Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:21])[N:6]2[CH3:20].[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27](Br)[CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Br:22][C:23]1[CH:28]=[C:27]([C:10]2[C:2]([Cl:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[N:6]([CH3:20])[C:5](=[O:21])[CH2:4]3)[CH:26]=[N:25][CH:24]=1
Reactant: Brc1cncc(Br)c1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2Cl
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: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2Cl
Temperature: 120 °C

Procedure:
To 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (525 mg, 1.71 mmol), prepared as described in Example 27a, was added 3,5-dibromopyridine (CAS#625-92-3, 1.2 g, 5.1 mmol), 1,2-dimethoxyethane (5.0 mL), and 2 M aqueous sodium carbonate (2.05 mL, 4.1 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (0.93 g, 0.10 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 3.55%) to furnish 5-(5-bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 336.9753 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.27 (a, 3H), 3.62 (s, 2H), 6.85 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.95-8.04 (m, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.70 (d, J=2.3 Hz, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:21])[C@H:11]([NH2:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([NH:29][C@@H:30]([C:42](O)=[O:43])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(OC(C)(C)C)=O>>[C:35]([N:20]([C@@H:11]([CH:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[OH:21])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:42](=[O:43])[C@H:30]([NH2:29])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: N[C@H](CCc1ccccc1)C(O)c1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)N(C(=O)OC(C)(C)C)[C@H](CCc1ccccc1)C(O)c1nc2ccccc2s1

Procedure:
(1 R)-1-[(RS)-(2-Benzothiazolyl)hydroxymethyl]-3-phenylpropylamine (72 mg) was coupled to N,N′-bis-Boc-D-ornithine to afford the title compound (11 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3, 3:2 mixture of diastereomers) δ 1.41 (s, 9H), 1.44 (s, 9H), 1.60 (m, 2H), 1.19 (m, 4H), 2.20 (m, 2H), 2.72-2.91 (m, 2H), 4.11 (m, 1H), 4.31 (m, 0.4H), 4.41 (m, 0.6H), 5.06 (m, 0.6H), 5.19 (d, J=1.1 Hz, 0.4H), 7.20 (m, 3H), 7.26 (m, 2H), 7.40 (t, J=8.5 Hz, 1H), 7.49 (t, J=9.3 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), and 7.98 (d, J=9.4 Hz, 1H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: O=C([O-])O
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(-c3nnn[nH]3)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(-c3nnnn3C)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 11.2 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide (44 mg, 0.172 mmol) in acetone (5 mL), sodium bicarbonate (84 mg, 1 mmol) and dimethyl sulfate (30 uL, 0.22 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (12 mg) and the other regioisomer (26 mg).
Reaction SMILES: [CH2:1]1[CH:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1.[CH2:15](Br)[CH3:16].O>CN(C=O)C>[CH2:15]([N:2]1[CH2:3][CH2:4][CH2:5][N:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:8][CH:7]2[CH2:1]1)[CH3:16]
Reactant: c1ccc2c(c1)CC1CNCCCN21
Reactant: CCBr
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCCN2c3ccccc3CC2C1
Reaction time: 10 h

Procedure:
1.88 g of 2,3,4,5,11,11a-hexahydro-1H-1,4-diazepino-[1,2-a]indole in 20 ml of DMF are stirred for one hour at 20° with 1.48 g of K tert.-butylate, 1.1 g of ethyl bromide are added and the solution is stirred for a further 10 hours. 200 ml of water are then added and the mixture is extracted several times with ethyl acetate. After drying and evaporating the organic phase, 2-ethyl-2,3,4,5,11,11a-hexahydro-1H-1,4-diazepino[1,2-a]indole is obtained. Hydrochloride, m.p. 204°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:7][CH:6]=[C:5]([CH2:8][OH:9])[CH:4]=1.CC(C)([O-])C.[K+].Cl[C:19]1[CH:24]=[CH:23][N:22]([C:25]2[CH:33]=[CH:32][C:31]3[C:27](=[C:28]([CH3:37])[N:29]([CH:34]4[CH2:36][CH2:35]4)[N:30]=3)[CH:26]=2)[C:21](=[O:38])[CH:20]=1.O>CC(N(C)C)=O>[CH:34]1([N:29]2[C:28]([CH3:37])=[C:27]3[C:31]([CH:32]=[CH:33][C:25]([N:22]4[CH:23]=[CH:24][C:19]([O:9][CH2:8][C:5]5[CH:4]=[C:3]([C:2]([F:10])([F:1])[F:11])[S:7][CH:6]=5)=[CH:20][C:21]4=[O:38])=[CH:26]3)=[N:30]2)[CH2:36][CH2:35]1
Reactant: OCc1csc(C(F)(F)F)c1
Reactant: Cc1c2cc(-n3ccc(Cl)cc3=O)ccc2nn1C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)ccc2nn1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of [5-(trifluoromethyl)thiophen-3-yl]methanol (100 g) in DMA (1363 ml) was added potassium tert-butoxide (61.3 g) at 5° C., and the mixture was stirred at the same temperature for 30 min. To the obtained mixture was added 4-chloro-1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)pyridin-2(1H)-one (136.5 g), and the mixture was stirred at an inside temperature of 70° C. for 1.5 hr. The reaction mixture was cooled to room temperature, water (1.4 L) was added, and the obtained suspension was stirred overnight. The precipitated solid was collected by filtration, and washed with water (2.8 L), ethanol (540 ml) and diisopropyl ether (500 ml) to give the title compound (168.6 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1)[CH3:2].[H-].[Na+].Cl[C:13]1[CH:21]2[CH:16]([CH:17]3[O:22][CH:20]2[CH2:19][CH2:18]3)[C:15](=[O:23])[CH:14]=1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:8][O:9][C:13]2[CH:21]3[CH:16]([CH:17]4[O:22][CH:20]3[CH2:19][CH2:18]4)[C:15](=[O:23])[CH:14]=2)[S:6][CH:7]=1)[CH3:2]
Reactant: O=C1C=C(Cl)C2C3CCC(O3)C12
Reactant: CCc1csc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1csc(COC2=CC(=O)C3C4CCC(O4)C23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of (4-ethyl-thiophen-2-yl)methanol (369 mg, 2 mmol) in THF (10 ml) is added sodium hydride, 60% dispersion in mineral oil, (88 mg, 2.2 mmol) in one portion and the reaction stirred at room temp for 3 hours. The resulting dark yellow solution is then cooled to 0° C., and 5-Chloro-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (341 mg, 2.4 mmol) is added and the resulting brown solution allowed to warm to ambient over 30 minutes, then stirred at room temp for 17 hours. Crude reaction is purified by flash chromatography to give 5-(4-ethyl-thiophen-2-ylmethoxy)-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one as a white solid (515 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C@@H:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28]([O:32][C:33]([NH:35][C:36]([CH3:41])([C:38](O)=[O:39])[CH3:37])=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:20])[C@H:10]([NH:11][C:38](=[O:39])[C:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])([CH3:41])[CH3:37])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
D-Homophenylalanine benzyl ester (0.87 g; 3.23 mmol), triethylamine (900 ml) and N-(t-butoxycarbonyl)-α-methylalanine (656 mg; 3.23 mmol) were dissolved in dry methylene chloride (6.5 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP-reagent) (1.43 g; 3.23 mmol) was added with stirring in small batches over 10 minutes. The reaction mixture was stirred at room temperature for 2.5 h then quenched by adding saturated brine (25 ml). The two phase system was extracted with methylene chloride (3×25 ml) and the combined methylene chloride extracts dried over magnesium sulfate powder, filtered and evaporated on a rotary evaporator under reduced pressure to give a colorless oil that solidified to an off white solid on standing at room temperature. This solid material was taken up in the minimum volume of methylene chloride and chromatographed on silica gel using an eluant composed of ethyl acetate and hexanes in the ratio 1:3 v/v. The product was isolated after evaporation of the volatiles as a white solid. The yield of the desired product was 1.30 g (88.5%). FAB-MS: -calculated for C26H34N2O5 454.2; found 455.5 (M+1).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[CH2:17][NH:18][CH2:19][CH3:20])[CH3:7].[CH2:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[CH2:32][NH:33][CH2:34][CH3:35])[CH3:22].[N:36]#[C:37][NH2:38]>CC(C)=O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[CH2:17][N:18]([CH2:19][CH3:20])[C:37]([NH2:38])=[NH:36])[CH3:7].[CH2:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[CH2:32][N:33]([CH2:34][CH3:35])[C:37]([NH2:38])=[NH:36])[CH3:22]
Reactant: N#CN
Reactant: CCNCC1Cc2ccccc2N1CC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCN(CC1Cc2ccccc2N1CC)C(=N)N
Temperature: 120 °C

Procedure:
A mixture of 25.3 g of 1-ethyl-2-ethylaminomethylindoline hemisulphate and 25 g of cyanamide is heated at 120° C. for 20 minutes. After cooling, acetone is added and the mixture is filtered. The crystals are taken up in icecold sodium bicarbonate solution and the aqueous phase is extracted with chloroform. The oily base obtained after drying and evaporating the chloroform phase is dissolved in a little methanol and the pH of the solution is adjusted to 6 with sulphuric acid. The solution is evaporated. The residue is triturated with acetone and 1-ethyl-2-(1-ethyl-guanidinomethyl)-indoline hemisulphate is obtained, m.p. 230° C.
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>O1CCCC1>[CH:27]([NH:30][C:31](=[O:32])[O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH:6]=[CH:7]2)([CH3:29])[CH3:28]
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Reactant: CC(C)N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)NC(C)C)ccc21
Reaction time: 4 h
Yield: 115.6 %

Procedure:
To a solution of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.1 g) in 50 ml of tetrahydrofuran was added potassium carbonate (milled, 1.3 g). Then isopropyl isocyanate (0.67 g) was added and the reaction mixture was stirred for 4 hours. The mixture was filtered and the filtrate was concentrated to yield a solid (3.2 g), which was eluted with 5% methanol/dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield an oil which solidified on standing (2.75 g), m.p. 131°-133° C.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(O)=O.C([O:29][C:30]([C@@H:32]1[CH2:37][C@@H:36]2[C@@H:34]([CH2:35]2)[N:33]1[C:38](=[O:52])[CH2:39][N:40]1[C:44]2=[N:45][CH:46]=[CH:47][CH:48]=[C:43]2[C:42]([C:49](=[O:51])[CH3:50])=[N:41]1)=[O:31])C=C>CN(C=O)C.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[C:49]([C:42]1[C:43]2[C:44](=[N:45][CH:46]=[CH:47][CH:48]=2)[N:40]([CH2:39][C:38]([N:33]2[C@H:32]([C:30]([OH:31])=[O:29])[CH2:37][C@@H:36]3[C@H:34]2[CH2:35]3)=[O:52])[N:41]=1)(=[O:51])[CH3:50]
Reactant: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(C)=O)c2cccnc21
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)O)c2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Allyl palladium chloride dimer (0.084 g, 0.231 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (0.288 g, 0.923 mmol) were dissolved in DMF (7.69 mL) under argon atmosphere. The reaction mixture was stirred at RT for 10 min. After cooling the reaction mixture to 10° C., formic acid (0.513 mL, 13.38 mmol) was added followed by TEA (1.865 mL, 13.38 mmol) and a solution of (1R,3S,5R)-2-[2-(3-acetyl-pyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid allyl ester (1 g, 2.3 mmol) in DMF (15.38 mL). The reaction mixture was stirred at 10° C. during 1 h. DMF was evaporated. The residue was poured into NH4Cl (saturated aqueous solution) and extracted with EtOAc (3×50 mL). The organic phases were combined, dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and filtered over a PL-Thiol cartridge. The filtrate was concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA) and the pure fractions were combined and lyophilized. White solid. MS (LCMS): 328.9 [M+H]+, 351.0 [MH+Na]; tR (HPLC conditions I): 1.84 min. 1H NMR (400 MHz, DMSO-d6): (ppm) 8.66 (dd, J=4.52, 1.59 Hz, 1H), 8.58 (m, J=6.36 Hz, 1H), 7.35-7.50 (m, 1H), 8.54-8.61 (m, 1H), 5.88 (d, J=16.87 Hz, 1H), 5.55 (d, J=17.12 Hz, 1H), 4.14-4.24 (m, 1H), 3.75-3.83 (m, 1H), 2.64 (s, 3H), 2.26-2.36 (m, 1H), 2.10-2.23 (m, 1H), 1.80-1.95 (m, 1H), 0.95-1.07 (m, 1H), 0.67-0.81 (m, 1H).
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[CH3:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[OH:26].[OH-].[Na+]>C(#N)C.O.[Cl-].[Na+].O>[CH2:11]([O:10][C:8]([N:3]1[CH2:4][CH2:5][C@@H:6]([O:26][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=2[CH3:18])[C@H:1]([OH:7])[CH2:2]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Reactant: Cc1cccc(O)c1C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (21.0 g, 92.0 mmol) was added to a stirred solution of 2,3-dimethylphenol (23.0 g, 188 mmol) and aqueous sodium hydroxide (100 ml, 2N, 200 mmol) in acetonitrile (400 ml). The reaction mixture was heated at reflux for 14 h. On cooling to room temperature, the reaction mixture was concentrated in vacuo before dilution with water (500 ml). Extraction with dichloromethane (4×100 ml) was followed by washing of the combined organics with aqueous sodium hydroxide (100 ml, 3N, 300 mmol), water (100 ml) and brine (100 ml). The organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish a crude product. Purification was carried out by silica gel chromatography using a gradient eluent system of iso-hexanes and ethyl acetate (100% iso-hexanes to 80:20 iso-hexanes:ethyl acetate) to furnish trans-benzyl-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate as a pale yellow syrup (16.8 g, 50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1.I[CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[Cs+].[Cs+].CN1C(=O)CCC1>CCOC(C)=O>[CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH2:33][CH2:34][OH:35])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1
Reactant: OCCI
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(O)ccc43)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OCCO)ccc43)cc2s1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
A stirred mixture of 1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (60 mg, 0.14 mmol) from Step 1 of Example 171, 2-iodoethanol (60 mg, 0.35 mmol), Cs2CO3 (137 mg, 0.42 mmol), and NMP (2 mL) was heated at 100° C. for 24 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to afford 2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)ethanol (26 mg, 39%) as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.32 (s, 1H), 7.16-7.19 (m, 2H), 6.91 (m, 1H), 5.36 (s, 2H), 4.13 (t, J=9.0 Hz, 2H), 3.98 (t, J=9.0 Hz, 2H), 3.65 (m, 1H), 3.08 (m, 1H), 2.80 (m, 1H), 2.14 (m, 1H), 1.84-1.92 (m, 2H), 1.78 (s, 3H), 1.63 (s, 3H), 1.28-1.40 (m, 4H); LCMS (ESI) m/z 479 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](OCC)=[O:11])[N:9]=1)[CH3:3].[BH4-].[Na+].C(O)(C)C.[ClH:21]>O>[ClH:21].[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[CH3:1]
Reactant: CCOC(=O)c1csc(CN(C)C)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CN(C)Cc1nc(CO)cs1

Procedure:
Alternatively, a mixture of 2.14 g of ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate and 0.38 g of sodium borohydride in 20 ml. of isopropanol was heated with stirring at reflux temperature for about 14 hours. The reaction mixture was cooled, and 2 ml. of water were added carefully followed by 4 ml. of 5N aqueous hydrochloric acid. The volatile constituents were removed by evaporation. Methanol (10 ml.) was added and the mixture heated to refluxing temperature for about one hour. Methanol was removed by evaporation and the residual solids digested in 10 ml. of isopropanol on the steam bath. The isopropanol solution was separated by decantation and the solids reextracted with 10 ml. of isopropanol. The isopropanol solutions and extracts were combined and the combined solution filtered while hot to remove insoluble material. The filtrate was chilled and a crystalline solid appeared which separated and was recovered by filtration. Recrystallization of the filter cake from isopropanol gave 1.73 g of 2-dimethylaminomethyl-4-thiazolemethanol hydrochloride melting at 153°-154° C.
Reaction SMILES: [CH3:1][C:2]([O-])(C)C.[K+].[Br:7][C:8]1[S:12][CH:11]=[C:10]([C:13](=O)[CH3:14])[CH:9]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[Br:7][C:8]1[S:12][CH:11]=[C:10]([C:13]([CH3:14])=[CH:1][CH3:2])[CH:9]=1
Reactant: CC(=O)c1csc(Br)c1
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=C(C)c1csc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of ethyl-triphenyl-phosphonium bromide (27.0 mmol, 10.02 g) in anhydrous THF (90 mL) was added at 0° C. a solution of KOtBu (27.0 mmol, 27 mL, 1 M in THF). The solution was stirred for 1 h at room temperature, cooled down to −78° C. and treated with a solution of 1-(5-bromo-thiophen-3-yl)-ethanone (19.1 mmol, 3.92 g) in anhydrous THF (30 mL) at the temperature. The reaction mixture was slowly warmed to room temperature overnight with stirring. After dilution of the reaction mixture with EtOAc (200 mL), it was washed with water (70 mL×2) and brine (70 mL), dried (MgSO4) and concentrated in vacuo. Chromatography on SiO2 (Hexanes/EtOAc, 20/1) gave 4.15 g (100%) of 2-bromo-4-(1-methyl-propenyl)-thiophene as a liquid of isomeric mixture (Z/E isomer, 9/1). Z isomer; 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J=1.7 Hz, 1H), 6.98 (d, J=1.7 Hz, 1H), 5.55 (m, 1H), 1.97 (quint, J=1.5 Hz, 3H), 1.72 (dq, J=7.0, 1.5 Hz, 3H). E isomer; 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=1.7 Hz, 1H), 6.94 (d, J=1.7 Hz, 1H), 5.90 (m, 1H), 1.94 (quint, J=1.1 Hz, 3H), 1.77 (d, J=6.9, 1.0 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[Na+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:15]#[N:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CCN(Cc2ccccc2)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1CCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
16.8 g (0.08 mole) (3RS)-1-benzyl-3-chloromethyl pyrrolidine and 5.88 g (0.12 mole) of sodium cyanide was dissolved in 250 ml dimethyl sulfoxide. The mixture was stirred at 60° C. for two days and at room temperature for one week. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to yield 14.7 g (92%) of the product.