Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[N:5]1([CH2:11][C:12]2[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=2)[O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][NH2:23])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1COCC1>[CH3:1][NH:2][C:3](=[S:4])[NH:23][NH:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][O:15][C:14]1[CH:24]=[CH:25][CH:26]=[C:12]([CH2:11][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[CH:13]=1)=[O:21]
Reactant: CN=C=S
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: C1CCOC1
Product: CNC(=S)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.5 g (6.6 mmol) of methylisothiocyanate are added to 1.0 g (3.3 mmol) of N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carboxamide in 20 ml of THF and the mixture is stirred at room temperature for 12 hours. The precipitate obtained is filtered off and recrystallised from ethanol. The analytical values are summarized in Table I.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH2:15].C(N(CC)CC)C>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:15]=[C:14](\[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])/[C:13]([O:23][CH2:24][CH3:25])=[O:22])=[C:3]([N+:10]([O-:12])=[O:11])[C:4]=1[CH3:9]
Reactant: C=C(CC(=O)OCC)C(=O)OCC
Reactant: Cc1c(N)ccc(I)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C/C(=C\c1ccc(N)c(C)c1[N+](=O)[O-])C(=O)OCC
Temperature: 80 °C
Yield: 42.8 %

Procedure:
To a solution of 4-iodo-2-methyl-3-nitrobenzenamine (59 mmol) in dimethylformamide (100 mL) was added diethyl itaconate (13.2 g, 71 mmol), tetrabutylammonium chloride (16.4 g, 59 mmol), triethylamine (236 mmol) and palladium acetate (675 mg, 3 mmol) under nitrogen. The reaction mixture was heated to 80° C. for 2 h. The crude reaction mixture was then filtered, diluted with ether (250 mL), washed with water (2×300 mL). The crude product was purified by flash chromatography using 20% ethyl acetate in hexane to give 8.5 g of the title compound. 1H NMR (500 MHz, CDCl3): in δ 7.58 (s, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 4.24-4.15 (m, 4H), 3.40 (s, 2H), 2.06 (s, 3H), 1.30-1.23 (m, 6H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[O:45][C:30]3=[CH:31][N:32]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41](=O)[NH2:42])=[CH:37][C:36]=4[F:44])[CH:34]=[C:29]3[CH2:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[O:45][C:30]3=[CH:31][N:32]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:36]=4[F:44])[CH:34]=[C:29]3[CH2:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C(N)=O)cc4F)ncc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C#N)cc4F)ncc3O2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic anhydride (50 mL) is added to a mixture of 4-[5-(4-carbamoyl-2-fluoro-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (50 mg) and triethylamine (100 mL) in dichloromethane (3 mL) and the reaction mixture is stirred at room temperature for 1 h. Aqueous NaHCO3 solution is added and the mixture is extracted with dichloromethane. The combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is triturated with diethyl ether, stirred for 1 h, filtered off, and dried to give the title compound. LC (method 7): tR=1.47 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=[N:40][C:35]2[CH:36]=CC=N[C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N)C.CCN(C(C)C)C(C)C>O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:40][CH:35]([CH3:36])[CH3:34])=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.9 %

Procedure:
To a DMF (1.0 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 80 mg, 0.244 mmol) was added HATU (112 mg, 0.293 mmol) and propan-2-amine (0.0250 ml, 0.293 mmol) at ambient temperature, followed by drop-wise addition of DIEA (0.128 ml, 0.733 mmol) at 0° C. After stirring for 5 minutes at ambient temperature, the reaction was poured into 1:1 water/saturated NaHCO3 (15 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by reverse-phase chromatography (5 to 54% acetonitrile/water) to yield the final product as white solid (26 mg, 29%). LCMS (apci) m/z=369.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[CH2:11](C(CC)(CC)C([O-])([O-])[O-])[CH3:12]>C(O)(=O)C>[CH3:11][C:12]1[O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[N:1]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: Cc1cc(N)cc(N)c1O
Solvent: CC(=O)O
Product: Cc1nc2cc(N)cc(C)c2o1
Temperature: 25 °C

Procedure:
1.00 g (7.20 mmol) 2,4-diamino-6-methyl-phenol, 5.00 mL acetic acid and 15.0 mL (81.8 mmol) triethylorthoacetate were combined and refluxed. The reaction mixture was cooled to RT overnight and evaporated down. The residue was extracted with 0.5 N sodium hydroxide solution and EtOAc and the organic phase was evaporated down. The flask residue was triturated with diethyl ether and the precipitate formed was suction filtered. The mother liquor was evaporated down and the residue was purified by flash chromatography. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccccn2)cc1
Solvent: CCOC(C)=O
Product: Nc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a solution of (4-nitro-phenyl)-pyridin-2-yl-amine (280 mg, 1.3 mmol) in ethyl acetate (10 ml) was added stannous chloride dihydrate (1.17 g, 5.2 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 10% sodium hydroxide solution. The organic layer was separated, washed with brine, dried and evaporated to dryness. Purification by column chromatography using ethyl acetate/hexane (2:3) yielded N-pyridin-2-yl-benzene-1,4-diamine (80 mg, 33%).
Reaction SMILES: Br[C:2]1[C:3]([CH2:9][CH3:10])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[CH:4]=[C:3]([CH2:9][CH3:10])[C:2]([C:11]#[N:12])=[CH:7][N:6]=1
Reactant: CN(C)C=O
Reactant: CCc1cc(N)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCc1cc(N)ncc1C#N

Procedure:
A mixture of 5-bromo-4-ethylpyridin-2-amine (intermediate 99, 110 mg, 0.55 mmol), zinc cyanide (71 mg, 0.60 mmol) and Pd(PPh3)4 (63 mg, 0.06 mmol) in DMF (1 ml) was flushed with argon and heated in a septum sealed vial at 85° C. for 18 h. The cooled reaction mixture was evaporated, preabsorbed onto isolate and purified by normal phase chromatography with a 12 g RediSep® column: eluting with a gradient from DCM to 20% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 6.92 (s, br, 2H), 6.37 (s, 1H), 2.57 (q, 2H), 1.17 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][C:13]=1[F:14])[CH:10]1[CH:6]([NH:7]C(=O)O1)[CH2:5]2>[Pd].CCO>[F:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][C:13]=1[F:14])[CH2:10][CH:6]([NH2:7])[CH2:5]2
Reactant: O=C1NC2Cc3cc(F)c(F)cc3C2O1
Agent: [Pd]
Solvent: CCO
Product: NC1Cc2cc(F)c(F)cc2C1

Procedure:
A solution of 6,7-difluoro-3,3a,4,8b-tetrahydroindeno[2,1-d]oxazol-2-one (Preparation 80) (145 mg, 0.69 mmol) and 10% palladium on carbon (15 mg) in EtOH (10 mL) was stirred under H2 for 1 h. The reaction mixture was filtered through celite and the solvent removed in vacuo to give the title compound: δH (CDCl3) 2.66 (2H, dd), 3.15 (2H, dd), 3.86-3.94 (1H, m), 7.00 (2H, t).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38][Si](C(C)(C)C)(C)C)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCOCC1.Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([OH:38])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-tert-butyldimethylsilyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.12 g, 4.54 mmol) in Dioxane (25 mL) was added TBAF (75% wt in water) (2.375 g, 6.81 mmol). The mixture was stirred at rt for 4 h then was diluted with 1N HCl (25 mL) and water (5 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried with Na2SO4, filtered, and partially concentrated under reduced pressure to about 10 mL volume. To the partially concentrated mixture was added 1N HCl (50 mL). The solids that formed were collected by filtration and were washed with water. The expected product, (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (2.58 g, 4.50 mmol, 99% yield), was isolated as a white solid. LCMS: m/e 571.47 (M−H)−, 3.60 min (method 1). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.80 (br. s., 1H), 7.92 (d, J=8.24 Hz, 2H), 7.18 (d, J=8.24 Hz, 2H), 5.32-5.26 (m, 1H), 4.75 (s, 1H), 4.62 (br. s., 1H), 3.90 (s, 3H), 3.07-2.99 (m, 1H), 2.33-2.21 (m, 2H), 2.10 (dd, J=17.09, 6.10 Hz, 1H), 2.06-1.94 (m, 2H), 1.70 (s, 3H), 1.01 (br. s., 3H), 1.00 (br. s., 3H), 0.98 (s, 3H), 0.91 (s, 6H), 1.79-0.89 (m, 17H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1ccc(OC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 1 (40 mg, 0.1 mmol) in dioxane (2 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was removed and the crude was purified by recrystallization from MeOH-ether to yield the title product (30 mg, 90%); LCMS; 98%, ESI+ Calcd: 322.3, found m/z: 323.6 (M+1); 1HNMR (400 MHz, DMSO-d6): δ 1.73-1.84 (m, 1H), 1.86-2.04 (m, 2H), 2.10-2.20 (m, 1H), 3.18-3.28 (m, 2H), 3.88-3.98 (m, 1H), 4.16-4.21 (m, 1H), 4.33 (dd, J=10.8 Hz, 3.6 Hz, 1H), 7.14 (dd, J=6.8 Hz, 2.0 Hz, 2H), 7.40 (dd, J=6.8 Hz, 2.4 Hz, 2H), 7.89-7.97 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]([NH:15][CH:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH2:17][CH2:18][CH3:19])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.CO.[OH-].[Na+]>C1COCC1>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]([NH:15][CH:16]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH2:17][CH2:18][CH3:19])=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1)c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
Part B: A round bottom flask was charged with (±)-ethyl 4-(1-((5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)amino)butyl)benzoate (3.96 g, 8.93 mmol), MeOH (70 mL) and THF (70 mL). NaOH aq. 1M (44.6 mL) was then added in one portion and reaction stirred at room temperature for 1 hour and at 50° C. for 2 hours. Reaction mixture was cooled down to room temperature and organic solvents removed under reduced pressure. Water added to dissolve the crude solid and pH adjusted to ca. 4.5 with HCl (aq. 1N). The yellow solid formed was then recovered by filtration with a buchner funnel and dried under high vacuum to provide (±)-4-(1-((5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)amino)butyl)benzoic acid as a yellow solid (3.23 g, 87.1%). MS (M+1): 416.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:21]([O-])=O)[C:14]=1[S:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[Cl-].[NH4+].C>C(O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:21])[C:14]=1[S:15][CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN(C)CCSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)CCSc1c(Cl)cc2c([nH]c3cnccc32)c1N
Temperature: 60 °C
Reaction time: 20 h
Yield: 107 %

Procedure:
A 50 ml round-bottom flask with a magnetic stirrer was charged with [2-(6-chloro-8-nitro-9H-β-carbolin-7-ylsulfanyl)-ethyl]-dimethyl-amine (106 mg, 0.30 mmol) in 8 ml of anhydrous ethanol. To the resulting orange mixture at RT was added 0.33 M aqueous ammonium chloride (1.95 ml, 0.64 mmol) and iron powder (540 mg, 9.67 mmol). The reaction mixture was heated to 60° C. and stirred vigorously for 20 hr. Next, the mixture was cooled to RT, diluted with ethyl acetate (20 ml) and activated charcoal (ca. 150 mg) was added. The resulting mixture was filtered through a pad of celite and the resulting filtrate concentrated to afford 103 mg of 6-chloro-7-(2-dimethylamino-ethylsulfanyl)-9H-β-carbolin-8-ylamine as a yellow solid. The crude product was used directly in the coupling step.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]2[NH2:18])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:20]1[N:21]([C:25]2[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:22]=[CH:23][CH:24]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]2[NH:18][C:31]([C:26]2[C:25]([N:21]3[N:22]=[CH:23][CH:24]=[N:20]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:32])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC1(Nc2ncc(C(F)(F)F)cc2F)CCCC1N
Reactant: O=C(O)c1ncccc1-n1nccn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(Nc2ncc(C(F)(F)F)cc2F)CCCC1NC(=O)c1ncccc1-n1nccn1

Procedure:
A solution of 1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-1-methylcyclopentane-1,2-diamine (Intermediate 28; 57 mg, 0.21 mmol), 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 51 mg, 0.27 mmol), EDC (51 mg, 0.27 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (36 mg, 0.27 mmol) and triethylamine (0.086 ml, 0.62 mmol) in DCM (3 ml) was stirred at room temperature for 18 hours. The reaction was then diluted with DCM (20 ml) and a saturated solution of sodium bicarbonate (10 ml), filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26].O>C(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[N:16]([CH3:25])[C:15]1=[O:26]
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(O)cc2F)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
A solution of 32.9 mL (0.033 mole) of boron tribromide (1M in methylene chloride) in 50 mL of methylene chloride was stirred, and a solution of 3.5 grams (0.011 mole) of 3-(2-fluoro-4-methoxyphenyl)-1-methyl-6-trifluoromethyluracil in 50 mL of methylene chloride was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into water. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The methylene chloride extract and the organic layer were combined and washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was conc-entrated under reduced pressure, yielding about 2.9 grams of 3-(2-fluoro-4-hydroxyphenyl)-1-methyl-6-trifluoromethyluracil, mp 185°-190° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:19]1([C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)COc1cccc(CCCCO)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(CCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of methyl 3-(4-hydroxybutyl)phenoxyacetate (174 mg) in dimethylformamide (8.0 ml) was added successively trityl chloride (223 mg) and N,N-dimethylaminopyridine (88 mg). After stirred overnight at room temperature, the mixture was quenched by addition of water and extracted with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash silica gel chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (228 mg) having the following physical data.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]1[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:5])=[O:4].[H-].[Na+].[CH3:30]I>C1COCC1.CCOC(C)=O>[CH3:27][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([O:19][CH3:30])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]=[C:7]1[Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1cc(C(O)Cc2ccccc2)nc1[Si](C)(C)C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(Cc1ccccc1)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(tert-butyl-dimethyl-silanyl)-4-(1-hydroxy-2-phenyl-ethyl)-imidazole-1-sulfonic acid dimethylamide (160 mg) at r.t. in THF (5 ml) under an argon atmosphere was added NaH (18 mg; 55% dispersion in mineral oil) in one portion. After 1 hour stirring at r.t., MeI (0.04 ml) was added and stirring at r.t. was continued overnight. The mixture was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give 2-(tert-butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1-sulfonic acid dimethylamide (111 mg) as light yellow viscous oil. MS (ISP): 424.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:21][CH2:22]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:30]2[CH2:31][CH2:32][CH2:33][O:29]2)[CH:11]=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCO2)cc1
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CC2)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(-c2ccc(N)cc2)n(C2CC2)c2cc(OC3CCCO3)ccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
2-(4-aminophenyl)-1-cyclopropyl-6-hydroxyindole-3-carbonitrile (0.29 g, 1.0 mmol), prepared in example 1DD, step A, is mixed with K2CO3 (0.35 g, 2.5 mmol), toluene-4-sulfonic acid tetrahydrofuran-2-yl ester (0.36 g, 1.5 mmol) and acetonitrile (5 mL) and the mixture is stirred at 80° C. overnight. The solvent is removed in vacuum and the residue is treated with DCM and chromatographed (silica gel, DCM/EtOAc, 9/1) to provide 2-(4-aminophenyl)-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indole-3-carbonitrile (0.27 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:3]=1.[C:19]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:32]2[CH2:31][CH2:30][N:29]([C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH2:34][CH2:33]2)[N:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[NH:7]2
Reactant: Cc1cc(OCCCC=O)nc2c1CCC(=O)N2
Reactant: c1cc2c(c(N3CCNCC3)c1)CCCC2
Product: Cc1cc(OCCCCN2CCN(c3cccc4c3CCCC4)CC2)nc2c1CCC(=O)N2

Procedure:
The title compound was prepared by reductive amination of 4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine according to the above procedure. MS: APCI: M+1: 450.0 (Exact Mass: 448.28).