Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:32]([CH2:44][CH:45]([CH3:47])[CH3:46])[S:33]([C:36]1[CH:41]=[CH:40][C:39](OC)=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8]C([C@@H](NC(N1CCOCC1)=O)CC1C=CC2C(=CC=CC=2)C=1)=O.[N:48]1([C:54]([NH:56][C@@H:57]([CH:61]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:58]([OH:60])=[O:59])=[O:55])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C1C=CC(C[C@H]([NH2:85])C(O)=O)=CC=1.N1(C(N[C@@H](CC2C3C(=CC=CC=3)C=CC=2)C(O)=O)=O)CCOCC1>>[N:48]1([C:54]([NH:56][C@@H:57]([CH:61]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C:58]([OH:60])=[O:59])=[O:55])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.[NH2:85][C:39]1[CH:40]=[CH:41][C:36]([S:33]([N:32]([CH2:44][CH:45]([CH3:47])[CH3:46])[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:58]([C@@H:57]([NH:56][C:54]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)=[O:55])[CH:61]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])(=[O:35])=[O:34])=[CH:37][CH:38]=1
Reactant: COc1ccc(S(=O)(=O)N(CC(C)C)[C@H](CO)CCCCNC(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)N2CCOCC2)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(O)[C@@H](NC(=O)N1CCOCC1)C(c1ccccc1)c1ccccc1
Agent: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](NC(=O)N1CCOCC1)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (XII) (example 28, step D) as described in general procedure B using (2S)-2-[(morpholine-4-carbonyl)-amino]-3,3-diphenyl-propionic acid. The (2S)-2-[(morpholine-4-carbonyl)-amino]-3,3-diphenyl-propionic acid derivative was prepared from L-diphenylalanine as described for the preparation of (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid (example 32, step A). The final product was obtained in 28% yield (14 mg).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[C:10]([S:24][CH2:25][CH3:26])=[N:11][C:12]2[C:17]([C:18]=1[CH3:19])=[CH:16][CH:15]=[C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=2)=[O:8])C.C1COCC1.CO>O>[C:20]([C:14]1[CH:13]=[C:12]2[C:17]([C:18]([CH3:19])=[C:9]([C:7]([OH:8])=[O:6])[C:10]([S:24][CH2:25][CH3:26])=[N:11]2)=[CH:16][CH:15]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1c(SCC)nc2cc(C(C)(C)C)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCSc1nc2cc(C(C)(C)C)ccc2c(C)c1C(=O)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 27.1 %

Procedure:
A solution of 600 mg (14.36 mmol) lithium hydroxide monohydrate in water (30 ml) was added to a solution of 1.7 g (5.1 mmol) 7-tert-butyl-2-ethylsulfanyl-4-methyl-quinoline-3-carboxylic acid ethyl ester in a THF/methanol blend (2:1 vv, 30 ml) and then the reaction solution was stirred for 16 h at 60° C. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with water and washed with EE. The aqueous phase was adjusted to pH 2 with 1M hydrochloric acid and then extracted with EE. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 420 mg (1.38 mmol, 27%) 7-tert-butyl-2-ethylsulfanyl-4-methyl-quinoline-3-carboxylic acid were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:11]2[CH2:14][CH:13]([NH:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH2:12]2)=[CH:6][CH:5]=1.Cl[C:33]([O:35][CH3:36])=[O:34].O>O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH:13]([N:15]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:33](=[O:34])[O:35][CH3:36])[CH2:14]2)=[CH:26][CH:27]=1
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.4 mg of a 75% dispersion of sodium hydride in mineral oil are added, at room temperature under an argon atmosphere, to a solution of 330 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorobenzyl)amine in 25 cm3 of tetrahydrofuran. The mixture is stirred at room temperature for 1 hour before adding thereto 59 mm3 of methyl chloroformate, and then the stirring is maintained for 18 hours under the same conditions. The reaction mixture is supplemented with 0.3 cm3 of distilled water and the tetrahydrofuran is expelled in a rotary evaporator. The residue obtained is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (97.5/2.5 by volume)]. 328 mg of methyl {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorobenzyl)carbamate are obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.97 (mt: 2H); 3.39 (mt: 2H); 3.71 (s: 3H); 4.24 (broad s: 1H); 4.45 (unresolved complex: 1H); 4.57 (s: 2H); from 6.65 to 6.80 (mt: 3H); from 7.15 to 7.30 (mt: 8H)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[C:15]([CH:27]([OH:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Product: C[C@H]1CC[C@H](Cn2c(C(O)c3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1

Procedure:
4-(5-chloropyridin-3-yl)-2-(hydroxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile was prepared using 4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (product of Step 2, Preparative Example 3.1) and benzaldehyde in a manner analogous to Example 6.1, Step 1. 1H NMR (600 MHz, CD3OD) δ 8.75 (d, J=2.2, 1H), 8.69 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.48 (d, J=7.5, 2H), 7.37 (t, J=7.5, 2H), 7.34-7.28 (m, 1H), 6.22 (s, 1H), 3.94 (s, 2H), 1.40 (t, J=14.0, 2H), 1.06-0.98 (m, 1H), 0.83-0.77 (m, 1H), 0.75-0.68 (m, 5H), 0.64-0.56 (m, 1H), 0.51-0.36 (m, 3H). MS ESI calc'd. for C27H26ClN5O [M+H]+ 472. found 472.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:43]=[C:44]([NH2:57])[C:45]4[C:49]([CH:50]=3)=[N:48][N:47](C3CCCCO3)[CH:46]=4)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:50]=[C:49]4[C:45]([CH:46]=[N:47][NH:48]4)=[C:44]([NH:57][C:6]([C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)=[O:8])[CH:43]=3)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1
Reactant: O=C(O)c1c[nH]cn1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
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: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1c[nH]cn1
Reaction time: 0.08 h

Procedure:
1H-Imidazole-4-carboxylic acid (7 mg) in DMF (0.2 ml) was treated with N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (27 mg) in DMF (0.2 ml) and DIPEA (0.03 ml). The reaction mixture was shaken for five min prior to treatment with 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg) in DMF (0.2 ml). The reaction mixture was shaken for five min and left to stand at 22° C. for 18 h. Solvent was removed in vacuo and the product re-dissolved in methanol (0.5 ml) prior to application on to an SCX SPE cartridge (1 g). The product was eluted after 1 h with 2M ammonia in methanol (2×3 ml), the fractions were combined and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method C) gave the title compound.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[C:2]1S.[OH-].[Na+].OO>O.[OH-].[Na+]>[S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: Sc1nc2cnc3ccccc3c2s1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)ncc1ncsc12
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
Thiazolo[4,5-c]quinoline-2-thiol (8.7 g, 0.04 mole) was suspended in a solution of sodium hydroxide (1.4 g, 0.04 mole) in water. A few drops of 50% sodium hydroxide were added to the suspension until most of the solid dissolved. Hydrogen peroxide (13.5 mL of 30%, 0.08 mole) was added dropwise over a period of 30 minutes while maintaining the temperature of the reaction mixture at 25-35° C. with a cold water bath. The bath was removed and the reaction mixture was stirred for 15 minutes. Sulfuric acid (2.5 g of 95.98%) was added dropwise to the reaction mixture. After 30 minutes the reaction was made basic (pH 9-9.5) with 50% sodium hydroxide. The reaction mixture was acidified (pH 2.5) with hydrochloric acid, a tan solid precipitated. The mixture was then heated on a steam bath for 15 minutes and the precipitate dissolved. The solution was allowed to cool to ambient temperature and a precipitate formed. The mixture was made basic (pH 9) with 50% sodium hydroxide. The resulting oily product was extracted with ethyl acetate. The extracts were combined, washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide 3.3 g of thiazolo[4,5-c]quinoline as a tan solid, m.p. 104.4-105° C. Analysis: Calculated for C10H6N2S: % C, 64.19; % H, 3.25; % N, 15.04; Found: % C, 64.15; % H, 3.26; % N, 14.9.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9](=[O:23])[C@@H:10]([CH3:22])[NH:11]C(OCC1C=CC=CC=1)=O.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CO.[Pd]>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9](=[O:23])[C@@H:10]([CH3:22])[NH2:11]
Reactant: C[C@@H]1CCCC[C@H]1OC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C[C@@H]1CCCC[C@H]1OC(=O)[C@@H](C)N

Procedure:
N-Benzyloxycarbonyl-D-alanine-trans-2-methylcyclohexyl ester (14.7 g, 47.5 mmol) and p-toluenesulfonic acid monohydrate (9.04 g, 47.5 mmol) were dissolved in 135 mL MeOH. The methanolic solution was hydrogenated over 2.51 g of 10% Pd/C at 40 psi in a Parr apparatus for 1 hour. The catalyst was removed by filtration through a Celite pad and the filtrate was concentrated under reduced pressure. The salt was precipitated by addition of ether. Yield: 13.8 g in 2 crops (81%) mp 145°-147°. Tlc on silica gel (CHCl3 :MeOH:HOAc=45:5:1) indicated a single ninhydrin positive spot. 250 MHz nmr (CD3OD, ppm) 0.92 (d, 3H, J=6.25 Hz, trans-2-methyl), 1.09-1.99 (m, 7H, aliphatic cyclohexyl protons), 1.53 (2d, 3H, β--CH3 of Ala), 2.37 (s, 3H, CH3 --Ar--SO3H), 4.09 (2q, 1H, J=7.35 Hz, 2.57 Hz; α--H of Ala), 4.51 (m, 1H, α--H of alcohol); 7.22, 7.69 (ABq, 4H, J=8.46 Hz, CH3 --ArH4 --SO3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=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.[NH2:65][C:66]1[CH:67]=[C:68]([CH:71]=[CH:72][CH:73]=1)[C:69]#[N:70]>C(Cl)Cl>[C:69]([C:68]1[CH:67]=[C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])[CH:73]=[CH:72][CH:71]=1)#[N:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: N#Cc1cccc(N)c1
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: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(C#N)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.54 mmol) in methylene chloride (10 mL), HATU (Aldrich, 247 mg, 0.65 mmol) was added followed by the addition of DIPEA (0.65 mmol) and 3-amino benzonitrile (Aldrich, 77 mg, 0.65 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 84 mg.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:22]([O:29][CH2:30][CH3:31])(=[O:28])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH3:27].[NH4+].[Cl-]>C1COCC1>[CH2:30]([O:29][C:22](=[O:28])[CH2:23][C@@H:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[CH2:25][CH2:26][CH3:27])[CH3:31]
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Reactant: CCC/C=C/C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@@H](CC(=O)OCC)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of (S)-(−)-N-benzyl-alpha-methyl-benzylamine (50 mL, 239 mmol) in THF (150 mL) at 0° C. is added nBuLi (2.5 M in THF) (100 mL, 250 mmol) under nitrogen atmosphere. The solution is cooled to −78° C. and ethyl trans-2-hexenoate (16.6 g, 117 mmol) is added. The solution is stirred for 1 hour and saturated NH4Cl solution is added. The solution is warmed to room temperature and is extracted with EtOAc. The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent to afford the (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 50%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)=[C:12]=[O:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc2[nH]ccc12
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc2[nH]ccc12
Temperature: 25 °C
Yield: 187.3 %

Procedure:
4-Aminoindole (0.5 g, 3.78 mmol) in toluene (50 mL) was treated with triphosgene (0.4 g, 1.35 mmol) and heated at reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was taken up in diethyl ether, filtered, and the filtrate was concentrated under reduced pressure to provide title compound as yellow oil (0.4 g). 1H NMR (300 MHz, CDCl3-d6) δ 6.62 (m, 1H), 6.84 (d, 1H), 7.1 (t, 1H), 7.23 (m, 2H), 8.3 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:19][CH:20]=C)[C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[O:22]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[CH2:19][CH:20]=[O:22])[O:3][CH2:4][CH2:5][O:6]1
Reactant: O=[O+][O-]
Reactant: C=CCC(CCCC1(C)OCCO1)C(=O)N1CCOC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(CCCC(CC=O)C(=O)N2CCOC2=O)OCCO1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-4 (4.0 g, 13.5 mmol), sudan III (10 mg) and CH2Cl2 (350 mL) at -78° C. under argon was bubbled ozone until red solution changed to yellow-orange. The solution was purged with argon for 30 minutes. PPh3 (5.28 g, 20.3 mmol) was added followed by the removal of the cooling bath. After 3.0 h, the reaction was concentrated. Flash chromatography (silica, 20%-50% EtOAc/hexanes) gave 2-5 as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=O.Cl>O>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([C:10]3[NH:1][C:2]4[C:7]([CH:9]=3)=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CCl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Product: c1ccc(-c2ccc(-c3cc4ccccc4[nH]3)cc2)cc1
Yield: 24.9 %

Procedure:
A mixture of 372 g (4 mols) of aniline and 230 g (1 mol) of ω-chloroparaphenyl-acetophenone was refluxed for 105 minutes. After cooling to about 50°-80° C, the mixture was poured into iced-water containing 50 ml of concentrated hydrochloric acid to give a precipitate which was filtered out, washed with water, dried and then recrystallized from N,N-dimethylformamide. The pure substance was then filtered out and washed with ethanol to give 67.2 g of 2-(4'-phenyl-phenyl)-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=O.[NH:16]1[C:24]2[CH:23]=[CH:22][N:21]=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[C:19]=2[CH:18]=[CH:17]1.ClC1C=C(C(=O)NCC)C=C(Cl)C=1C(O)=O>>[C:26]([NH:25][C:20]1[C:19]2[CH:18]=[CH:17][N:16]([C:4]([C:3]3[C:7]([Cl:15])=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]=3[Cl:1])=[O:6])[C:24]=2[CH:23]=[CH:22][N:21]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1nccc2[nH]ccc12
Reactant: COC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Agent: CCNC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Product: COC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(C)=O)nccc32)c(Cl)c1

Procedure:
This was prepared using 2,6-dichloro-4-(methoxycarbonyl)benzoic acid and N-(1H-pyrrolo[3,2-c]pyridin-4-yl) acetamide (Intermediate 29) in an analogous manner.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[N-:45]=[N+:46]=[N-:47].CN(C)C(=[NH2+])N(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:16][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([CH3:14])[C:8]=1[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][N:45]=[N+:46]=[N-:47]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: CN(C)C(=[NH2+])N(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CN=[N+]=[N-])cc(Cl)c1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27.8 %

Procedure:
A stirred, ambient temperature solution of 1-(4-chlorobenzoyl)-2-chloro-4,6-dimethylbenzene (6.90 g, 24.7 mmol) in dry carbontetrachloride (200 ml) was treated with N-bromosuccinimide (4.40 g, 24.7 mmol) and benzoylperoxide (250 mg, 1.03 mmol). The mixture was refluxed 4 hours, cooled to 0° C., and filtered. The precipitate was washed with carbon tetrachloride and the combined filtrate and wash were evaporated to dryness at 40° C. under vacuum. The oily residue was dissolved in dichloromethane (150 ml) treated with tetramethylguanidinium azide (8.1 g, 51.2 mmol), and stirred 20 minutes at ambient temperature. The solvent was evaporated under vacuum and the semisolid residue was triturated with diethyl ether (200 ml) and filtered. The solid was washed well with diethyl ether, and the combined filtrates and washes were extracted with water (2×150 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, and evaporated to dryness under vacuum. The residue was triturated with hexane (400 ml), decanted, and evaporated under vacuum at 30° C. The residual oil was chromatographed on silica gel (500 g) eluted with 93:7 (v/v) hexane-ethyl acetate using a preparative high performance liquid chromatograph to provide 2.2 g (28%) oily 3-chloro-4-(4-chlorobenzoyl)-5-methylbenzyl azide [I.R. (neat): 2110, 1680 cm-1 ; 60 MHz 'H NMR (CDCl3): 2.17 (3H), 4.33 s (2H), 7.14 m (1H), 7.23 m (1H), 7.41 dm (J=9 Hz, 2H), 7.74 dm (J=9 Hz, 2H)] and 2.4 g (30%) oily 3-chloro-2-(4-chlorobenzoyl)-5-methylbenzyl azide [IR (neat): 2105, 1670 cm-1 ; 60 MHz 'H NMR (CDCl3): 2.39 s (3H), 4.23 s (2H), 7.17 s (1H), 7.21 s (1H), 7.40 dm (J=9 Hz, 2H), 7.75 dm (J=9Hz, 2 H)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1
Reactant: O=C(O)CCc1cc(Br)c(OCc2cccc([N+](=O)[O-])c2)c(Br)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(COc2c(Br)cc(CCC(=O)O)cc2Br)c1
Temperature: 70 °C
Yield: 29.1 %

Procedure:
A mixture of 3-[3,5-dibromo-4-(3-nitrobenzyloxy)phenyl]propionic acid (0.66 g, 1.44 mmol) and Na2S2O4 (2.0 g, 11.5 mmol) in ethanol (50 mL, 90%) was stirred at 70° C. over night. The reaction mixture was concentrated and purified on column (silica gel, chloroform/methanol, 9:1), to give 0.18 g (29%) of 3-[3,5-dibromo-4-(3-amino-benzyloxy)phenyl]propionic acid. MS: m/z 429.1 (M+−1).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:21][C@H:22]1[C@@H:27]2[O:28]C(C)(C)[O:30][C@@H:26]2[CH:25]=[C:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:13]([O:21][C@H:22]1[C@H:27]([OH:28])[C@H:26]([OH:30])[CH:25]=[C:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:23]1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C1=C[C@H]2OC(C)(C)O[C@H]2[C@H](OC(=O)c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)C1=C[C@@H](O)[C@@H](O)[C@H](OC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 54 %

Procedure:
Para-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) was added to a room temperature solution of Example 13D in methanol (50 mL). After stirring overnight, the reaction mixture was concentrated and the concentrate was purified by flash chromatography using ethyl acetate to afford 0.90 g (54%) of the desired product as a colorless oil.
Reaction SMILES: CC([Si](C)(C)[O:6][CH:7]1[CH2:10][C:9]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:11]2)[CH2:8]1)(C)C.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH:7]1[CH2:8][C:9]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:11]2)[CH2:10]1
Reactant: CCOC(=O)C1CC2(CC(O[Si](C)(C)C(C)(C)C)C2)CN1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2(CC(O)C2)CN1C(=O)OCc1ccccc1
Temperature: 45 °C

Procedure:
To a solution of 7-ethyl 6-(phenylmethyl) 2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-6-azaspiro[3.4]octane-6,7-dicarboxylate (151) (1.87 g, 4.2 mmol) in THF (20 mL) was added glacial acetic acid (0.48 mL), followed by TBAF (8.5 mL, 1M solution in THF) and the reaction heated to 45° C. for 18 h. The reaction was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO3 followed by brine, and then dried over MgSO4 and concentrated in vacuo to afford the title compound as a clear oil in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.17-7.48 (m, 5H) 4.83-5.15 (m, 3H) 3.88-4.34 (m, 4H) 3.35-3.47 (m, 2 H) 2.02-2.39 (m, 3H) 1.65-1.96 (m, 3H) 1.00-1.22 (m, 3H). LC-MS ESI (M+H)+=334.17.