Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].[Cl-].[NH4+]>O1CCCC1>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([OH:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=Cc1ccccc1Br
Reactant: CCCCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCC(O)c1ccccc1Br
Temperature: 25 °C
Yield: 49 %

Procedure:
Magnesium pieces (6.56 g) were added to anhydrous tetrahydrofuran (10 ml) in a stream of nitrogen and the mixture was stirred at room temperature. A solution (200 ml) of 1-bromoheptane (48.4 g) in anhydrous tetrahydrofuran was dropwise added thereto while heating gradually and the mixture was stirred at 40° C. for 1 hour. Thereto was dropwise added a solution (100 ml) of 2-bromobenzaldehyde (25 g) in anhydrous tetrahydrofuran at room temperature and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:8) to give the subject compound (18.9 g) as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][CH:13]=1.[H-].[Na+].[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34])[CH:6]=[C:5]2[CH2:11][C:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C(Cc2c[nH]c3ccc(F)cc23)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC=C(Cc2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)C1
Reaction time: 0.5 h

Procedure:
A stirred solution of tert-butyl 5-[(5-fluoro-1H-indol-3-yl)methyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (430 mg, 1.30 mmol) in tetrahydrofuran is treated with NaH (60% in mineral oil, 78 mg, 1.95 mmol) portion-wise under nitrogen at room temperature, stirred for 0.5 hr, treated with benzenesulfonyl chloride (0.25 ml, 1.95 mmol), stirred for 17 hr under nitrogen at room temperature, quenched with ice-water and diluted with ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts and organic phase are washed with water and saturated NaCl, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane, 1/9) to afford the title compound as a yellow solid, 350 mg, mp 63-65° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C(OC([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=2)[C:29](=[O:37])[NH:28]1)=O)(C)(C)C>>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[N:7]=[C:2]([NH:36][C:33]4[CH:34]=[C:35]5[C:30]([C:29](=[O:37])[NH:28][NH:27]5)=[CH:31][CH:32]=4)[CH:3]=[CH:4][C:5]=3[N+:17]([O-:19])=[O:18])[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)n[nH]1
Product: O=c1[nH][nH]c2cc(Nc3ccc([N+](=O)[O-])c(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Yield: 16.2 %

Procedure:
6-[6-(5-Cyclopropyl-2H-pyrazol-3-ylamino)-5-nitro-pyridin-2-ylamino]-1,2-dihydro-indazol-3-one was prepared by the reaction of (6-Chloro-3-nitro-pyridin-2-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine and 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester in a similar manner as described above to afford 17 mg of the desired product as a bright yellow solid (16.2% yield). H-NMR (CD3OD) δ 8.32(d, 1H), 7.68(d, 1H), 7.65(s, 1H), 7.17(d, 1H), 6.38(d, 1H), 6.24(s, 1H), 1.79(m, 1H), 0.84(m, 2H), 0.48(m, 2H). MS (ES+): m/e=393.2 (M+H), 391.2 (M−H); LC/Method A/4.149 min, 100% purity by area %.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]Br)[C:3]=1[O:10][CH3:11].[C-:12]#[N:13].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:12]#[N:13])[C:3]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1c(Cl)ccnc1CBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1c(Cl)ccnc1CC#N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-Chloro-3-methoxy-2-bromomethyl-pyridine (4.69 g) and sodium cyanide (5.11 g) are added to ml of a 1/1 mixture of water and ethanol. The reaction is stirred at 60° C. for 3 hours. The ethanol is evaporated and the residue diluted in water and extracted with methylene chloride. The desired product is obtained by chromatography using hexane/ethyl acetate (9/1) as solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C1C=CC2N(O)N=NC=2C=1.[C:24]([C:28]1[CH:44]=[CH:43][C:31]([CH2:32][NH:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([C:28]1[CH:44]=[CH:43][C:31]([CH2:32][N:33]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(O)c1ccc(Cl)c2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2ccc(Cl)c3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a solution of 64 mg (0.33 mmol) of 4-chloro-1H-indole-7-carboxylic acid in 2 ml DCM 50 mg of HOBT (0.33 mmol) were added and the reaction mixture was stirred for 15 min at rt under nitrogen. 85 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine in 1 ml DCM were added and then 63 mg (0.33 mmol) of EDC.HCl. The reaction mixture was stirred over night at rt to yield a slight turbid yellow solution. The solvent was evaporated and the residue was dissolved in 1,2-dichloro ethane. The reaction mixture was stirred at reflux for 3 h. The solvent was evaporated and the residue was purified by column chromatography (25 g silica gel, heptane/EtOAc 7:3) to yield 90 mg (65%) product as a light yellow viscous oil. MS (ISP) 463.4 (M+H)+.
Reaction SMILES: CC(C)CCC1NC2C(C=1)=CC=CC=2.[C:15]([CH:18]=[CH:19][CH2:20][CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:17])=[O:16]>>[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:17])=[O:16]
Reactant: O=C(O)C=CCCc1cc2ccccc2[nH]1
Agent: CC(C)CCc1cc2ccccc2[nH]1
Product: O=C(O)CCCCc1cc2ccccc2[nH]1

Procedure:
Refer to 28b) using 2-(4-carboxy-3-buten-1-yl) indole as the starting material.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:7].CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O.C(=O)(O)[O-].[Na+].O1CCOCC1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[CH:3]=[CH:4][N:5]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[C:6]1=[O:7]
Reactant: COC(CN(C(=O)Nc1ccccc1F)C1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2ccn(-c3ccccc3F)c2=O)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
tert-Butyl 4-(1-(2,2-dimethoxyethyl)-3-(2-fluorophenyl)ureido)piperidine-1-carboxylate (1.39 g, 3267 μmol) was dissolved in a mixture of water (8.0 ml) and methanesulfonic acid (8.0 ml, 123281 μmol). Mixture was heated to 100° C. and held for 15 minutes. Mixture was cooled to room temperature. Reaction was neutralized with sodium carbonate (6.15 g, 58025 μmol). Mixture was diluted with aqueous sodium bicarbonate. 1,4-Dioxane (10 ml) was added to the mixture followed by di-tert-butyl dicarbonate (880 mg, 4032 μmol). Reaction stirred vigorously at room temperature for 3 hours. Reaction was quenched with aqueous ammonium chloride. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as clear colorless oil in 64% yield. MS (M−C4H10O+H)−=288.1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:33][CH2:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@H:10]4[O:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:43]6[CH:44]=[CH:45][C:40]([O:39][CH2:38][CH2:37][N:34]7[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]7)=[CH:41][CH:42]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Reactant: CN1CCN(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCN(CCOc2ccc(-c3cnc(N4CCO[C@H](Cn5nnc6ncc(-c7cnn(C)c7)nc65)C4)nc3)cc2)CC1
Temperature: 105 °C
Reaction time: 18 h
Yield: 3.9 %

Procedure:
(S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine 15 mg (0.03 mmol) was dissolved in dioxane 1 ml, and 1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenoxy)ethyl)piperazine 17 mg (0.05 mmol), 1M Na2CO3 98 μl (0.09 mmol), and Pd(pph3)4 2 mg (0.001 mmol) were added and then charged with nitrogen, followed by stirring at 105° C. for 18 hours. After the reaction, the reaction mixture was extracted with EA and brine, and the organic layer was dried over MgSO4. Column chromatography (methylene chloride methanol=20:1) gave a product 0.7 mg (4%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH:9]=[N:8]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCN(C[C@@H](O)C)CC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[OH-].[Li+]>C1COCC1.CO.O>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)c1
Yield: 5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidin-1-yl)propan-2-ol (127 mg, 0.191 mmol) was hydrolyzed by lithium hydroxide (80 mg, 1.913 mmol) in THF/methanol/water (20/10/5 ml) to yield 15 mg (5% yield) of the titled. 1H NMR (CD3OD, 400 MHz): δ 7.46-8.45 (d, 1H), 8.33-8.32 (d, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.63-7.61 (m, 3H), 7.39-7.34 (m, 3H), 7.11-7.09 (d, 1H), 7.06-7.01 (m, 2H), 5.43 (s, 2H), 4.05-4.00 (m, 1H), 3.25-3.19 (t, 2H), 2.64-2.33 (m, 4H), 1.93-1.85 (m, 4H), 1.30-1.26 (m, 1H), 1.20-1.18 (d, 3H). MS: m/z=510.2 (M+1), HPLC: 96.39% in method A.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](#N)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([C:5]2[NH:3][CH2:2][CH2:1][N:4]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: N#Cc1ccccc1
Product: c1ccc(C2=NCCN2)cc1
Yield: 95 %

Procedure:
The procedure described in Example 5 is followed except that 206 parts of benzonitrile and 132 parts of ethylenediamine are employed. 273.6 parts (95% of theory) of 2-phenylimidazoline, of boiling point 295° C./1,013 mbar, are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23](O)=[O:24].S(Cl)(Cl)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:24]
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)N1CCN(C)CC1
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a mixture of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylic acid (5 g), dichloromethane (45 ml) and N,N-dimethylformamide (11 ml), thionyl chloride (2.1 g) was added at 7° C. under ice cooling. After stirring for 1.5 hours at the same condition, to a solution of N-methylpiperazine (3.7 g) in dichloromethane (37 ml), the reaction mixture was added under ice cooling and stirred for 2 hours. The reaction mixture was adjusted to pH=8.5 by saturated potassium carbonate and extracted with chloroform. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was distilled off to give a residue, which was chromatographed on alumina eluting with a chloroform. The fractions containing the desired product were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to afford 6-methyl-5-(4-methylpiperazin-1-ylcarbonyl)-4-(3-nitrophenyl)-2-phenyl-pyrimidine (3.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]=[N+:14]=[N-:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-hydroxybenzene sulfonyl chloride synthesized in Synthetic example 1 (3.76 g, 19.5 mmol, and 1.00 Eq) was dissolved in acetone (50 mL) and then water (50 mL) was added thereto. The obtained mixed solution was cooled to 0° C. and NaN3 (1.41 g, 21.7 mmol, and 1.11 Eq) was added to the solution slowly, followed by stirring at 0° C. for 1 hour. After the stirring, acetone was removed by the evaporator (30° C., 150 mbar) and a water layer was extracted with dichloromethane (3×30 mL). The obtained organic layer was dried with sodium sulfate and dichloromethane was removed by the evaporator. The product as oil (3.06 g, 15.4 mmol, and 79%) was dried in vacuo to obtain 4-hydroxybenzenesulfonyl azide.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:8][NH:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[F:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28](O)=[O:29])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28]([N:7]2[CH2:8][C:3]([O:13][CH3:14])([O:2][CH3:1])[CH2:4][CH2:5][CH:6]2[C:9]([O:11][CH3:12])=[O:10])=[O:29])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: COC(=O)C1CCC(OC)(OC)CN1
Product: COC(=O)C1CCC(OC)(OC)CN1C(=O)c1nc(C)sc1-c1cccc(F)c1

Procedure:
Methyl 1-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5,5-dimethoxypiperidine-2-carboxylate was prepared according to general procedure A using product methyl 5,5-dimethoxypiperidine-2-carboxylate and 5-(3-fluorophenyl)-2-methylthiazole-4-carboxylic acid.
Reaction SMILES: C(=O)(O)[O-].[Na+].O1CCCC1.[I-].[I-].[Ca+2].O.[BH4-].[Na+].[C:17]([C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[C:24]([C:30](OCC)=[O:31])[N:25]2[CH2:28][CH3:29])=[CH:21][CH:20]=1)#[N:18]>C(O)(=O)C>[CH2:28]([N:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([C:17]#[N:18])[CH:27]=2)[CH:23]=[C:24]1[CH2:30][OH:31])[CH3:29]
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2n1CC
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(CO)cc2ccc(C#N)cc21
Temperature: 0 °C
Yield: 83.8 %

Procedure:
In a 1 l flask, 26.27 g of ethyl 6-cyano-1-ethylindole-2-carboxylate and 0.91 g of sodium bicarbonate were dissolved with 300 ml of tetrahydrofuran and then cooled to 0° C. To this mixture was added CaI2.H2O and then slowly added NaBH4. The reaction mixture was stirred while slowly warming from 0° C. to room temperature with stirring. After examined by TLC, ice and a catalytic amount of acetic acid were added thereto at 0° C. and the mixture was stirred. The reaction solution was evaporated to remove tetrahydrofuran, and the residue was diluted with water and extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO4 and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(1:2)]. The fractions containing the desired product were combined and then evaporated to obtain 18.2 g of the title compound as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>>[NH2:1][C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[F:34][C:33]([C:31]([OH:37])=[O:32])([F:36])[F:35]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Boc-L-Ile-D-Pro-OBzl (21.5 g, 51.4 mmol) was dissolved in TFA (50 ml) and left with standing on ice for one hour. On completion of the reaction, TFA was removed by evaporation, and the residue was vacuum-dried to obtain H-L-Ile-D-Pro-OBzl-TFA. The compound was dissolved in DMF (100 ml), and Boc-D-Tyr(Me)-OH (16.7 g, 56.5 mmol) was then added. HBTU (29.4 g, 77 mmol), HOBt.H2O (7.87 g, 51 mmol), and triethylamine (25.2 ml, 180 mmol) were further added and stirred for 3 hours under ice-cooling. The reaction solution was concentrated, dissolved in ethyl acetate, and successively washed with an aqueous 10% citric acid solution, an aqueous 4% sodium bicarbonate solution, and saturated saline. The product was dried over MgSO4 and concentrated, and the resulting foam substance was purified by flash silica gel chromatography (4×30 cm, 1% methanol/chloroform) to obtain the foam title compound (22.0 g, 37 mmol, 72% yield). TLC: Rf=(CHCl3/MeOH=9/1).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CSc1ccc(C2=C(Br)CCC2)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: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1

Procedure:
Under nitrogen, 1.5 g (5.6 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Step 2) was reacted with 1.5 g (11 mmol) of 4-fluorophenylboronic acid (Lancaster) in 30 mL of toluene, 20 mL of ethanol, and 25 mL of 2M Na2CO3 in the presence of 250 mg of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography with hexane gave 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylthio)benzene (41 in Synthetic Scheme X when R5 =SCH3, R10 =F, and R1, R2, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as a colorless solid: mp 46°-47° C.; NMR (CDCl3) δ 2.04 (m, J=7 Hz, 2H), 2.45 (s, 3H), 2.86, (t, J=7 Hz, 4H), 6.86-6.94 (m, 2H), 7.08 (br s, 4H) , 7.10-7.18 (m, 2H) .
Reaction SMILES: [CH2:1]([N:8]1[C:16](=O)[CH:15]2[CH:10]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCC2C(=O)N(Cc3ccccc3)C(=O)C21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC2CN(Cc3ccccc3)CC21

Procedure:
19.2 g (0.08 mol) of crude 6-benzyl-1-methyl-5,7-dioxooctahydropyrrolo[3,4-b]pyridine are reduced with 6.1 g (0.16 mol ) of lithium aluminum hydride in absolute tetrahydrofuran in accordance with the working instructions of Example Ic.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.O>[Br:16][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][N:11]2[CH2:13][CH2:14][CH2:15][C:10]=12
Reactant: Fc1ccc(-c2cc3n(n2)CCC3)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1ccc(-c2nn3c(c2Br)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (44.5 g, 0.22 mol) in 600 mL chloroform is added at 0° C. N-bromosuccinimide (117 g, 0.66 mol). The mixture is stirred 17 h at RT. Thereafter, the mixture is diluted with water and extracted with dichloromethane. The combined organic phases are dried and evaporated. The obtained crude material is purified by column chromatography on silica (6 cm×40 cm, eluent dichloromethane). The obtained product is further purified by trituration with a MTBE-hexane mixture and 38.2 g (61%) of the product are obtained as solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[CH3:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:19][C:7]1[O:6][C:5]([C:3]([OH:2])=[O:4])=[CH:9][C:8]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21][CH3:20])=[CH:14][CH:13]=1
Reactant: CSc1ccccc1B(O)O
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Product: CSc1ccccc1-c1ccc(OCc2cc(C(=O)O)oc2C)cc1

Procedure:
Compound (105) was prepared from compound (20) and (2-methylsulphanyl-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.86 mins, m/z (ES−)=353 (M−H for C20H18O4S).