Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]1=3)[CH2:30][CH2:29][O:28]4)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:33]1[CH:38]=[C:37]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]2=4)[CH2:30][CH2:29][O:28]5)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)[CH:36]=[N:35][CH:34]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: OB(O)c1cncnc1
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: COCCOC
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(-c3cncnc3)c2C12COc1cc3c(cc12)CCO3
Yield: 28.3 %

Procedure:
A mixture of 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.11 g, 0.21 mmol), pyrimidine-5-boronic acid (0.04 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol), 2.00 M sodium carbonate (1.00 mL) and 1,2-dimethoxyethane (10.0 mL) was heated at reflux for 16 h under nitrogen. After the organic solvent was evaporated in vacuo, the black residue was extracted with ethyl acetate (3×35.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluting with ethyl acetate:hexane (35%) to afford the title compound (0.03 g, 26%): mp 263-266° C.; 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.14 (s, 2H), 7.39 (t, 1H), 7.10, (d, 1H), 6.87 (d, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 6.46 (s, 1H), 6.07 (s, 1H), 5.03 (ABq, 2H), 4.62-4.48 (m, 2H), 4.58 (ABq, 2H), 3.01 (t, 2H); 13C NMR (75 MHz, CDCl3) δ 177.3, 162.5, 161.0, 157.4, 155.9, 151.6, 142.2, 141.7, 132.8, 132.3, 131.3, 129.3, 125.7, 120.6, 120.2, 118.3, 117.0, 112.7, 109.7, 109.4, 93.5, 78.9, 72.5, 57.7, 37.1, 28.9; MS (ES+) m/z 506.5 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:27][C:26]1[C:21]([NH:20][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1cccnc1N
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cccnc1NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The benzyl 4-{[(3-methyl-2-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate was prepared as described in EXAMPLE 1, except that 1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid (5.00 g, 18.99 mmol), 2-amino-3-methylpyridine (2.16 g, 19.94 mmol), EDC (4.37 g, 22.79 mmol), and HOAt (2.71 g, 19.94 mmol) and DMF (3 mL) were used as starting materials. Benzyl 4-{[(3-methyl-2-pyridinyl)amino]carbonyl}-1-piperidine was isolated as an off-white solid and used without further purification.
Reaction SMILES: [H-].[Na+].C(S)C.[H][H].C[O:9][C:10]1[C:11](OC)=[CH:12][C:13]2[S:19](=O)[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:21]=1>CN(C)C=O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[S:19][CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:21]=1
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)S(=O)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)C=CC=CS2

Procedure:
Sodium hydride (8.8 g of a 50% w/w dispersion in oil) was added over 30 minutes to a solution of ethanethiol (20.8 g) in dry dimethylformamide at 0°. After evolution of hydrogen had ceased additional ethanethiol (8.8 ml) was added followed by 7,8-dimethoxy-2,3,4,5-tetrahydro-1-benzothiepin-1-oxide. The mixture was heated at reflux for 3 hours, cooled and the solvent was removed in vacuo. The residue was taken up in water (100 ml) and extracted with diethyl ether (2×100 ml). The aqueous solution was acidified with conc. hydrochloric acid, saturated with solid sodium chloride and extracted with chloroform (2×100 ml). The organic extract was dried (Na2SO4) and the solvent was removed in vacuo to give a cream coloured solid. This material was chromatographed on a silica gel column eluting with methylene chloride/methanol mixtures (gradient 0 to 3% v/v methanol) to give the 7-hydroxybenzothiepin (20.7 g), m.p. 165°-166°. Further elution of the column gave, after recrystallisation from methanol, the isomeric 8-hydroxybenzothiepin (2.25 g), m.p. 173°-175°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C=O)C.C(OCC)(=O)C>[CH:19]1([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
4-Nitrophenol (2.0 g, 14.4 mmol) was dissolved in DMF (50 mL) and potassium carbonate (6.0 g, 43 mmol) and bromomethylcyclopropane (1.51 mL, 16 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with a saturated aqueous solution of sodium chloride (2×50 mL). Drying (MgSO4) and concentration afforded 2.23 g (75%) of 1-cyclopropylmethoxy-4-nitrobenzene as an oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]([OH:19])[CH2:12]2.[NH2:20][C:21]1[CH:28]=[C:27](F)[C:24]([C:25]#[N:26])=[CH:23][N:22]=1>C1COCC1>[NH2:20][C:21]1[CH:28]=[C:27]([O:19][CH:13]2[CH:14]3[CH2:17][CH2:18][N:11]([CH2:16][CH2:15]3)[CH2:12]2)[C:24]([C:25]#[N:26])=[CH:23][N:22]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: OC1CN2CCC1CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cnc(N)cc1OC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of KHMDS in THF (1 M, 6.6 ml, 6.60 mmol) was added drop wise to a solution of racemic quinuclidin-3-ol (928 mg, 7.29 mmol) in THF (2 ml) at room temperature. After 55 min a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 500 mg, 3.65 mmol) in THF (2 ml) was added and the reaction mixture stirred for 3 days at room temperature. The reaction mixture was partitioned between saturated aqueous NH4Cl and DCM, extracted with DCM (8×), the combined DCM layers were dried over Na2SO4 and evaporated. The residue was preabsorbed onto silica gel and purified by normal phase chromatography with a 12 g RediSep® silica column, eluting with a gradient from DCM to 20% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as a beige solid. (UPLC-MS 6) tR 0.32; ESI-MS 245.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.ClCC(OC(=O)CCl)=O.[CH2:19]([N:21](CC)CC)[CH3:20].O>C1C=CC=CC=1>[NH2:21][CH2:19][CH2:20][NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: CCN(CC)CC
Agent: O=C(CCl)OC(=O)CCl
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C)nc(NCCN)c1
Reaction time: 3 h

Procedure:
2-amino-4,6-dimethylpyridine(1.69 g), chloroacetic anhydride(3.54 g), and triethylamine(3.83 ml) were stirred in benzene(30 ml) for 1 hour while being cooled with ice. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. To the solution of the residue in dimethylformamide(23 ml) was added potassium phthalimide(2.82 g) and then the mixture was refluxed with stirring for 3 hours. After a large amount of water was added thereto, the depositing crystals were collected by filtration. The solution of the crystals in ethanol(50 ml), with hydrazine monohydrate(1.34 ml) added thereto, was refluxed with stirring for 3 hours and then concentrated under a vacuum. The residue, with water added thereto, was acidified with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then was concentrated under a vacuum. The solution of the residue in tetrahydrofuran(45ml) was dropped into the suspension of lithium aluminium hydride(0.64 g) in tetrahydrofuran(45 ml) while being cooled with ice and the mixture was stirred at room temperature for 1 hour. A small amount of water was added thereto and then the resulting deposit was filtrated out. The filtrate was concentrated under a vacuum, thereby yielding 1.90 g of the aimed compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH2:8][O:9][C:19](=[O:21])[CH3:20])=[N:6][CH:7]=1
Reactant: COc1cc(Br)cnc1CO
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Br)cnc1COC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (5-bromo-3-methoxy-pyridin-2-yl)-methanol (Stage 194.1.3, 2.79 mmol) and triethylamine (4.18 mmol) in dichloromethane was added slowly acetyl chloride (3.35 mmol) and the RM was stirred for 1 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 60%). The fractions containing product were evaporated together to give the title compound as a white solid. (HPLC: tR 2.72 min (Method A); M+H=260, 262 MS-ES)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Hg](C#N)C#N.[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@@H:21]1Br)(=[O:18])[CH3:17]>>[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@H:21]1[S:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: O=[N+]([O-])c1cccc(S)c1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2cccc([N+](=O)[O-])c2)SC[C@H]1OC(C)=O
Yield: 26.9 %

Procedure:
If the procedure described in Preparation I is followed starting from 10 g (64.5.10-3 mol) of 3-nitrobenzenethiol, 16.29 g (64.5.10-3 mol) of mercuric cyanide (Hg(CN)2) and 25.2 g (70.9.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 7.44 g (yield: 27%) of the expected product are obtained after purification by flash chromatography using a toluene/ethyl acetate mixture (9/1 v/v) as the eluent, followed by crystallization from ether.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[N:7]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([NH:36][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([NH:11][C:12]5[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=5)[C:6]=4[N:7]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1
Reactant: COc1cc(Nc2csc3cnc(Cl)nc23)cc(OC)c1OC
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: COc1cc(Nc2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc(OC)c1OC
Yield: 74.5 %

Procedure:
N2-(6-Morpholinopyridin-3-yl)-N7-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2,7-diamine (21 mg, 74% yield) was prepared in the same manner as Step 10 of Example 1 using 2-chloro-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-7-amine (20 mg, 0.057 mmol) and 6-morpholinopyridin-3-amine (12 mg, 0.068 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH3:12])([CH3:11])[CH2:6][C:5]2([CH3:14])[CH3:13].C([Li])(C)(C)C.[N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O1CCCC1>[CH3:11][C:7]1([CH3:12])[C:8]2[C:4](=[CH:3][C:2]([N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:10][CH:9]=2)[C:5]([CH3:14])([CH3:13])[CH2:6]1
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 59.3 %

Procedure:
5-Bromo-1,1,3,3-tetramethyl-indan 19b (1.4 g, 5.53 mmol) was dissolved in 10 mL of tetrahydrofuran and cooled to −78° C. in a dry ice-acetone bath. t-Butyllithium (4.4 mL, 11.1 mmol) was added dropwise at the same temperature and the mixture was stirred for 40 minutes. A solution of di-tert-butyl azodicarboxylate (1.59 g, 6.92 mmol) in 10 mL of tetrahydrofuran was added dropwise by a constant-pressure addition funnel. The reaction mixture was stirred at −78° C. for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction was quenched with 5 mL of methanol and was warmed up to room temperature. The mixture was extracted with ethyl acetate (20 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(1,1,3,3-tetramethyl-2,3-dihydro-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 19c (1.326 g, yield 59.3%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:6](N)[CH:5]=1.N([O-])=O.[Na+].[BrH:23]>O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:6]([Br:23])[CH:5]=1
Reactant: Br
Reactant: COC(=O)c1ccc(OC2CC(F)(F)C2)c(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(OC2CC(F)(F)C2)c(Br)c1
Reaction time: 0.25 h

Procedure:
1.0 g of 3-Amino-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl ester was dissolved in 100 ml of half-concentrated aqueous HBr-solution. Then, a solution of 295 mg NaNO2 in 5 ml of water was added dropwise at 0° C. Stirring was continued at 0° C. for 15 minutes. Then, a solution of 558 mg CuBr in 10 ml of half-concentrated aqueous HBr-solution was added dropwise and the reaction mixture was stirred for 2 h at room temperature. Then, the reaction mixture was extracted three times using 100 ml of EA each. The organic layer was then washed three times using 100 ml of a saturated aqueous NaHCO3-solution, dried using MgSO4 and volatiles were evaporated to yield 150 mg of the title compound that was used without further purification.
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:20])([F:19])[C:8]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[O:31][N:30]=1>O>[F:20][C:7]([F:19])([F:6])[C:8]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[O:31][N:30]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 90 °C

Procedure:
A DMF solution (25 mL) of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (2.66 mmol max) was treated with Cs2CO3 (1.73 g, 5.32 mmol) followed by 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.699 g, 2.66 mmol). The resulting suspension was heated to 90° C. for 30 min. The cooled reaction mixture was diluted with H2O (25 mL) and then extracted with EtOAc (3×25 mL). The pooled organic portions were washed with H2O and brine. Drying (Na2SO4) and filtration were followed by concentration. Column chromatography (SiO2, EtOAc/hexanes) afforded the title compound in excellent purity as a pale yellow solid (900 g, 75% over two stages): 1H NMR (DMSO-d6) δ 8.32 (d, J=6.0 Hz, 1H), 8.25 (bs, 1H), 8.11-8.06 (m, 2H), 7.98 (d, J=3.0 Hz, 1H), 8.86-8.81 (m, 2H), 6.82-6.81 (m, 1H), 5.95 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:28].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CF
Temperature: 80 °C
Reaction time: 19 h

Procedure:
91.1 To a stirred solution of 150 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (example 17.2) at r.t. in 3.3 ml DMF under an argon atmosphere was added 1.71 ml tetrabutylammonium fluoride solution (1 M in THF). The mixture was heated to 80° C. and stirring at that temperature was continued for 19 h. The mixture was cooled to r.t., diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; cyclohexane->cyclohexane/EtOAc 1:1) to give 44 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-fluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as off-white amorphous solid. MS 361.0 ([M−H]−)
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[CH2:13]([O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16]([C:18]1([NH:27][C:10]([C:5]2[C:4]3[CH:3]=[CH:2][NH:1][C:9]=3[CH:8]=[CH:7][CH:6]=2)=[O:12])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3[nH]ccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a solution of 1H-indole-4-carboxylic acid (250 mg, 1.55 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-60% EtOAc in heptane) to give a pure product (55) as white solid (278 mg, 52%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:14]1([NH:20][C:21](=[S:22])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC(N)=O
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)CNC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
A mixture of glycinamide hydrochloride (8.25 g), triethyl amine (10.0 g), phenyl-isothiocyanate (10.1 g), and methylene chloride (300 mL) was heated at reflux for 1 hour. The mixture was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with methylene chloride, then with diethyl ether and air dried to give 2-(3-phenyl-thioureido)-acetamide (9.7 g), m.p. 150°-152° C. Anal. Calcd. for. C9H11N3O S: C, 51.66; H, 5.30; N, 20.08. Found: C, 51.41; H, 5.04; N, 20.02. Mass spectrum (EI, M.+) m/z 209. 1H-NMR (DMSO-d6; 400 MHz) δ9.88 (s, 1 H), 7.70 (t, 1 H), 7.52 (s, 1 H), 7.47 (d, 2 H), 7.31 (t, 2 H), 7.15 (s, 1 H), 7.09 (t, 1 H), and 4.08 ppm (d, 2 H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][N:14]=1>C1COCC1>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[CH2:8][O:18]2)=[CH:15][N:14]=1
Reactant: C[S+](C)C
Reactant: Cc1ccc(C=O)cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc(C2CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 137.9 %

Procedure:
DMSO (4 mL) was added to NaH 60% dispersion in oil (0.314 g, 7.8 mmol, 1.3 eq.) and heated it to 65° C. for 1 h. THF (10 mL) was added at the same temperature and heated for another min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1.2 g, 5.9 mmol, 1 eq.) was added and stirred for 10 min and solution of 6-methylnicotinaldehyde (0.720 g, 5.9 mmol, 1 eqv) in THF was added dropwise. After complete of addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get product 2-methyl-5-(oxiran-2-yl)pyridine (1.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]1([Mg]Cl)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:19]([C:9]2[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[OH:20])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C3CCCCC3)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Cyclohexylmagnesium chloride (2.0 M, 0.21 mL, 0.41 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by reverse-phase HPLC to give cyclohexyl(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 0.2 mL concentrated HCl and heated to 65° C. for 2 hours and concentrated afford the desired product as a white powder.