Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:18])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2>>[Br:5][C:6]1[CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[C:13]([NH:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:18])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: CCOC(=O)C(=O)Nc1ccc(Br)c2cccnc12
Reactant: O=[N+]([O-])O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2cccnc12
Temperature: 0 °C
Yield: 88 %

Procedure:
10 ml 100% nitric acid was cooled to 0° C. and 1.0 g (3.1 mmol) 5-Bromo-8-ethoxalylaminoquinoline was added gradually. The reaction mixture was stirred at 25° C. for 1/2h and then poured into 150 ml ice-water. The precipitate was filtered off, washed with water and ethanol to give 1.0 g (88%) of 5-Bromo-8-ethoxalylamino-7-nitroquinoline. M.p. 213°-215° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[C:66]([O:74][CH3:75])[CH:65]=1>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][C:66]=1[O:74][CH3:75]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1OC
Yield: 5.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.25 g, 1.1 mmol), then reacted with methyl 4-amino-2-methoxybenzoate (Acros) (0.077 g, 0.43 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-2-methoxy-benzoic acid methyl ester as a white solid (Yield 0.012 g, 54%).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[CH2:28][C@H:27]([CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[N:26]([CH2:35][C:36]3[N:40]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[C:44]([F:50])[CH:43]=4)[CH:39]=[N:38][CH:37]=3)[CH2:25][C:24]2=[O:51])[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[H][H]>CO.CCOC(C)=O.[Pd]>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[CH2:28][C@H:27]([CH2:29][CH2:30][S:31]([CH3:34])(=[O:32])=[O:33])[N:26]([CH2:35][C:36]3[N:40]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[C:44]([F:50])[CH:43]=4)[CH:39]=[N:38][CH:37]=3)[CH2:25][C:24]2=[O:51])[CH:13]=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)CC[C@H]1CN(c2cc(Cl)ccc2-c2cccc(OCc3ccccc3)c2)C(=O)CN1Cc1cncn1Cc1ccc(C#N)c(F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CS(=O)(=O)CC[C@H]1CN(c2cc(Cl)ccc2-c2cccc(O)c2)C(=O)CN1Cc1cncn1Cc1ccc(C#N)c(F)c1
Reaction time: 1.5 h

Procedure:
To a solution of the product from Step D (383 mg, 0.527 mmol) in 10 mL of 1:1 MeOH/EtOAc was added trifluoroacetic acid (0.10 mL) and 10% palladium on carbon (300 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 1.5 hours, the solution was filtered through celite, the filter pad was rinsed with 1:1 MeOH/THF, and the filtrate was concentrated in vacuo. The crude material containing the titled product was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:27][C:24]2[CH:25]=[N:26][C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CC(C)N1CCN(c2ccc(N)cn2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cn2)CC1
Temperature: 90 °C
Reaction time: 48 h
Yield: 71.3 %

Procedure:
To a solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.85 g, 3.1 mmol) in isopropanol are added 6-(4-isopropyl-piperazin-1-yl)-pyridin-3-yl-amine (0.68 g, 3.1 mmol) and diisopropylethylamine (0.6 mL, 4.6 mmol) and the mixture is stirred at 90° C. for 48 hours. The solvent is removed in vacuo and the product taken up in DCM-10% citric acid. The organic layer is discarded and the aqueous solution basified with sat. NaHCO3 (pH 7-8) and extracted using DCM. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a purple solid (0.92 g, 71%). HPLC (254 nm): Rt 3.30 min (95.8%); m/z 416/418 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:23])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH:21]=C)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)(=[O:26])C>ClCCl>[C:1]12([CH2:11][NH:12][C:13](=[O:23])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH:21]=[O:26])[CH:15]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C=Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Reactant: CC(=O)O
Solvent: ClCCl
Product: O=Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: -78 °C

Procedure:
N-(1-Adamantylmethyl)-5-chloro-2-vinylisonicotinamide (Example 29(i)) (1.70 g) was dissolved in dichloromethane (50 mL), treated with acetic acid (1 mL) and cooled to −78° C. under nitrogen. Ozone was bubbled through the resulting solution for 2 hours while maintaining the temperature. Nitrogen was subsequently bubbled through the solution for 10 minutes and dimethylsulfide (2 mL) was added. The solution was warmed to room temperature washed with sodium bicarbonate (2×10 mL) and brine (30 mL); the organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:dichloromethane (1:20) to afford the sub-titled compound (1.13 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]#[N:21])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]#[N:21])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(CC#N)CCNCC1
Temperature: 0 °C

Procedure:
4-Cyanomethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (36 g) was dissolved in methylene chloride (600 ml), cooled to 0° C. then trifluoroacetic acid (207.8 g, 134.9 ml) was added under an argon atmosphere and the mixture was stirred over night allowing the temperature of the reaction mixture to rise to RT. The reaction mixture was then concentrated in vacuo, the residue taken up in methylene chloride and washed several times with 1M aqueous NaOH (to pH 12). The layers were separated, the organic layer washed with brine, dried over sodium sulphate and concentrated to give 4-cyanomethyl-piperidine-4-carboxylic acid ethyl ester a brown oil (14.2 g) which was essentially pure according to NMR and used in next reaction step without further purification. MS (ESI): 197.2 (MH+).
Reaction SMILES: ClC1C=C(Cl)N2N=CC(CC3C=CC=C(C(F)(F)F)C=3C)=C2N=1.[OH-].[Na+].Cl[C:27]1[NH:28][C:29]2[N:30]([N:34]=[CH:35][C:36]=2[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[C:39]=2[CH3:48])[C:31](=[O:33])[CH:32]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.Cl>O.O1CCCC1.C(O)C.C(OCC)(=O)C>[CH3:48][C:39]1[C:40]([C:44]([F:47])([F:46])[F:45])=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][C:36]1[CH:35]=[N:34][N:30]2[C:31]([OH:33])=[CH:32][C:27]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[N:28][C:29]=12
Reactant: Cc1c(Cc2cnn3c(=O)cc(Cl)[nH]c23)cccc1C(F)(F)F
Reactant: C1COCCN1
Agent: Cc1c(Cc2cnn3c(Cl)cc(Cl)nc23)cccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Cc2cnn3c(O)cc(N4CCOCC4)nc23)cccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidine (1.9 g, 5.28 mmol) in water (10.0 mL) and tetrahydrofuran (40 mL) stirred at 0° C. was added a solution of 1M NaOH solution (5.28 g, 13.2 mmol) in dropwise during 5 min. The reaction mixture was stirred at 40° C. for 1 hour. Excess solvent was removed. The residue was dissolved with ethyl acetate (100 mL) and water (25 mL). The pH of aqueous layer was adjusted to pH 7. Two layers were separated. Aqueous Layer was extracted with ethyl acetate (50 mL×2). Combined layers were dried and concentrated to dryness. The product was obtained and used in next step. (1.64 g, 91%); LC/MS: MS (ES+) m/e 342 (MH+). To a solution of 5-chloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-7(4H)-one (1.21 g, 3.54 mmol) in ethanol (3 mL) stirred under nitrogen at 20° C. was added neat morpholine (0.925 g, 10.62 mmol). The reaction vessel was sealed and irradiated (microwave) at 145° C. for 4 hr. Reaction mixture diluted with ethyl acetate (50 mL) and water (15 mL). The pH of aqueous layer was adjusted with conc. HCl solution to 5. Two layers were separated. Aqueous layer was extracted with ethyl acetate (50 mL) again. Combined layers were dried and concentrated. The crude material was then purified with column chromatography (silica gel, CH3OH/DCM 0-10%). Desired product was obtained and used in next step. (520 mg, 37%); LC/MS: MS (ES+) m/e 393 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:21]([F:24])([F:23])[F:22])[CH:5]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:12]=2[C:21]([F:24])([F:23])[F:22])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(Sc2c(C(F)(F)F)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C(F)(F)F)n(Cc3ccccc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 3, using the following starting materials: 3-(6-chloro-2-trifluoromethyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and benzyl bromide.
Reaction SMILES: [OH-].[NH4+:2].[I:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7]>>[I:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:2])=[O:7]
Reactant: O=C(Cl)c1ccccc1I
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccccc1I

Procedure:
A total of 50 ml of a 15 M ammonium hydroxide solution was reacted with 15 g o-iodobenzoyl chloride for 20 minutes. The crude product was recovered as in Example 1. The product was recrystallized from ethanol to yield 7.8 g of o-iodobenzamide, m.p. 187°-189°, Rf 0.63.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[CH:23][N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:27]N1C(=O)CCC1=O>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[CH:23][N:19]3[C:20](=[O:22])[C:21]=2[I:27])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cccc(/C=C/c2cc(=O)n3cc(C)sc3n2)c1OCC1CC1
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sc(C)cn3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (700 mg, 1.810 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (641 mg, 2.841 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.31-0.33 (m, 2H), 0.53-0.56 (m, 2H), 1.22 (br s, 1H), 2.43 (s, 3H), 3.76-3.81 (m, 2H), 3.81 (s, 3H), 7.05-7.11 (m, 2H), 7.25-7.28 (m, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.80 (s, 1H), 8.14 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 495.10 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.CN(C)[CH:18]=[O:19]>>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Fc1cc(F)c(Br)cc1Br
Agent: [Li]CCCC
Product: O=Cc1cc(Br)c(F)cc1F

Procedure:
As a raw material, 17.7 g of 1,5-dibromo-2,4-difluorobenzene obtained in Production Example II-5-a was subjected to lithiation with n-butyllithium by the procedure of Production Example II-5-b, was subjected to formylation with N,N-dimethylformamide, to give 10.7 g of 5-bromo-2,4-difluorobenzaldehyde. This compound was allowed to react with benzothiophene by the procedure of Production Example II-12-a to yield an alcohol, and then the alcohol was oxidized by the procedure of Production Example II-10-b, to give 9.7 g of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[Si:19]([O:26][CH2:27][C@H:28]([OH:34])[CH2:29][O:30][CH:31]([CH3:33])[CH3:32])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[H-].[Na+]>C1COCC1>[Si:19]([O:26][CH2:27][C@@H:28]([CH2:29][O:30][CH:31]([CH3:33])[CH3:32])[O:34][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)OC[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.46 g), (2R)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-isopropoxypropan-2-ol (product of step iii) (0.66 g), THF (5 mL) and 60% sodium hydride (80 mg), to give the subtitle compound as a colourless oil. Yield: 0.56 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC(OC)=CC=2)=[CH:12][C:11]=1[CH:26](O)[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29].FC1C(B(C2C(F)=C(F)C(F)=C(F)C=2F)C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.C[Si]([C:71]#[N:72])(C)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH:26]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:71]#[N:72]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)CC(C)(C)C)c2)cc1
Reactant: C[Si](C)(C)C#N
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(O)cc2C(C#N)CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)-3,3-dimethylbutan-1-ol (160 mg) and tris(pentafluorophenyl)borane (20 mg) in acetonitrile (3 mL) was added trimethylsilyl cyanide (81 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (97 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[NH:21][CH:20](SC)[NH:19][C:18]2=[O:26])=[CH:13][CH:12]=1>O>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18](=[O:26])[NH:19][CH:20]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])[NH:21][C:22]2=[O:23])=[CH:15][CH:16]=1
Reactant: CC(C)CN
Reactant: CSC1NC(=O)N(c2ccc(C)cc2)C(=O)N1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(N2C(=O)NC(NCC(C)C)NC2=O)cc1
Reaction time: 5 h
Yield: 89.5 %

Procedure:
Isobutylamine (1.60 g.) was added to acetic acid (1.20 g.) at 20°-25° C. during 15 minutes. 3-(4-Methylphenyl)-6-methylthiotetrahydro-1,3,5-triazine-2,4-dione (4.98 g.) was then added, and the whole mixture stirred at 120°-125° C. for 5 hours and then cooled. Water (50 ml.) was added and the mixture stirred thoroughly. The solid produced was collected by filtration, washed with water and dried to give 3-(4-methylphenyl)-6-isobutylaminotetrahydro-1,3,5-triazine-2,4-dione (4.90 g., 89%), m.p. 297°-301° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[C:16]([CH2:30][NH2:31])=[CH:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C1COCC1>[CH2:6]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[C:16]([CH2:30][NH:31][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCn1cc(CN)c2cc(-c3cccc(C)c3)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCn1cc(CNS(C)(=O)=O)c2cc(-c3cccc(C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Methanesulfonyl chloride (33 μl, 0.434 mmol) was added to a solution of (1-octyl-5-m-tolyl-1H-indol-3-yl)methanamine (152 mg, 0.434 mmol) and triethylamine (91 μl, 0.651 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to stir at room temp for 60 min, the precipitate formed was filtered off, the filtrate was concentrated, and the residue was subjected to column chromatography (silica gel, CH2Cl2) to give sulphonamide 22 in 61% yield.
Reaction SMILES: C([O:3][P:4](/[CH:9]=[CH:10]/[C@@:11]1([NH:30]C(=O)OC(C)(C)C)[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)[CH2:12]1)([O:6]CC)=[O:5])C.Br[Si](C)(C)C>ClCCl>[NH2:30][C@:11]1(/[CH:10]=[CH:9]/[P:4](=[O:3])([OH:6])[OH:5])[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)[CH2:12]1
Reactant: CCCCCCCCc1ccc([C@H]2CC[C@@](/C=C/P(=O)(OCC)OCC)(NC(=O)OC(C)(C)C)C2)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCc1ccc([C@H]2CC[C@](N)(/C=C/P(=O)(O)O)C2)cc1
Reaction time: 16 h
Yield: 82.6 %

Procedure:
Tert-butyl (1R,3S)-1-((E)-2-(diethoxyphosphoryl)vinyl)-3-(4-octylphenyl)cyclopentylcarbamate (0.2 g, 0.373 mmol) (10035787-0263) was dissolved in dichloromethane (3.73 ml) in a sealed vial to give a colorless solution. Bromotrimethylsilane (0.484 ml, 3.73 mmol) (Fluka) was added and the reaction stirred for about 16 h. Solvents were removed under reduced pressure to a thick oil. Methanol (4 mL) and water (0.2 mL) were added. The solution was sonicated and stirred, resulting in a cloudy reaction where a heavy precipitate forms. The solution was stirred for about 4 h. Add water (5 mL) and more product precipitated. The resulting solid was collected by vacuum filtration, washed with water and then pentane and dried under vacuum to provide (E)-2-((1R,3S)-1-amino-3-(4-octylphenyl)cyclopentyl)vinylphosphonic acid (0.117 g, 0.308 mmol, 83% yield) as a white solid: LCMS (method a) Rt=3.01 min.; MS m/z: 380.21 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[NH:19][C:20]1[N:24]([CH3:25])[C:23]2[CH:26]=[C:27]([O:33][CH3:34])[C:28]([C:30]([OH:32])=O)=[CH:29][C:22]=2[N:21]=1.[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1>>[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:30]([C:28]2[C:27]([O:33][CH3:34])=[CH:26][C:23]3[N:24]([CH3:25])[C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:8][NH:9][C:10]([C:12]5([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]5)=[O:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:21][C:22]=3[CH:29]=2)=[O:32])=[CH:38][CH:37]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1cc(CNC(=O)C3(C(F)(F)F)CC3)ccc1Cl)n2C
Product: COc1cc2c(cc1C(=O)Nc1ccc(Br)cc1)nc(Nc1cc(CNC(=O)C3(C(F)(F)F)CC3)ccc1Cl)n2C

Procedure:
The title compound was prepared from 2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-methoxy-1-methyl-1H-benzimidazole-5-carboxylic acid (92 mg; 0.19 mmol) and 4-bromoaniline (33 mg; 0.19 mmol) in accordance with Example 59, step (a). Yield: 73 mg (59%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.16 (1H, s) 8.40 (1H, t, J=6.0 Hz) 8.25 (1H, s) 7.85-7.81 (1H, m) 7.76-7.68 (3H, m) 7.51-7.46 (2H, m) 7.40 (1H, d, J=8.2 Hz) 7.22-7.17 (1H, m) 6.92-6.86 (1H, m) 4.25 (2H, d, J=6.0 Hz) 3.97 (3H, s) 3.71 (3H, s) 1.37-1.32 (2H, m) 1.23-1.18 (2H, m). MS m/z: 650, 652, 654 [M+H]+.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:23]4[CH2:25][CH2:24]4)=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:23]4[CH2:25][CH2:24]4)=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate (1.17 g, 3.43 mmol) and lithium hydroxide monohydrate (0.58 g, 13.70 mmol) in tetrahydrofuran (60 mL) and water (10 mL) was refluxed for 2 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 mL); washed with 1 M aqueous hydrochloric acid (80 mL) and brine (80 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo to afford the title compound which was used without further characterization. MS (ES+) m/z: 328.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=O.[Br-].[CH3:26][O:27][C:28]1[CH:53]=[CH:52][CH:51]=[CH:50][C:29]=1[CH2:30][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=[CH:30][C:29]1[CH:50]=[CH:51][CH:52]=[CH:53][C:28]=1[O:27][CH3:26]
Reactant: COc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Agent: [Br-]
Product: COc1ccccc1C=Cc1cc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)ccc1OC

Procedure:
4-{4-Methoxy-3-[2-(2-methoxyphenyl)vinyl]phenoxy}-5-methyl-7-nitroindane was prepared in a similar manner to those described in Reference Example 15 using 2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde instead of 2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde and using (2-methoxybenzyl)triphenylphosphonium bromide instead of furfuryltriphenylphosphonium bromide.