Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)#[N:2].[NH2-].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21]Cl>>[Cl:18][CH2:19][CH2:20][CH2:21][C:3]1([C:1]#[N:2])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: ClCCCCl
Reactant: N#CC1c2ccccc2-c2ccccc21
Agent: [NH2-]
Agent: [Na+]
Product: N#CC1(CCCCl)c2ccccc2-c2ccccc21

Procedure:
9-cyanofluorene was reacted with sodium amide and 1,3-dichloropropane to give 9-(3-chloropropyl)-9-cyanofluorene. A solution of 10.0 g. of 9-(3-chloropropyl)-9-cyanofluorene in 200 ml. of morpholine containing 2.0 g. of potassium iodide was stirred at 160° C. for sixteen hours. After cooling the reaction mixture to room temperature, the solution was diluted with 500 ml. of water, and the aqueous mixture was extracted several times with ethylacetate. The organic extracts were combined, washed with water, and the product was extracted therefrom into 0.6N hydrochloric acid. The aqueous acid layer was separated and made alkaline by the addition of 10 percent sodium hydroxide solution. The alkaline solution was extracted with fresh ethyl acetate, and the extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure provided 9-(3-morpholinopropyl)-9-cyanofluorene.
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[CH:18][C:13]3=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[N:5]1)([CH3:3])[CH3:2].[N+:24]([O-])([OH:26])=[O:25].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[C:13]3=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc2ccsc2nc1C1=NC(C)(C(C)C)C(=O)N1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc2c([N+](=O)[O-])csc2nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 3 °C
Reaction time: 3 h

Procedure:
Methyl 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)thieno[2,3-b]pyridine-5-carboxylate (3.94 g, 0.0119 mol) is dissolved in 200 mL concentrated H2SO4 at room temperature. While cooling to 3° C. in an ice bath, 1.5 mL (0.024 mol) concentrated HNO3 is added, then the mixture is allowed to warm to room temperature. After three hours, the reaction mixture is poured onto ice, neutralized with solid NaHCO3 to pH 6 and is extracted with methylene chloride. The extract is filtered, then dried over sodium sulfate, refiltered and concentrated to a yield solid weighing 4.33 g (97%), which upon crystallization from methanol water has mp 201°-202.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[Li+].[Br-:13]>>[Br:13][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cn1ncc([N+](=O)[O-])c1CCl
Reactant: [Br-]
Agent: [Li+]
Product: Cn1ncc([N+](=O)[O-])c1CBr
Yield: 70 %

Procedure:
Reaction of 5-(chloromethyl)-1-methyl-4-nitro-1H-pyrazole (80 mg, 0.54 mmol) with LiBr according to general procedure B gave 5-(bromomethyl)-1-methyl-4-nitro-1H-pyrazole (70 mg, 70%) as a white crystalline solid, m.p. 71-73° C. 1H NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 4.82 (s, 2H), 3.95 (s, 3H). Analysis found: C, 27.76; H, 3.08; N, 18.99. C5H6BrN3O2.0.02hexane requires: C, 27.73; H, 2.86; N, 18.95. HRMS (FAB+) found: 219.97223, 221.97012 (M+1), calcd. for C5H279/81BrN3O2: 219.97216, 221.97012.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[O:39](S(C(F)(F)F)(=O)=O)[S:40]([C:43]([F:46])([F:45])[F:44])(=O)=[O:41]>C(Cl)Cl.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][NH:30][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:41])=[O:39])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=S(=O)(NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 29.3 %

Procedure:
A solution of 2-[10a-(4-chloro-benzene sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yloxy]-ethylamine (71 mg, 0.168 mmol) in CH2Cl2 (5 mL) at −78° C. was treated with 2,6-lutidine (33 μL, 0.284 mmol), Tf2O (45 μL, 0.948 mmol) and warmed slowly to ambient temperature. After 17 h, the reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative-chromatography over silica gel (eluted in hexanes/EtOAc 1:1) to afford the title compound (29 mg, 30%): 1H NMR (CDCl3 400 MHz) δ 7.61 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.08 (m, 1H), 6.44 (m, 1H), 5.22 (dd, J=11.7, 2.9 Hz, 1H), 4.12 (d, J=11.7 Hz, 1H), 3.57 (m, 3H), 3.01 (m, 1H), 2.56 (m, 1H), 2.33 (m, 1H), 1.91 (m, 2H), 1.56 (m, 1H), 1.15 (m, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOC1
Temperature: 25 °C

Procedure:
To tetrahydro-3-furanmethanol (25 g) in dry DCM (250 mL) at 0° C. under nitrogen was added triethylamine (68 mL) in a single portion. Methanesulphonyl chloride (24.7 mL) was added dropwise over 15 mins. The reaction was warmed to room temperature and was left over a weekend. The mixture was taken up in DCM (50 mL) and washed with saturated sodium bicarbonate solution (100 mL). The organics were dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a brown oil in quantitative yield.
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6]2[C:7](=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=2[CH3:12])[N:8]=1)[CH3:2].[H-].[Na+].[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)#[N:20].O>CN(C=O)C>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][N:8]2[C:7]3=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]([CH3:12])=[C:6]3[N:5]=[C:4]2[S:3][CH2:1][CH3:2])=[CH:31][CH:32]=1)#[N:20]
Reactant: CCSc1nc2c(C(=O)OC)sc(C)c2[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2c(C)sc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (5.7 g) in DMF (30 ml) was added sodium hydride (60% oil, 0.98 g) under ice-cooling. After stirring the reaction mixture for 20 minutes, to the mixture was added dropwise a solution of (2'-cyanobiphenyl-4-yl)methyl bromide (7.25 g) in DMF (20 ml), followed by stirring for one hour at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried, then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate - hexane afforded pale yellow prisms (7.6 g, 77%), m.p. 149°-151° C.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]([O:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:16]1[CH:12]([O:11][CH:7]([CH2:8][CH2:9][CH3:10])[CH3:6])[CH2:13][CH2:14][C:15]1=[O:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(C)OC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(C)OC1CCC(=O)N1C(=O)c1ccccc1
Yield: 65.3 %

Procedure:
12.4 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3.2 g of 5-(2-pentyloxy) pyrrolidin-2-one in 130 cm3 of tetrahydrofuran. The mixture is maintained at this temperature for 20 minutes, then a solution of 2.62 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. The solution is returned to ambient temperature, concentrated and chromatographed on silica (eluent: hexane-ethyl acetate 7-3). 3.35 g of expected product is obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:31])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[C:28](O)=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:37][C@@H:34]1[CH2:35][CH2:36][N:32]([C:28]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:11]4[CH:12]=[C:7]([CH:8]=[CH:9][C:10]=4[CH3:31])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:6])[CH:14]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=2)=[O:29])[CH2:33]1
Reactant: N[C@@H]1CCNC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C(=O)N3CC[C@@H](N)C3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the product of step v) (100 mg), (R)-pyrrolidin-3-amine (20 mg) and N,N-diisopropylethylamine (0.13 mL) in DMF (2 mL) was added HATU (140 mg) and the reaction stirred at room temperature for 10 minutes. The reaction mixture was filtered and purified by HPLC to yield the title compound as a solid (65 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([OH:20])[C@H:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C@:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:26]#[C:25][C@:27]2([OH:35])[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([OH:20])[C@H:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CC(C)O[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)O[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@@H]1O
Temperature: 75 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
A mixture of 464 mg of 2-benzyl-6-(cis-3-isopropyloxy-4-hydroxypyrrolidine-1-yl)-3-iodopyridine, 176 mg of (3R)-3-ethynyl-3-quinuclidinol, 122 mg of tetrakis(triphenylphosphine)palladium (0), 10 mg of cuprous iodide, 0.44 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 168 mg of the target compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[O:32][CH3:33])[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:47]([CH3:49])[CH3:48]>CN(C)C=O.C(OCC)(=O)C>[CH:47]([N:37]1[CH2:36][CH2:35][CH:34]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[O:32][CH3:33])[CH2:14][CH2:13]2)=[O:11])[CH2:39][CH2:38]1)([CH3:49])[CH3:48]
Reactant: CC(C)I
Reactant: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCN(C(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g of 4-(1-(4-Fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine hydrochloride obtained in Example 11(5) was dissolved in 2 ml of dimethylformamide, and 93 mg of potassium carbonate and 41 μl of 2-iodopropane were added, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=4:1) to give 0.15 g of 1-isopropyl-4-(1-(4-fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine as an oil.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH:26][CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:29]1)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:53]([O:56][C@@H:57]([CH3:61])[C:58](Cl)=[O:59])(=[O:55])[CH3:54]>ClCCl>[C:53]([O:56][C@@H:57]([CH3:61])[C:58]([N:26]([CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[CH2:29]1)[C@@H:21]([C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[S:12][C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:59])(=[O:55])[CH3:54]
Reactant: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
to a solution of (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (130 mg, 0.214 mmol) in dichloromethane (2.1 mL, 0.1 M solution) at room temperature was added N,N-diisopropylethylamine (112 μL, 0.64 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (54.2 μL, 0.428 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude product was purified on flash column chromatography to yield (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (115 mg, 75%). NMR (CDCl3, 400 MHz): δ 7.85 (1H, m), 7.37-7.24 (7H, m), 7.21 (1H, m), 7.09 (2H, m), 7.05 (1H, m), 6.96 (1H, m), 6.1 (1H, m), 5.4 (2H, m), 5.28 (1H, m), 4.82 (2H, m), 4.19-3.97 (3H, m), 3.70-3.49 (2H, m), 3.13 (1H, m), 2.76 (1H, m), 2.52 (1H, m), 2.18 (3H, s), 1.61 (3H, m), 0.99 (9H, s). LC/MS (uplc): MH+ 722.3, 1.40 min.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][NH:6][CH2:5][CH:4]1[OH:8].[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[N:14][CH:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(=O)(O)[O-].[Na+]>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([N:6]2[CH2:7][C@@H:3]([NH:2][CH3:1])[C@H:4]([OH:8])[CH2:5]2)=[N:14][CH:15]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CNC1CNCC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN[C@@H]1CN(c2ccc(Br)cn2)C[C@H]1O
Yield: 39.3 %

Procedure:
Dissolve 4-methylamino-pyrrolidin-3-ol (430 mg, 3.29 mmol) in acetonitrile (10 mL) and add 5-bromo-2-fluoro-pyridine (868 mg, 4.93 mmol) and diisopropylethylamine (0.688 mL, 3.95 mmol). Reflux the mixture for 3 days. Dilute the mixture with saturated sodium bicarbonate and extract with dichloromethane (3×). Combine the organic fractions, dry over sodium sulfate, filter, and evaporate. Purify by silica gel chromatography, eluting with 0-7.5% methanol in dichloromethane with 2N ammonia to give 352 mg (37%) of the title compound as a yellow foam. MS/ES m/z (79Br) 272.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][C:4]([N:6]([C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16]1)C1C=CC=C(OC)C=1)=[O:5].[CH:26]1[C:31]([CH:32]=O)=[CH:30][C:29]2[O:34][CH2:35][O:36][C:28]=2[CH:27]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.ClCCCl>[O:36]1[C:28]2[CH:27]=[CH:26][C:31]([CH2:32][N:18]3[CH2:19][C@H:15]([N:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:25])[CH3:24])[CH2:32][C:31]4[CH:26]=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[CH2:16][C@H:17]3[C:20]([O:22][CH3:23])=[O:21])=[CH:30][C:29]=2[O:34][CH2:35]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@@H]1C[C@@H](N(C(=O)CC(C)(C)C)c2cccc(OC)c2)CN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of the crude amine (9b) (140 mg) prepared above, piperonal (74 mg, 0.49 rmnol) and glacial acetic acid (2 drops) in 1,2-dichloroethane (0.5 mL) was stirred for 30 min at room temperature. 95% Sodium cyanoborohydride (32 mg, 0.48 mmol) was added in small portions and stirring was continued for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution (2 mL), extracted with dichloromethane, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane-ethyl acetate (90:10-75:25) to give the title pyrrole (10) (115 mg, 71.4%) as a pale yellow oil:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([CH3:12])[N:6]2[CH3:11].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:12][C:5]1[N:6]([CH3:11])[C:7]2[C:3]([C:4]=1[C:13]([O:15][CH3:16])=[O:14])=[C:2]([Cl:1])[CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)c1c(C)n(C)c2cccc(Cl)c12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)n(C)c2cccc(Cl)c12
Temperature: 85 °C
Yield: 48 %

Procedure:
Methyl 4-chloro-1,2-dimethyl-1H-indole-3-carboxylate (9.70 mmol, 1.0 equiv.) was dissolved in CCl4 (97 ml), and NBS (9.70 mmol, 1.0 equiv.) and benzoyl peroxide (0.19 mmol, 0.02 equiv.) were added. The mixture was heated for 1 h at 85° C. The resulting succinimide was filtered out, the filtrate was concentrated, and the residue was purified by column chromatography (20% ethyl acetate in hexane). Yield: 48%
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39](F)[CH:38]=1)[CH3:35].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH3:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([O:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([N:10]([C:11]([CH:13]3[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]3)=[O:12])[C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:30])([CH3:31])[CH3:32])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[CH2:21][CH2:22]2)[CH:38]=1)[CH3:35]
Reactant: CN(C)Cc1ccnc(F)c1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)[C@H]1CC[C@H](O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)[C@H]2CC[C@H](Oc3cc(CN(C)C)ccn3)CC2)CC1
Temperature: 90 °C

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-hydroxy-trans-cyclohexyl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (40 mg, 0.088 mmol) and (N,N-dimethyl)-(2-fluoro-pyridin-4-ylmethyl)amine (84 mg, 0.55 mmol) in DMF (1 mL) were treated with sodium hydride (22 mg, 60% oil dispersion, 0.55 mmol). After the bubbling slowed, the reaction mixture was sealed and heated by microwave (90° C.) for 70 min. The reaction mixture was treated with 10% citric acid (2-3 mL) followed by water (2-3 mL). The organics were extracted twice with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give the Compound 337, 18 mg (35% yield): MS (m/z): 578.0 [M+H]+; HPLC retention time 3.53 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N:15]=[C:16]=[S:17])[NH:8][CH:7]=1>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][C:16](=[S:17])[NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:6]([Cl:5])=[CH:7][NH:8]2
Reactant: S=C=Nc1cccc2[nH]cc(Cl)c12
Reactant: NCCN
Solvent: ClCCl
Product: NCCNC(=S)Nc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
Ethylenediamine (0.711 mL, 10.6 mmol) is added to a solution of 3-chloro-4-isothiocyanatoindole (0.370 g, 1.77 mmol) in methylene chloride (15 mL). The resulting solution is stirred at room temperature for 1 hour. The reaction mixture is concentrated by rotary evaporation and the crude material purified via silica gel column chromatography using 7% methanol (ammonium hydroxide treated)/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.484 g of 4-[N'-(2-aminoethyl)thioureido]-3-chloroindole as a white solid (90% yield).
Reaction SMILES: C1C=NC2N(O)N=NC=2C=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:13]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)CCl>C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][NH:18][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][CH:13]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(O)c1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCCc1ccc(F)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
1.5 g (10.8 mmol) of HOAt were added to a solution of 15.0 g (108.0 mmol) of 4-fluorophenethylamine and 13.2 g (108.0 mmol) of benzoic acid in DCM and the mixture was then cooled to 0° C. 22.8 g (119.0 mmol) of EDC were then added at this temperature and the mixture was then stirred for 16 h at RT. The reaction solution was then washed successively with a 1M aqueous hydrochloric acid (2×300 ml), a 2M aqueous NaOH solution (300 ml) and brine (200 ml). The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 20.5 g (84.2 mmol, 78%) of N-(4-fluorophenethyl)benzamide were obtained as the residue.