Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]2[C:5]([C:6]([CH:13]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1(P(=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[C:11]([C:10]1[C:2]([F:1])=[CH:3][CH:4]=[C:5]2[C:9]=1[NH:8][CH:7]=[C:6]2/[CH:13]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1c(F)ccc2c(C=O)c[nH]c12
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c[nH]c2c(C#N)c(F)ccc12
Yield: 58.3 %

Procedure:
To a mixture of 6-fluoro-3-formyl-1H-indole-7-carbonitrile (D142) (3 g) in CH3CN (30 mL) was added ethyl (triphenylphosphoranylidene)acetate (11.1 g). The reaction was heated to reflux overnight. After the mixture was filtered, the filtrate was concentrated and purified by column chromatography to afford ethyl (2E)-3-(7-cyano-6-fluoro-1H-indol-3-yl)-2-propenoate (D143) (2.4 g) as a light yellow solid.
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[C@H:11]([NH2:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[C:2]([O:5][C@H:6]1[C@H:11]([NH:12][C:36](=[O:37])[CH2:35][O:34][CH3:33])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a suspension of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (0.500 g, 1.31 mmol) in CH2Cl2 (20 mL) was added triethylamine (0.544 mL, 3.915 mmol), followed by 2-methoxyacetyl chloride (0.13 mL, 1.44 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was washed once with saturated aqueous NaHCO3 (3 mL) and once with brine (3 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel (5:1 EtOAc:hexanes) afforded (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(2-methoxyacetamido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (0.380 g, 70% yield).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])[S:11][C:10]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([S:14](=[O:16])(=[O:17])[NH2:15])[S:11][C:10]=2[CH:18]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: NS(=O)(=O)c1cc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 24 h

Procedure:
Allyl bromide (2.07 ml, 24.0 mmol) was added dropwise to a stirred solution of 6-hydroxy-2-sulfamoylbenzo[b]thiophene (5.0 g, 22.0 mmol) in dimethylsulfoxide (15.0 ml). A solution of K2CO3 (3.34 g, 24.0 mmol) in water (7.5 ml) was added dropwise to the reaction solution at 25° C. After 24 hours, the reaction mixture was diluted with water (50 ml). The solid that formed was collected and dried, 3.75 gm (13.9 mmol), m.p. 101°-102° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br[CH2:16][CH2:17][Cl:18]>CN(C)C=O>[Cl:18][CH2:17][CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCCl)c2ccc(F)cc21
Temperature: 0 °C

Procedure:
5-Fluoro-1H-indol-2,3-dione (8.92 g) was dissolved in dimethylformamide (60 ml). Sodium hydride (60% dispersion in mineral oil, 3.08 g) was added in portions with stirring and cooling (ice-water bath) and the mixture was stirred until gas evolution ceased. 1-Bromo-2-chloroethane (5.4 ml, 9.3 g) was added dropwise. The mixture was stirred at room temperature for 24 hours and then quenched into water and extracted into chloroform. The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel, eluent chloroform, to give 1-(2-Chloroethyl)-5-fluoro-1H-indole-2,3-dione as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-])[CH:5]=[CH:6][CH:7]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1ccccc1C=Cc1cccc(F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)O
Product: N#Cc1cccc(C=Cc2cccc(F)c2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(3-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a beige crystalline material. Mp. 111-112° C. (iPrOH), MS: m/e=224 (M+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([O:7][CH:8]([CH3:10])C)=[N:4][CH:3]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]2[N:19]([CH:26]=[CH:27][N:28]=2)[CH:20]=[C:21](B(O)O)[CH:22]=1>>[CH2:8]([O:7][C:5]1[S:6][C:2]([C:21]2[CH:22]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:29])[C:18]3[N:19]([CH:26]=[CH:27][N:28]=3)[CH:20]=2)=[CH:3][N:4]=1)[CH3:10]
Reactant: Cc1ccccc1-c1cc(B(O)O)cn2ccnc12
Reactant: CC(C)Oc1ncc(Br)s1
Product: CCOc1ncc(-c2cc(-c3ccccc3C)c3nccn3c2)s1

Procedure:
Example 190 was prepared using the procedure describe for Example 34, step 4 from 5-bromo-2-(isopropyloxy)thiazole and 8-o-tolylimidazo[1,2-a]pyridin-6-ylboronic acid. LCMS (Conditions C): Tr 2.63 min.; (M+H)+: 336.31
Reaction SMILES: N#N.[NH2:3][C:4]1[C:8]([Br:9])=[CH:7][NH:6][N:5]=1.CN(/[CH:13]=[C:14](\[Cl:19])/[CH:15]=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)C>C(O)(=O)C>[Br:9][C:8]1[CH:7]=[N:6][N:5]2[CH:15]=[C:14]([Cl:19])[CH:13]=[N:3][C:4]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CN(C)/C=C(\Cl)C=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#N
Solvent: CC(=O)O
Solvent: CCO
Product: Clc1cnc2c(Br)cnn2c1
Temperature: 70 °C
Yield: 80.8 %

Procedure:
A 5 L 4-neck round bottom flask equipped with mechanical stirrer, thermocouple, condenser and N2 bubbler was charged with 3-amino-4-bromopyrazole (40.0 g, 240 mmol), 2-Chloro-1,3-bis(dimethylamino)trimethinium hexafluorophosphate (77.0 g, 252 mmol) in acetic acid (390 ml)/ethanol (580 ml). The reaction mixture was heated to 70° C. for 8 hrs. Cool to 0° C. Filter off solids. Wash solids with 500 ml water then 500 ml MeOH and dried under high vac to afford the title compound (45.1 g, 194 mmol). LRMS (APCI) calc'd for (C6H3BrClN3) [M+H]+, 231.9; found 231.9. 1H NMR (CDCl3, 500 MHz) δ 8.74 (s, 1H), 8.52 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH2:21]([C:23]1[CH:28]=[C:27](/[CH:29]=[CH:30]/[C:31]#[N:32])[CH:26]=[CH:25][N:24]=1)[CH3:22]>>[CH2:21]([C:23]1[CH:28]=[C:27]([C:29]2[CH:30]=[C:31]([NH2:32])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)[CH:26]=[CH:25][N:24]=1)[CH3:22]
Reactant: CCc1cc(/C=C/C#N)ccn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: CCc1cc(-c2cc(N)n3nc(-c4ccco4)nc3c2)ccn1

Procedure:
The title compound, mp. 184-186° C. and MS m/e (%): 305 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and (E)-3-(2-ethyl-pyridin-4-yl)-acrylonitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 28.7 %

Procedure:
The title compound (D22) (18 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D12) (40 mg, 0.14 mmol) and 3-(trifluoromethyl)benzyl bromide (0.031 ml, 0.21 mmol). (Na2CO3: 2.5 eq; reaction time: 4 hrs; 60° C.)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=O)=[N:18][CH:19]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:11]([O:10][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([F:13])=[CH:19][N:18]=1)=[O:9])[CH3:12]
Reactant: O=Cc1ccc(F)cn1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cn1
Temperature: 50 °C
Reaction time: 72 h
Yield: 52.5 %

Procedure:
A solution of ethyl cis-2-amino-1-cyclopentane carboxylate hydrochloride (0.250 g, 1.29 mmol) in ethanol (10 mL) was treated with 5-fluoro-pyridine-2-carbaldehyde, glacial acetic acid (10 drops), sodium cyanoborohydride (0.162 g, 2.58 mmol) and stirred for 72 h at 50° C. The reaction was extracted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0-10% methanol in dichloromethane) to afford the desired product, cis-2-[(5-fluoro-pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.179 g, 0.678 mmol, 52.5%), as a light yellow oil. LC-MS (ESI) calcd for C14H19FN2O2 266.14, found 267.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Br:14][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)C(Br)c1ccc(F)cc1Cl
Temperature: 80 °C

Procedure:
Methyl 2-chloro-4-fluorophenylacetate (3.15 g, 15.6 mmol), N-bromosuccinimide (2.77 g, 15.6 mmol) and AIBN (255 mg, 1.56 mmol) were suspended in benzene (50.0 mL) and degassed via N2 stream. The resulting mixture was heated to 80° C. for 12 h. After cooling to rt, the mixture was partially concentrated in vacuo and partitioned between ether and water. The layers were separated, and the organic layer was washed with water and brine. The organics were dried (MgSO4), filtered and concentrated in vacuo. The resulting crude oil was purified by flash chromatography on silica gel (gradient elution; 0%-20% EtOAc/hexanes as eluent) to afford the title compound i-1a. 1HNMR (500 MHz, CDCl3): δ 7.82 (dd, 1H, J=6.0, 8.8 Hz), 7.17 (dd, 1H, J=2.6, 8.3 Hz), 7.08 (m, 1H), 5.88 (s, 1H), 3.84 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH3:35])=[N:33][N:34]=[C:30]3[C@H:29]([CH2:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])[N:28]=[C:27]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=3)[C:26]=2[CH:49]=1)(=O)=O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([C:27]2[C:26]3[CH:49]=[C:22]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:23]=[CH:24][C:25]=3[N:31]3[C:32]([CH3:35])=[N:33][N:34]=[C:30]3[C@H:29]([CH2:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])[N:28]=2)=[CH:47][CH:46]=1
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccnc3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
3-Pyridinylboronic acid (27.2 mg), sodium carbonate (43.0 mg) and bis(triphenylphosphine)palladium(II) chloride (12.95 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (100 mg) in DME (3 ml) and water (1 ml) was added and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with water (10 ml) and brine (10 ml). The organic phase was dried and the solvent evaporated. The residue was chromatographed (0-10% methanol:DCM) product was further purified by MDAP (formate modifier) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(3-pyridinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a white oil (11.9 mg).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[CH:16]([NH2:19])([CH3:18])[CH3:17]>>[CH:16]([NH:19][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5])([CH3:18])[CH3:17]
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Reactant: CC(C)N
Product: CC(C)Nc1cccc(-c2ccccc2)c1C#N
Temperature: 95 °C

Procedure:
The product of example 1a above, 2-fluoro-6-phenylbenzonitrile, (0.12 g, 0.61 mmol), and isopropylamine (3 mL) were combined in a sealed tube that had been flushed with argon. The tube was heated in an oil bath to 95° C. for 7 days. The excess isopropylamine was evaporated, .and the residue was flash chromatographed on silica gel eluted with 0-3% ethyl acetate in hexane, and then crystallized from hexane to give the title product as a white crystalline product. ES (+) MS m/e=237 (MH+)
Reaction SMILES: [Si:1]([O:18][C@@H:19]([CH3:23])[C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.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.[N:57]([CH2:60][CH2:61][CH2:62][C:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[NH:67][N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]>C(#N)C>[N:57]([CH2:60][CH2:61][CH2:62][C@:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[N:67]([C:20](=[O:22])[C@@H:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:23])[N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
To a solution of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid (339 mg, 1.09 mmol) in acetonitrile (6 mL) was added HATU (550 mg, 1.45 mmol) followed by DIEA (0.378 mL, 2.17 mmol). After stirring at room temperature for 15 minutes, a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (260 mg, 0.72 mmol) in acetonitrile (4 mL) was added. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The brown oil was chromatographed (9:1 hexanes/ethyl acetate) to provide the less polar diastereomer, (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (121 mg) and the more polar diastereomer, (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (175 mg) as pale yellow oils. Absolute stereochemistry was assigned by examination of a protein inhibitor co-crystal structure of Eg5 and (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:23]Br>C(Cl)Cl.ClC1C=CC=CC=1>[Br:23][C:18]1[CH:17]=[C:16]([CH:13]2[CH2:14][CH2:15][CH:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: BrBr
Reactant: CCCC1CCC(C2CCC(c3ccc(O)cc3)CC2)CC1
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: CCCC1CCC(C2CCC(c3ccc(O)c(Br)c3)CC2)CC1
Temperature: 0 °C
Yield: 39.6 %

Procedure:
4-(4-(4-Propylcyclohexyl)cyclohexyl)phenol (0.5 g) was dissolved in a mixed solvent of methylene chloride (5 ml) and chlorobenzene (1 ml), to which was then added dropwise a solution of bromine (0.28 g) in methylene chloride (2 ml) under ice cooling while stirring. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 minutes, added in ice water, and then extracted with methylene chloride. An organic layer was washed with water, rinsed with a sodium thiosulfate aqueous solution, and then dried over anhydrous magnesium sulfate. The methylene chloride solution was concentrated in vacuo and then subjected to isolation and purification by silica gel column chromatography, thereby obtaining a white crystal (0.25 g) of 2-bromo-4-(4-(4-propylcyclohexyl)cyclohexyl)phenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:12]=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5]2.[O-:15]Cl=O.[Na+].[OH-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:15])=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5]2
Reactant: O=Cc1c(O)ccc2cc(Br)ccc12
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1c(O)ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.4 %

Procedure:
To a ice-cooled mixture of 6-Bromo-2-hydroxy-1-naphthaldehyde (24.0 g) and aqueous NaH2PO4 solution (3.2 g in 30 mL of water) in DMSO (160 mL) was added dropwise a solution of NaClO2 (80%; 15.1 g) in water (150 mL) over 1 h. After being stirred for 5 h at room temperature, a solution of NaClO2 (80%; 2.16 g) in water (20 mL) was added, and the reaction mixture was further stirred for 2 h at room temperature. The mixture was alkalized with 1N-NaOH, and the precipitate was filtered off. The filtrate was washed with AcOEt and iPr2O, and then the aqueous phase was acidified with conc. HCl. The precipitate was filtered, washed with water, and dried in vacuo to give the title compound (22.3 g) as a brown powder.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:14]>C1(C)C=CC=CC=1>[Br:14][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][CH2:12][OH:13]
Reactant: OCCC(CCO)c1ccccc1
Reactant: Br
Solvent: Cc1ccccc1
Product: OCCC(CCBr)c1ccccc1
Temperature: 180 °C

Procedure:
3-Phenylpentane-1,5-diol (452 mg, 2.51 mmol) was dissolved in 48% aqueous hydrobromic acid (284 μL, 2.51 mmol) and toluene (2.5 mL), placed in a sealed tube, and heated in a microwave oven at 180° C. for 10 minutes. The mixture was cooled and purified by column chromatography on silica gel, eluting with 0-100% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.57 (br s, 1H), 1.81-1.97 (m, 2H), 2.08-2.23 (m, 2H), 2.97 (quintet, J=5.0 Hz, 1H), 3.06-3.14 (m, 1H), 3.24-3.31 (m, 1H), 3.42-3.49 (m, 1H), 3.49-3.56 (m, 1H), 7.17-7.25 (m, 3H), 7.28-7.33 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]1[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:5].Cl.CCN(C(C)C)C(C)C.[CH2:40]([S:43](Cl)(=[O:45])=[O:44])[CH2:41][CH3:42]>O1CCOCC1>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]1[CH2:9][N:10]([S:43]([CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])[CH2:11]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC(C(NC(=O)c2ccc(Cl)cc2Cl)c2ccccc2)C1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CC(C(NC(=O)c2ccc(Cl)cc2Cl)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of 2 (500 mg, 1.15 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in dioxane (5.0 mL) and stirred at room temperature for 2 h. The reaction was concentrated under vacuum. The residue was dissolved in CH2Cl2 (10 mL) and DIPEA (300 mg, 2.30 mmol) and added 1-propanesulfonyl chloride (164 mg, 1.15 mmol). The reaction was stirred at room temperature for 20 h. The reaction was concentrated under vacuum and the residue was purified by column chromatography (silica gel) using 0 to 35% EtOAc in hexanes to afford 3a as white solid (285 mg, 56%); 1H-nmr (300 MHz, CDCl3) δ 7.69 (d, J=8.5 Hz, 1H), 7.60-7.30 (m, 10H), 7.08 (d, J=8.5 Hz, 1H), 5.68 (dd, J=9.5, 6.5 Hz, 1H), 5.29 (br s, 1H), 3.76-3.71 (m, 2H), 3.55-3.35 (m, 2H), 3.19-3.01 (m, 2H), 2.69 (br s, 1H), 1.98-1.82 (m, 2H), 1.08 (t, J=7 Hz, 9H); LC-MS (214) 98%, 3.30 min, m/z 475 (MMeOH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9](C)([CH3:41])[CH2:10][NH:11][CH2:12][C:13]1[O:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1.[CH3:43][C:44](C)(C)CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:9]1([CH2:10][NH:11][CH2:12][C:13]2[O:17][CH:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=3)[NH:23][CH:22]=[C:21]4[CH:30]3[CH2:31][CH2:32][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:34][CH2:35]3)[CH:14]=2)[CH2:8][CH2:44][CH2:43][CH2:41]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CNCC(C)(C)C)c4)cc23)CC1
Reactant: CC(C)(C)CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CNCC5CCCC5)c4)cc23)CC1
Yield: 25.1 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-cyclopentylmethanamine (137 mg, 1.4 mmol) for 2,2-dimethyl-1-propanamine to afford 22 mg of the title compound (25.1%).