH3:22])=[N:24][O:25][C:26]=1[CH3:31])[CH:18]=2)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(C)(C)OC(=O)NCc1nc2ncc(Br)cc2[nH]1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li+]
Agent: [OH-]
Product: Cc1noc(C)c1-c1cnc2nc(CNC(=O)OC(C)(C)C)[nH]c2c1
Temperature: 120 °C
Yield: 68.6 %

Procedure:
To a dry 20 mL microwave vessel equipped with a stir bar, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (125 mg, 0.153 mmol) and LiOH (110 mg, 4.58 mmol) were combined. The vessel was capped with septa and purged three times with vacuum and nitrogen. The mixture was suspended into degassed, 10:1 dioxane: H2O (2.5 mL). To the suspension, (6-Bromo-1H-imidazo[4,5-b]pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (500 mg, 1.528 mmol), 3,5-dimethylisoxazole-4-boronic acid (323 mg, 2.292 mmol) and pinacol (271 mg, 2.292 mmol) were added. The reaction mixture was purged again with vacuum and nitrogen three times and sealed using a microwave crimped septa. The reaction vessel was placed in a microwave reactor and heated at 120° C. for 2.5 hrs. The reaction was complete based on LC/MS (M+1=344). The resulting brown suspension was concentrated under reduced pressure to dryness and reconstituted with 20 mL of 10% MeOH-DCM. 30 g of 230-400 mesh SiO2 was then added and the resulting slurry was stirred vigorously. Removed solvent under reduced pressure and packed compound absorbed on silica into a 40 g SIM cartridge. Purified crude using SiO2 flash chromatography (120 g ISCO cartridge; 230-400 mesh SiO2) equilibrated with 10% MeOH-DCM containing 0.5% triethylamine to give 360 mg of the title compound as an amber oil (69%).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[CH:32][CH2:33][C:34](O)=[O:35])=[CH:27][CH:26]=1.C1(N(C2CCN(C(=O)C=CCCC)CC2)S(C2C=CC=C(C(F)(F)F)C=2)(=O)=O)CC1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:35])[CH2:33][CH:32]=[C:31]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: O=C(CC=C(c1ccc(F)cc1)c1ccc(F)cc1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
N-Cyclopropyl-N-{1-[4,4-bis(4-fluorophenyl)-but-3-enoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (33) was prepared by reacting N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide with 4,4-bis(4-fluorophenyl)-but-3-enoic acid following the procedure described for the synthesis of N-cyclopropyl-N-(2-hexenoyl)piperin-4-yl-3-trifluoromethyl-benzenesulfonamide (30) in Example 19, step a. 1H NMR (CDCl3): δ 8.12 (s, 1H), 8.03 (d, 1H), 7.86 (d, 1H), 7.71 (t, 1H), 7.15 (m, 6H), 6.96 (m, 2H), 6.21 (t, 1H), 4.68 (m, 1H), 4.02 (m, 1H), 3.61 (m, 1H), 3.15 (d, 2H), 2.93 (m, 1H), 2.51 (m, 1H), 1.93 (m, 1H), 1.69 (m, 2H), 1.25 (m, 1H), 0.90 (m, 5H). LC: 100%. MS (M+H+): 605.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH:7]([CH3:9])C)[CH2:3][OH:4].[N:23]#[C:24]Br>>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([N:6]([CH2:5][CH:2]2[CH2:3][O:4][C:24]([NH2:23])=[N:1]2)[CH2:7][CH3:9])=[CH:11][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)N(C[C@H](N)CO)c1ccc(Cc2ccccc2)cc1
Reactant: N#CBr
Product: CCN(CC1COC(N)=N1)c1ccc(Cc2ccccc2)cc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-[(4-benzyl-phenyl)-isopropyl-amino]-propan-1-ol was reacted with cyanogen bromide to give S)-4-{[(4-benzyl-phenyl)-ethyl-amino]-methyl}-4,5-dihydro-oxazol-2-ylamine. Colorless gum. MS (ISP): 310.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:11][CH2:12][CH2:13]O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.CCN(S(F)(F)[F:35])CC>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:11][CH2:12][CH2:13][F:35])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC(CCCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Solvent: ClCCl
Product: CCC(CCCF)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-6-hydroxyhexan-3-yl)-1H-indol-4-yl)methanesulfonamide (21 mg, 0.05 mmol), as described in Example 45 Step A, in dichloromethane (2 mL) was added DAST (16 mg, 0.1 mmol) at −78° C. The mixture was gradually warmed to room temperature and stirred for 3 h, then quenched with methanol (0.5 mL). The crude product was purified by PREP-TLC eluting with PE/EA (2/1, v/v) to obtain the title compound as colorless oil. LC/MS m/z=444.7[M+Na]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.[N:16]([Si](C)(C)C)=[N+:17]=[N-]>CC#N.CCOC(C)=O>[N:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[N+:16]=[N-:17]
Reactant: Nc1ccc(I)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-iodobenzenamine (2.38 g, 10.9 mmol) in MeCN (20 mL) at 0° C. was added tert-butyl nitrite (1.95 mL, 1.69 g, 16.4 mmol) and azidotrimethylsilane (1.70 mL, 1.49 g, 12.9 mmol). The reaction mixture was warmed to room temperature and stirred for 6 h, heated to 40° C. for 18 h, and diluted with EtOAc. The aqueous phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated to give 1-azido-4-iodobenzene which was used in the next step without further purification.
Reaction SMILES: [CH:1]([B:5]([O:10][CH:11]([CH3:13])[CH3:12])OC(C)C)([CH2:3][CH3:4])[CH3:2].[C:14]([Li])#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl.[B].C=C(C)C>C(OCC)C>[CH:1]([B:5]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[O:10][CH:11]([CH3:12])[CH3:13])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)B(OC(C)C)OC(C)C
Reactant: [Li]C#CCCCCCC
Agent: C=C(C)C
Agent: Cl
Agent: [B]
Solvent: CCOCC
Product: CCCCCCC#CB(OC(C)C)C(C)CC

Procedure:
sec-Butyl(1-octynyl)isopropoxyborane was prepared following the method of Example 12 with sec-butyldiisopropoxyborane (10.79 g, 58 mmol) in ethyl ether (58 mL) and added to a solution of 1-octynyllithium (64 mmol in 64 mL, THF) and quenched with HCl in ethyl ether (18.82 mL, 64 mmol). Yield: 10.1 g (74%), bp 68°-70° C. (0.1 mm Hg); n20D 1.4366; proton NMR (CDCl3)δ4.60 (septet, =18 Hz, 1H), 2.23 (triplet, 2H), 1.17 (d, J=18 Hz, 6H), 0.87 (m, 9H); boron NMR (CDCl3)δ+41.6 ppm(s); mass spectrum (chemical ionization, isobutene) m/e 237 M+H, 15%); IR (thin film) 2183, 1324 cm-1. Anal Calcd. for C15H29BO: C, 76.77; H, 12.38; B, 4.58. Found: C, 76.30; H, 12.39; B, 4.63.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[OH:18])=[C:8]([Cl:19])[CH:7]=1)[CH3:5].[OH-].[Na+].Cl>CO>[Cl:19][C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:20])=[O:2])[CH:11]=[CH:10][C:9]=1[CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[OH:18]
Reactant: COC(=O)C(C)c1ccc(C[C@@H]2CCC[C@@H]2O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C[C@@H]2CCC[C@@H]2O)c(Cl)c1
Yield: 80.5 %

Procedure:
3 g of methyl-2-[3-chloro-4-(cis-2-hydroxycyclopentane-1-yl methyl)phenyl]propionate were incorporated with 80 ml of an aqueous methanol containing 1.2 g of sodium hydroxide and then refluxed under heat for two hours. After the end of the reaction, the reaction mixture was treated to concentrate the solvent at a reduced pressure, incorporated with 50 ml of water and washed with 50 ml of ethyl acetate, after which the aqueous layer obtained was adjusted to a pH of 2 with conc. hydrochloric acid. The aqueous layer so adjusted was extracted with 50 ml of ethyl acetate, washed with water, dried and then freed of the solvent to obtain a residue. The thus obtained residue was adsorbed onto a silica gel-packed column and then eluted with chloroform-methanol (10:1) to obtain 2.3 g (yield 80%) of oily 2-[3-chloro-4-(cis-2-hydroxycyclopentane-1-yl methyl)phenyl] propionic acid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(C=Nc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2ccc(Cl)cc2)cc1
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
(a) 0.312 g of 50% sodium hydride is suspended in 10 ml of anhydrous dimethylformamide, and 1.16 g of 4-[N-(4-chlorophenyl)formimidoyl]phenol is added to the suspension at 20° to 25° C. with stirring. Subsequently over a period of 15 minutes, 1.27 g of ethyl 2-bromo-2-methylpropionate is added dropwise to the resulting mixture at the same temperature with stirring. The mixture is stirred at the same temperature for 30 minutes, then at 50° to 55° C. for 2 hours and thereafter at 80° C. for 3 hours. The reaction mixture is poured into cold water, extracted with ether, and the extract is washed with 5% aqueous solution of sodium hydroxide and then with water. After drying, the solvent is distilled off to give 1.5 g of ethyl 2-[4-{N-(4-chlorophenyl)formimidoyl}phenoxy]-2-methylpropionate.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[F:5][C:6]([F:37])([F:36])[C:7]1[CH:8]=[C:9]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)=[O:11]>C(#N)C>[F:37][C:6]([F:5])([F:36])[C:7]1[CH:8]=[C:9]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:2][CH2:3][OH:4])[CH2:14][C@H:13]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)=[O:11]
Reactant: OCCBr
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCO)C[C@H]1Cc1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 85 %

Procedure:
2-Bromoethanol (310 mg) was added to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)-benzyl]piperazine (1 g) in acetonitrile (10 ml). The reaction mixture was stirred at 70° C. for 19 hours. The mixture was filtered, and the residue on filter was washed with dichloromethane twice. The filtrate and combined washings were concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with methanol in dichloromethane (2% then 5%) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-hydroxyethyl)-2-[4-(trifluoromethyl)benzyl]piperazine (927 mg) as an amorphous powder.
Reaction SMILES: [BrH:1].[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10](N)[C:11]([N+:14]([O-:16])=[O:15])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.N([O-])=O.[Na+]>O>[Br:1][C:10]1[CH:9]=[C:8]([N:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)[CH:13]=[N:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: Br
Reactant: Nc1cc(N2CCOCC2)cnc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ncc(N2CCOCC2)cc1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A three neck round bottom flask equipped with a magnetic stir bar, a dropping funnel and a thermometer, was charged with CuBr (629 mg, 4.4 mmol) and HBr (25 mL). The solution was cooled to −5° C. (ice salt bath). Solid 5-morpholino-2-nitropyridin-3-amine (983 mg, 4.4 mmol) was slowly added, followed by the slow addition of a NaNO2 (333 mg, 4.8 mmol) solution in H2O (25 mL) via the dropping funnel, ensuring that the temperature did not rise above 0° C. The reaction mixture was stirred at −5° C. for 1 h, warmed to room temperature and stirred an additional 1.5 h. The reaction was deemed complete by LCMS and the mixture was cooled again to 0° C., quenched with 6 N NaOH to pH 12, diluted with water and extracted with EtOAc. EtOAc was washed with water (×2), brine (×1) dried and concentrated. The residue was azeotroped with EtOH dried under high vacuum, obtaining 4-(5-bromo-6-nitropyridin-3-yl)morpholine (1.21 g, 4.20 mmol, 96% yield) as a light yellow solid. LCMS (m/z): 288.2 (MH+), 0.65 min. 1H NMR (400 MHz, CDCl3) δ ppm 8.08-7.99 (d, J=2.3 Hz, 1H) 7.41 (d, J=2.3 Hz, 1H) 3.98-3.81 (m, 4H) 3.45-3.30 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNS(C)(=O)=O)C1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 156.5 %

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)amino]methyl}-1,4-oxazepane-4-carboxylate (162 mg) in ethanol (0.5 mL) was added 4.0 M hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from ethanol-water to give the title compound (109 mg) as colorless crystals.