Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S1(=O)CCN(CC[NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:48])[CH3:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)CC1.Cl[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]1>>[CH:46]([C@H:43]1[C@@H:12]2[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28][C@@:11]2([NH:10][CH2:51][CH2:52][N:53]2[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]2)[CH2:45][CH2:44]1)[C@@:25]1([CH3:30])[C@@H:16]([C@:17]2([CH3:42])[C@@H:22]([CH2:23][CH2:24]1)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=1)[CH2:19][CH2:18]2)[CH2:15][CH2:14]3)([CH3:48])[CH3:47]
Reactant: CS(=O)(=O)N1CCN(CCCl)CC1
Reactant: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in Example B2 for the synthesis of 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine (prepared as described below) as the alkylating reagent in Step 3. The product was isolated as a white solid (11 mg, 56%). LCMS: m/e 724.6 (M+H)+, 2.44 min (method 10). 1H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.63-3.29 (m, 7H), 3.25-3.14 (m, 1H), 3.13-2.99 (m, 4H), 2.93 (s, 3H), 2.50 (dd, J=13.0, 2.6 Hz, 1H), 2.32-0.98 (m, 26H), 1.25 (s, 3H), 1.12 (s, 3H), 1.08 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 0.83 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]2[CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17]([Br:20])=[C:16]([CH3:18])[N:15]=[C:14]2[CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)c(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1Br

Procedure:
To a stirred suspension of 8-methyl-6-(2,4-dimethylimidazol-1-yl)-2-(1H)-quinolone (0.5 g) in chloroform (10 cm3) was added N-bromosuccinimide (NBS) (0.374 g) at room temperature. After 5 minutes the reaction mixture was evaporated to dryness and the residue chromatographed on silica (Merck "MK 60.0385" [Trade Mark]) eluting with ethyl acetate:methanol, 10:1. Combination and evaporation of the appropriate fractions afforded a solid which on recrystallisation from ethyl acetate/methanol gave 8-methyl-6-(5-bromo-2,4-dimethylimidazol-1-yl)-2-(1H)-quinolone, m.p. 273°, (0.277 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[C:12]([CH:18]2[CH2:20][O:19]2)[C:11]=1[O:21][CH3:22])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(O)C.[CH3:27][CH:28]([NH2:30])[CH3:29].CCN(C(C)C)C(C)C>>[Cl:16][C:14]1[C:13]([CH3:17])=[C:12]([CH:18]([OH:19])[CH2:20][NH:30][CH:28]([CH3:29])[CH3:27])[C:11]([O:21][CH3:22])=[C:10]([CH:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:9])[CH:15]=1
Reactant: CC(C)N
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C(O)CNC(C)C
Temperature: 80 °C
Yield: 4.9 %

Procedure:
tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]carbamate (100 mg, 0.29 mmol, from Example 190, Step 1) was stirred in ethanol (2.0 mL, 34 mmol), 2-propanamine (120 μL, 1.5 mmol) and DIPEA (260 μL, 1.5 mmol) was added. The mixture was stirred at 80° C. over the weekend. Purification by preparative LC/MS (pH 10) gave the desired compound (5.7 mg, 5%). LCMS calculated for C20H34ClN2O4 (M+H)+: m/z=401.2. found: 401.1.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C1C(=O)N([I:30])C(=O)C1.C(O)(C(F)(F)F)=O>C(#N)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:13]=[C:14]([O:20][CH3:21])[C:15]([O:18][CH3:19])=[CH:16][C:17]=3[I:30])=[N:8]2)=[C:4]([NH2:22])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(I)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC

Procedure:
A solution of 2-Fluoro-8-(3,4-dimethoxy-benzyl)adenine (50 mg, 0.165 mmol), NIS (74 mg, 0.33 mmol), TFA (18.8 mg, 12.7 L, 0.165 mmol) in acetonitrile (120 L) was stirred at room temperature for 24 h. Following solvent removal, the product (12 mg, 16.9%) was collected through silica gel column purification (CHCl3:MeOH:AcOH at 80:1:0.5 to 30:1:0.5). MS m/z 430.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:15])[N:7]([CH2:16][C:17]([O:19]C)=[O:18])[C:6]=2[N:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O.C1COCC1>[CH3:1][C:2]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:15])[N:7]([CH2:16][C:17]([OH:19])=[O:18])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1c(=O)c2cccn2c2c(C)ccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc2c1n1cccc1c(=O)n2CC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
Methyl 2-(1-methyl-6-oxopyrido[2,3-e]pyrrolo[1,2-a]pyrazin-5(6H)-yl)acetate (517 mg, 1.91 mmol) was dissolved in 20 mL of MeOH/H2O/THF (1:1:4). LiOH (68.5 mg, 2.86 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solvents were removed and residue was dissolved in water, washed with ether, then neutralized with 2N HCl to pH=3. 356 mg (73%) white solid was obtained after filtration and dried under vacuum. 1H NMR (400 MHz, DMSO) δ 12.90 (s, 1H), 8.27-8.17 (m, 2H), 7.29-7.19 (m, 2H), 6.80 (dd, J=2.9, 3.9 Hz, 1H), 5.02 (s, 2H), 2.85 (s, 3H). 13C NMR (101 MHz, DMSO, APT) δ 169.8, 154.5, 143.1, 141.4, 135.9, 123.9, 123.3, 122.8, 119.5, 113.3, 112.7, 41.6, 22.2. HRMS (m/z): calcd for C13H12N3O3 (M+H) 258.0879. found 258.0894.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C1COCC1.[C:19]([C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1)#[CH:20]>CCN(CC)CC>[C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:9])[CH:24]=[CH:25][CH:26]=1)#[CH:20]
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1ccsc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2sccc2C)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A dry 25 mL flask was charged with 3-methylthiophene-2-carboxylic acid (0.201 g, 1.41 mmol) followed by thionyl chloride (10 mL). The reaction was heated to 50° C. for 2 h after which the reaction was cooled to room temperature and concentrated to afford the crude acid chloride. The crude acid chloride was dissolved into 10 mL of THF and 3-ethynyl-phenylamine (0.165 g, 1.41 mmol) was added to the solution followed by NEt3, and the mixture was allowed to stir at 55° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc and water. The organic layer was then washed once with of 1M HCl (˜10 mL) and then twice with of saturated aqueous NaHCO3 (˜10 mL) The organic extracts were combined, dried over anhydrous Na2SO4(s) and then concentrated to give the title compound as a tan solid (265 mg, 1.10 mmol, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]([CH3:26])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][N:10]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:9]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:37])[C:34]([CH3:36])=[CH2:35].O>C(Cl)Cl.CO>[C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]([CH3:26])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][N:10]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:9]=2)=[CH:4][CH:3]=1)(=[O:37])[C:34]([CH3:36])=[CH2:35]
Reactant: C=C(C)C(=O)Cl
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C=C(C)C(=O)Nc1ccc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
A solution of tert-butyl (2-(((3-(4-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (0.150 g, 0.000338 mol) in DCM (3 mL) was cooled to 0° C. TEA (0.068 g, 0.000677 mol) and methacryloyl chloride (0.042 g, 0.000406 mol) were added and the reaction mixture stirred for 15 mins at 0° C. The reaction was poured into water (25 mL) and extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (30 mL), dried over sodium sulphate and concentrated under vacuum. The residue was purified by SGC using DCM:MeOH (0%-5%) as eluent to obtain tert-butyl (2-(((3-(4-methacrylamidophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (0.080 g, Yield: 45%). ESI-MS: m/z=512.3 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=[O:36])[S:33][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:31]=[C:32]([CH:35]=[O:36])[S:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1cc(-c2csc(C=O)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 10 °C

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (150 mg, 0.4 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (115 mg, 0.48 mmol, 1.2 eq), PdCl2(dppf)-CH2Cl2 adduct (29 mg, 0.04 mmol, 0.09 eq), and potassium carbonate (170 mg, 1.2 mmol, 3 eq) were diluted in dioxane (3 mL) and water (1.5 mL) in a 2-5 mL microwave tube. The mixture was degassed by bubbling argon through for 5 minutes, then the reaction was heated in a microwave oven under regular absorption at 10° C. for 5 minutes. The reaction mixture was filtered through a thiol SPE cartridge, washing well with acetone, and the solvent was removed in vacuo. The crude residue was triturated from diethyl ether to give a pink solid. Minor impurities were present, but this material was suitable for use in the reductive amination step as is (210 mg, 0.52 mmol, 129%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:21][CH2:20][C:19](=O)[CH2:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:21][CH2:20][CH:19]([N:26]3[CH2:27][CH2:28][CH2:29][CH:25]3[CH3:24])[CH2:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCN1
Reactant: O=C1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1CCCN1C1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
[4-((S)-3-Oxo-cyclopentyl)-phenyl]-carbamic acid benzyl ester (618 mg, 2 mmol, 1 equiv.) was dissolved in DCE (20 mL). To this solution was transferred a solution of 2-methylpyrrolidine (212 mg, 2.5 mmol, 1.25 equiv.) in 3 mL of DCE, followed by acetic acid (360 mg, 6 mmol, 3 equiv) in DCE (2 mL), then by addition of powder NaBH(OAc)3 (1.27 g, 6 mmol, 3 equiv.) in one portion under N2 at r.t. The yellowish milky solution was stirred at r.t. 24 h. The reaction was diluted with DCM (20 mL) and quenched with 10 mL of NaHCO3. The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), brine (15 mL), dried (anhydrous potassium carbonate), filtered, and concentrated. The residue, a thick oil, was dissolved in DCM, and purified on a silica gel column to afford 0.61 g (81%) of the title compound.
Reaction SMILES: [F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:20])[CH2:3]1.O.NN>CO.[Ni]>[F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:20])[CH2:3]1
Reactant: CN1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C(F)C1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)C(F)C1
Yield: 99.8 %

Procedure:
A solution of compound 135 (0.09 g, 0.324 mmol) in dry methanol (3 mL) was treated with hydrazine hydrate (0.1 mL, 3.245 mmol) followed by Ra—Ni (˜0.05 g at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 5 min. The reaction was brought to room temperature, filtered through celite bed and washed with methanol (2 10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 136 (0.08 g, quantitative) as a semi-solid. 1H NMR (DMSO-d6) δ 1.78-1.86 (m, 2H), 1.95-2.07 (m, 2H), 2.26 (s, 3H), 2.69-2.78 (m, 2H), 3.11-3.17 (m, 1H), 4.41 (s, 2H), 4.68 (dddd, 1H, J=4.5, 9.9, 9.9, 48.7 Hz), 6.45 (dd, 1H, J=2.1, 8.5 Hz), 6.71 (d, 1H, J=1.5 Hz), 6.93-7.04 (m, 2H), 10.36 (s, 1H); ESI-MS m/z (%): 248 (MH+, 100).
Reaction SMILES: CCCCCC.[H-].[Na+].[CH3:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.CN(C=O)C>[CH3:9][C:10]1[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
Hexane was used to wash 80 mg (2.0 mmol) of 60% NaH/mineral oil and 6 mL of DMF was added followed by 352 mg (2.0 mmol) of 2-methyl-5-nitro-1H-indole. After 0.33 hours, 0.24 mL (2.0 mmol) of benzyl bromide was added, stirred 0.5 hours and diluted with water. The mixture was extracted with EtOAc, the EtOAc washed with a saturated NaCl solution, dried MgSO4) and on concentrating at reduced pressure, crystals formed. These were washed with MeOH to give 400 mg (75% yield) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole, mp, 150°-152° C.
Reaction SMILES: [CH2:1]([C:8]1(O)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH:9]1[NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH:1](=[C:8]1/[CH:9]([NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])[CH2:10][C:11]2[C:16]/1=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC1Cc2ccc(OC)cc2C1(O)Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC1Cc2ccc(OC)cc2/C1=C/c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 1-benzyl-1-hydroxy-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate (184 mg, 0.539 mmol) in toluene (4 ml) was added methanesulfonic acid (3.50 μl, 0.054 mmol) and stirred at room temperature over night. The solution was evaporated, re-dissolved in dichloromethane, washed with sodium bicarbonate and brine, dried over sodium bicarbonate and evaporated to dryness to obtain the desired (Z)-ethyl 1-benzylidene-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate as a pale yellow oil. m=154 mg (88%)
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:11][C:12]#[C:13][C@H:14]([OH:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[OH-].[Na+]>CCOCC.O>[Br:11]/[CH:12]=[CH:13]/[C@H:14]([OH:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1
Reactant: O[C@@H](C#CBr)COc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: O[C@@H](/C=C/Br)COc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
AlCl3 (2.79 g, 21 mmol) was added in portions to a mixture of lithium aluminum hydride (LAH) (1.06 g, 28 mmol) and ether (70 mL). A solution of (3S)-l-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (14 mmol) in ether (10 mL) was added cautiously. A vigorous reaction with evolution of gas was observed. The mixture was warmed to reflux on a water bath for 30 minutes. The reaction mixture was then cooled to 0° C. and treated with 2.8 mL water (slowly, vigorous reaction), 2.8 mL 15% NaOH, and finally 8.4 mL water. The resulting suspension was then stirred 10 minutes, filtered and the solids were washed with THF and ether. The solution was concentrated under vacuum to afford 2.94 g (81% yield for two steps) of (1E, 3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butene, a compound of formula (DD); 1H NMR (CDCl3) 8 2.41 (t, 1H), 3.85 (dd, 1H), 3.99 (dd, 1H), 4.50 (m, 1H), 6.31 (dd, 1H), 6.52 (dd, 1H), 6.83 (m, 2H), 6.97 (t, 2H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=O)C.[Li+].[BH4-].Cl>C1COCC1.O>[C:13]([O:12][C:10]([N:8]1[CH2:9][C:6]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH2:4][OH:3])[CH2:7]1)=[O:11])([CH3:15])([CH3:16])[CH3:14]
Reactant: CCOC(=O)C1(NC(=O)OC(C)(C)C)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CO)CN(C(=O)OC(C)(C)C)C1

Procedure:
3-tert-Butoxycarbonylamino-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (520 mg; 1.5 mmol) in THF (15 ml) is refluxed with LiBH4 (67 mg; 3 mmol) for 20 minutes. The reaction mixture is diluted with water, acidified with 2N HCl to destroy excess of LiBH4, neutralized again with 2N Na2CO3 and extracted with TBME three times. The organic phases are combined, dried over Na2SO4 and evaporated to dryness, yielding the desired product as colorless crystals. 1H-NMR (400 MHz; DMSO-d6: 7.27 (bs, 1H); 5.07 (bt, 1H); 3.78 (bs, 4H); 3.46 (d, 2H); 1.40 (s, 9H); 1.38 (s, 9H). MS (m/z) ES+: 303 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([CH3:18])=[N:16][N:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:19][CH2:20][C:21]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[H-].[Na+]>CN(C)C=O.O>[CH3:18][C:17]1[N:13]([C:5]2[CH:4]=[C:3]([CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH2:2][O:19][CH2:20][C:21]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]=[N:15][N:16]=1
Reactant: Cc1nnnn1-c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnnn1-c1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3-(Bromomethyl)-5-(trifluoromethyl)phenyl)-5-methyl-1H-tetrazole (30.0 mg, 0.09 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (29.0 mg, 0.1 mmol) were combined in dimethylformamide (2 mL) and cooled to 0° C. The reaction was treated with sodium hydride (2.4 mg, 0.1 mmol), stirred at 0° C. for 1 hr and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (40% ethyl acetate/hexanes) gave 40 mg (81%). LC/MS (HPLC method 3): tR=3.14 min, 532.24 (MH)+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[F:27][C:23]1[CH:22]=[C:21]([CH:11]2[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1c1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O)CC1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-3) (18.1 g, 38.2 mmol) in THF (76 mL) at room temperature was added TBAF (50 mL of a 1.0 M solution in THF, 49.7 mmol). The mixture was stirred at room temperature for 2 hours then poured into water. The mixture was extracted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The mixture was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield (4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (1-4). 1H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 1 H), 7.07 (bd, J=7.6 Hz, 1 H), 7.01 (bd, J=7.5 Hz, 1 H), 6.92 (dt, J=8.4 Hz, 1 H), 4.83 (bs, 1 H), 4.50 (q, J=5.2 Hz, 1 H), 3.89 (bs, 1 H), 3.58 (ddd, J=1.2, 3.6, 12.0 Hz, 1 H), 2.62 (bs, 1 H), 2.0 (dt, J=4.4, 17.6 Hz, 1 H), 1.23 (s, 6 H). MS m/z 304.1 (M+23)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH:23][C:9](=[O:11])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN)OC
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COC(CNC(=O)OCc1ccccc1)OC
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (74.5 Kg) was charged to a 200-gallon reactor, followed by toluene (235.1 Kg). The mixture was stirred for 15 minutes and cooled to 5° C. A solution of aminoacetaldehyde dimethylacetal (30 Kg) and triethylamine (28.9 Kg) in toluene (26.1 Kg) was charged slowly to the reactor over a 1 hour period while maintaining the internal temperature below 30° C. The mixture was stirred at 20° C. until there remained no more than 1.0% CbzOSu, as determined by HPLC. Water (150 Kg) was charged to the reactor and the contents of the reactor were stirred for 15 minutes. The layers were separated and the organic layer was washed with 5% ammonium chloride (2×151 Kg) followed by a water wash (150 Kg). The product was taken onto the next step as a solution, without isolation.