Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[NH:46][C:44](=[O:45])[CH:43]([CH:47]([OH:54])[CH:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[CH:39]([CH:56]([CH3:58])[CH3:57])[N:38]([CH3:59])[C:36](=[O:37])[CH:35]([CH2:60][CH:61]([CH3:63])[CH3:62])[N:34]([CH3:64])[C:32](=[O:33])[CH:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[CH:27]([CH3:70])[NH:26][C:24](=[O:25])[CH:23]([CH3:71])[NH:22][C:20](=[O:21])[CH:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[CH:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[CH:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5].O>C(O)C.C(O)C(O)C>[CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[C@H:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:57])[CH3:58])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:62])[CH3:63])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5]
Reactant: C/C=C/CC(C)C(O)C1C(=O)NC(CC)C(=O)N(C)CC(=O)N(C)C(CC(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(CC(C)C)C(=O)NC(C)C(=O)NC(C)C(=O)N(C)C(CC(C)C)C(=O)N(C)C(CC(C)C)C(=O)N(C)C(C(C)C)C(=O)N1C
Solvent: CCO
Solvent: CC(O)CO
Solvent: O
Product: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C

Procedure:
100 g of ciclosporin A were dissolved in 770 g of polymer of Example 2, 100 ml of ethanol and 75 ml of propylene glycol, and the clear viscous solution was then dispensed into capsules. Infinite dilution of this solution with water was possible.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:30])[C@H:11]([NH:22]C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1.ClCCl>[ClH:1].[CH2:2]([O:9][C:10](=[O:30])[C@H:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)ccc1O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C[C@@H](N)C(=O)OCc2ccccc2)ccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4N Hydrogen chloride in 1,4-dioxane solution (9 ml) was added to an ice-cooled solution of (2R)-2-(tert-butyloxycarbonylamino)-3-(4-hydroxy-3-methoxyphenyl)propionic acid benzyl ester (2.90 g) in dichloromethane (29 ml). After being stirred at the same temperature for 2 hours, the mixture was concentrated under reduced pressure to give (2R)-2-amino-3-(4-hydroxy-3-methoxyphenyl)propionic acid benzyl ester hydrochloride (2.8 g) as an oil.
Reaction SMILES: C(OC(C1N=C(Br)C2C=C(C3C=CC(OC4C=CC=CC=4)=CC=3)SC=2C=1O)=O)CCC.[CH2:32]([O:36][C:37]([C:39]1[C:40]([OH:62])=[C:41]2[CH:48]=[C:47]([C:49]3[CH:54]=[CH:53][C:52]([O:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:51][CH:50]=3)[S:46][C:42]2=[C:43](Br)[N:44]=1)=[O:38])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([O:36][C:37]([C:39]1[C:40]([OH:62])=[C:41]2[CH:48]=[C:47]([C:49]3[CH:54]=[CH:53][C:52]([O:55][C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)=[CH:51][CH:50]=3)[S:46][C:42]2=[CH:43][N:44]=1)=[O:38])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)c1nc(Br)c2sc(-c3ccc(Oc4ccccc4)cc3)cc2c1O
Agent: CCCCOC(=O)c1nc(Br)c2cc(-c3ccc(Oc4ccccc4)cc3)sc2c1O
Product: CCCCOC(=O)c1ncc2sc(-c3ccc(Oc4ccccc4)cc3)cc2c1O

Procedure:
The title compound was prepared from a mixture of 4-bromo-7-hydroxy-2-(4-phenoxy-phenyl)-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester and 7-bromo-4-hydroxy-2-(4-phenoxy-phenyl)-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester, example 7-c, under conditions analogous to experimental example 13-a with isolation of the lower Rf isomer. MS: (+) m/z 420.06 (M+1).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:16][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc3oc4c(c3c2)CCCCCC4)cc1
Yield: 60.9 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.70 mmol), 4-t-butylbenzoyl chloride (0.14 mL, 0.73 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (17 mL) provided 4-tert-butyl-N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)benzamide (0.16 g). MS (ESI) m/z 376 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[O:18])[NH:7]1.[H-].[Na+].I[CH3:26]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[O:18])[N:7]1[CH3:26]
Reactant: CI
Reactant: O=c1[nH]n(Cc2ccc(F)c(F)c2)c2ccc([N+](=O)[O-])cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of 1-(3,4-difluoro-benzyl)-5-nitro-1,2-dihydro-indazol-3-one (prepared in analogy to example 80 using 3,4-difluorobenzylbromide (step A)) (0.2 g) in DMF was added NaH (0.019 g) and the solution was stirred for 1 hour. Iodomethane (0.14 g) was then added and the mixture was stirred overnight. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford a crude orange residue. Flash column chromatography of the crude residue over silica gel afforded the desired 1-(3,4-difluoro-benzyl)-2-methyl-5-nitro-1,2-dihydro-indazol-3-one (0.11 g) as a yellow solid. MS (ESI−): 318.1 ([M−H]−).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.[NH3:15]>CO.[Cu]>[NH2:15][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1
Reactant: Clc1cccc(Cl)c1-c1nsnc1Cl
Reactant: N
Agent: [Cu]
Solvent: CO
Product: Nc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A solution in methanol containing 5.31 g of 3-chloro-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole, 1.91 g of copper powder and 1.97 g of cuprous chloride saturated with ammonia gas was placed in a stainless steel vessel. After sealing the vessel, the solution was stirred at 120° C. for 24 hours. After allowing the mixture to cool, insoluble materials were removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain 2.19 g of 3-amino- 4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C(#N)C>[CH3:12][N:13]([CH:15]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH3:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.9 %

Procedure:
Ethyl acetoacetate (35.4 g) was dissolved in acetonitrile (200 ml), and dimethylformamide dimethyl acetal (30.9 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give ethyl 2-dimethylaminomethyleneacetoacetate (50.4 g, Y.:99%) as a red oil.
Reaction SMILES: C(CC(OCC)=O)#N.BrCCCBr.[CH2:14]([O:16][C:17]([C:19]1([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]C1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(C#N)CCCC1
Agent: BrCCCBr
Solvent: CCOC(=O)CC#N
Product: CCOC(=O)C1(C#N)CCC1
Yield: 67 %

Procedure:
1-Cyano-cyclobutanecarboxylic acid ethyl ester was prepared from ethyl cyanoacetate (10.0 g, 88.4 mmol) and 1,3-dibromopropane (8.9 ml, 88.5 mmol) in the same manner as 1-cyano-cyclopentanecarboxylic acid ethyl ester giving 1-cyano-cyclobutanecarboxylic acid ethyl ester as a yellow oil (9.03 g, 67%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=3[O:29][CH3:30])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:31](N1C=CN=C1)([N:33]1C=CN=C1)=O.CN>CN(C)C=O>[CH3:31][NH:33][C:24]([C:23]1[CH:27]=[CH:28][C:20]([O:19][C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=2)=[C:21]([O:29][CH3:30])[CH:22]=1)=[O:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(C(=O)O)ccc1Oc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
4-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-(methyloxy)benzoic acid (E264, Step 4) (145 mg, 0.35 mmol) was dissolved in dry dimethylformamide (5 ml), treated with 1,1′-carbonyldiimidazole (85 mg, 0.53 mmol) and the resulting mixture stirred at room temperature for 3 hours. The mixture was treated with methylamine (0.53 ml, 1.05 mmol, 2M in THF) and stirred for 4 hours. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (1:1 ethyl acetate:pentane) to afford the title compound (0.10 g); MS (ES+) m/e 327 [(M+H)—CO2tBu]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH2:24])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36][N:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH:24][C:40]([C:37]4[CH:36]=[N:35][C:34]([O:33][CH3:32])=[N:39][CH:38]=4)=[O:41])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(N)CC2)no1
Reactant: COc1ncc(C(=O)O)cn1
Product: COc1ncc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)cc(F)c43)CC2)cn1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-yl}-amide (example 32) has been coupled with 2-methoxy-pyrimidine-5-carboxylic acid to yield the title compound as light yellow solid. MS: 581.2 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](I)=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.CCCCCC.[CH:22](=[O:28])[C:23]1[O:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH:22]([C:23]2[O:27][CH:26]=[CH:25][CH:24]=2)[OH:28])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=Cc1ccco1
Reactant: Cc1cc(F)cc(C)c1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(F)cc(C)c1C(O)c1ccco1
Temperature: -75 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 5-fluoro-2-iodo-1,3-xylene (11 g, 44 mmol) in tetrahydrofuran (110 ml) is added 1.6 molar solution of n-butyl lithium in hexane (33 ml, 52 mmol) under nitrogen atmosphere at −75° C. The resulting solution is stirred at −75° C. for 60 minutes and to this mixture, a solution of furfural (6.3 g, 65.6 mmol) in THF (20 ml) is added over 20 minutes. The resulting solution is stirred at −75° C. for 2 hours. The cooling bath is removed and the mixture is allowed to reach room temperature, and then stirred for 5 hours. The reaction mixture is quenched with ice cold water (1000 ml) and extracted with ethyl acetate (3×250 ml), dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo to give a residue which is purified by flash chromatography (hexane/ethyl acetate) to afford (4-Fluoro-2,6-dimethylphenyl)furan-2-ylmethanol (6 g).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1)[NH2:6])=[N+:2]=[N-:3].[C:20]1([C@H:26]([CH3:30])[C:27](O)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>ClCCl>[N:1]([CH2:4][C@H:5]([NH:6][C:27](=[O:28])[C@H:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:30])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: CCCC(C)COc1ccc([C@@H](N)CN=[N+]=[N-])cc1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(C)COc1ccc([C@H](CN=[N+]=[N-])NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A solution of (1R)-2-azido-1-(4-(2-methylpentyloxy)phenyl)ethanamine (9.0 g, 34.3 mmol) in dichloromethane (100 mL) was cooled to 0° C. To this solution, (S)-2-phenylpropanoic acid (7.0 mL, 51.5 mmol), N,N-diisopropylethylamine (35.9 mL, 206 mmol) and HATU (19.57 g, 51.5 mmol) were added. The ice bath was removed and reaction mixture was stirred at room temperature for 3 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (60 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (30→40% ethyl acetate in hexanes) to afford (2S)-N-((1R)-2-azido-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (12.5 g, 92% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 7.21-7.34 (m, 5H), 6.98 (d, J=8.6 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.37 (d, J=8.1 Hz, 1H), 5.10 (ddd, J=7.9, 5.8, 5.7 Hz, 1H), 3.76 (dd, J=9.1, 5.8 Hz, 1H), 3.61-3.70 (m, 2H), 3.46-3.56 (m, 2H), 1.87-1.98 (m, 1H), 1.52 (d, J=7.3 Hz, 3H), 1.26-1.51 (m, 3H), 1.21 (dddd, J=12.3, 7.6, 5.3, 5.0 Hz, 1H), 1.01 (d, J=6.5 Hz, 3H), 0.93 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 395.3 [(M+H)+, calcd for C23H31N4O2 395.3].
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH:12](C)C(=O)C.N1C2C(=CC=CC=2)C=C1>C(O)(=O)C>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:12]=[CH:11]2
Reactant: CC(=O)C(C)C
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: c1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: Fc1ccc2[nH]ccc2c1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A mixture containing 4-Fluorophenylhydrazine hydrochloride (5.0 g; 30.75 mmol; ALDRICH), 3-methyl-2-butanone (3.7 g; 43 mmol; ALDRICH) and acetic acid (30 ml) was stirred for 30 min. under nitrogen to obtain the clear solution. The mixture was then refluxed at 130° C. The appearance of UV-Vis Abs. Max at 255 nm and the disappearance of the peak at 282 nm confirmed the formation of the indole. At the end of 40 min. the reaction was stopped and the mixture was poured into crushed ice (100 g). The residue was extracted into ethyl acetate (100 ml×2), washed with water (100 ml×2) and ethyl acetate layer was dried over anhydrous sodium sulfate. After filtration, ethyl acetate was removed, and the residue was dried to give 4.15 g of the indole (Yield 76%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C@H:17]3[CH2:29][CH2:28][O:27][C@H:18]3CO2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[C:30]([N:33]1C2C(=CC=C(N)C=2C(OC)=O)[C@H]2CCO[C@H]2[CH2:34]1)(=[O:32])[CH3:31].BrC1C=C(F)C=CC=1S(Cl)(=O)=O>>[C:30]([N:33]1[C:21]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])(=[O:10])=[O:11])[C:22]=2[C:23]([O:25][CH3:26])=[O:24])[C@H:17]2[CH2:29][CH2:28][O:27][C@H:18]2[CH2:34]1)(=[O:32])[CH3:31]
Reactant: COC(=O)c1c(N)ccc2c1N(C(C)=O)C[C@@H]1OCC[C@H]21
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1OCC[C@H]21
Agent: O=S(=O)(Cl)c1ccc(F)cc1Br
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1N(C(C)=O)C[C@@H]1OCC[C@H]21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from methyl cis-(3aRS,9bRS)-5-acetyl-7-amino-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylate (Intermediate 29) and 2-bromo-4-fluorobenzenesulfonyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].O[CH2:16][CH:17]([CH2:19]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[C:7]2[C:5]=1[N:6]=[CH:19][CH:17]=[CH:16]2)([O-:3])=[O:2]
Reactant: Nc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c2cccnc12
Yield: 69.8 %

Procedure:
In a similar fashion using route 10 general procedure 20, 2-nitro-5-(trifluoromethyl)aniline (1.0 g, 4.85 mmol), glycerol (1.4 g, 15.0 mmol) and 3-nitrobenzenesulfonic acid sodium salt (1.42 g, 6.31 mmol) gave the title compound (820 mg, 80%) which was used in the next step without purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[O:6]=[C:5]([CH:7]=[CH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)C=CCCc1ccccc1
Temperature: -25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a suspension of 60% NaH (2.76 g, 69 mmol) in anhydrous DMF (50 mL) at 0° C. is added a solution of methyl acetoacetate (8 g) in DMF (50 mL) dropwise over 10 minutes. The mixture is cooled to -25° C. and 2.5M n-butyllithium (27.6 mL, 69 mmol) is added dropwise over 5 minutes. The mixture is stirred for 5 minutes and 1-bromo-3-phenylpropane (10.48 mL, 69 mmol) is added dropwise over 5 minutes. The cooling bath is removed and the mixture is stirred at room temperature for 2 hours. The mixture is poured into water and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (6:1 hexane:ethyl acetate) to produce methyl 3-keto-7-phenylheptenoate as an oil (8 g, 50% ): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.50-1.68 (m, 4H), 2.42-2.62 (m, 4H), 3.40 (s, 2H), 3.70 (s, 3H), 7.10-7.18 (m, 2H), 7.18-7.30 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]2[N:10]([N:16]=[CH:17][CH:18]=2)[C:11]([C:14]#[N:15])=[CH:12][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:9]2[N:10]([N:16]=[CH:17][CH:18]=2)[C:11]([C:14]#[N:15])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)n2nccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N)c2ccnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a clear solution of (7-cyano-pyrazolo[1,5-a]pyridin-4-yl)-carbamic acid tert-butyl ester (3 g, 11.6 mmol) in methylene chloride (40 mL) was added TFA (8 mL). The mixture was stirred at rt for 3 h, and then concentrated under reduced pressure. The residue was partitioned between EtOAc (100 mL) and sat. NaHCO3 solution (50 mL). The aqueous solution was separated and extracted with EtOAc (2×50 mL). The combined organic solutions were dried over Na2SO4, filtered though SiO2 pad, and concentrated under reduced pressure. Crystallization in EtOAc and 95% EtOH gave compound 777F (1.07 g, 58%) as a dark yellow solid. HPLC: 97% at 1.96 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 159 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[CH:6]=[C:5]2[C:17]([F:20])([F:19])[F:18].Cl.[NH2:22][CH2:23][CH2:24][SH:25].[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:25][CH2:24][CH2:23][NH2:22])[N:8]=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[CH:6]=[C:5]2[C:17]([F:20])([F:19])[F:18]
Reactant: NCCS
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(Br)c(Cl)cc2n1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(Br)c(SCCN)cc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A solution of 6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline (0.500 g, 1.36 mmol), 2-aminoethanethiol hydrochloride (0.185 g, 1.63 mmol), NaH (60% in mineral oil, 0.136 g, 3.40 mmol) in 6.8 mL DMF was stirred at 0° C., then allowed to warm to rt. After 4 h, the mixture was poured into a cold saturated NH4Cl:water (60 mL, 1:1). The solution was extracted with EtOAc (2×60 mL), and the combined organic layers washed sequentially with water (30 mL), brine (30 mL), dried over MgSO4, filtered, and concentrated. Flash chromatography (9:1 CH2Cl2:MeOH) afforded 0.404 g (73%) of 2-{[6-bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl}-1-ethanamine, a yellow-brown solid. Data for 2-{[6-bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl}-1-ethanamine: 1H NMR (400 MHz, CDCl3) δ 8.13 (broad s, 1H), 7.63 (s, 1H), 7.10 (s, 1H), 5.54 (hept, 1H, J=6.2), 3.17-3.25 (m, 2H), 3.08-3.15 (m, 2H), 1.41 (d, 6H, J=6.2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[C:14]1=[O:32].Cl.O1CCOCC1>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[C:14]1=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCC(Nc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1ccc(NC2CCCN(C3CCNCC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Tert-butyl 3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (7.9 g, 17 mmol) was dissolved in CH2Cl2 (100 mL) and MeOH (10 mL). 4N HCl in dioxane (29 mL, 118 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2) to afford 3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (6.2 g, 17 mmol, 100% yield) as yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>C(OCC)(=O)C>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[CH:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: N#Cc1cccc(N)c1
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(Nc2cccc(C#N)c2)c1

Procedure:
2 g of 3-fluoro-4-nitroanisole and 15 ml of 3-aminobenzonitrile were stirred for 65 hours at 140° C. The batch was then diluted with ethyl acetate, washed three times with water and once with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.