Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@:24]([CH3:30])([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Li+]>O1CCCC1>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@:24]([CH2:26][OH:27])([CH3:30])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC(=O)[C@]1(C)CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.6 %

Procedure:
To a solution of methyl(2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-methyl-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 45, 72.9 mg, 0.118 mmol) in Tetrahydrofuran (THF) (2.5 ml) at 0° C. lithium borohydride (0.174 ml, 0.354 mmol) was added and the reaction mixture was stirred at room temperature and under nitrogen atmosphere for 3 days. Volatiles were evaporated in vacuo and the residue was dissolved in Methanol (2 ml)/HCl 1 N in water (3 ml). After 1 h stirring combined solvents were evaporated in vacuo. The residue was dissolved in Ethyl acetate (4 ml) and washed with NaHCO3 sat. sol. 2×3 ml. Organic phase was dried and evaporated and the residue was purified by flash chromatography on silica gel using a Biotage SNAP 10 g as column and Dichloromethane/Methanol 95:5 as eluent affording the title compound (39.8 mg, 0.068 mmol, y=57.2%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:42]=[CH:41][C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]3[N:28]=[C:27]([N:29]4[C:33]([C:34]([F:37])([F:36])[F:35])=[C:32]([C:38]([OH:40])=[O:39])[CH:31]=[N:30]4)[CH:26]=[CH:25][CH:24]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-:43].[Li+].Cl.[O:46]1CCOCC1>C(#N)C>[C:33]([OH:46])([C:34]([F:37])([F:36])[F:35])=[O:43].[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:42]=[CH:41][C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]3[N:28]=[C:27]([N:29]4[C:33]([C:34]([F:35])([F:37])[F:36])=[C:32]([C:38]([OH:40])=[O:39])[CH:31]=[N:30]4)[CH:26]=[CH:25][CH:24]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1COCCO1
Reactant: [OH-]
Agent: CC(=O)N1CCC(c2ccc(COc3ccc(C)cc3-c3cccc(-n4ncc(C(=O)O)c4C(F)(F)F)n3)cc2)CC1
Agent: Cl
Agent: [Li+]
Solvent: CC#N
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the title compound from Example 12 Step F (24 mg, 0.035 mmol) in DCM (1 mL) were added DIEA (62 μL, 0.35 mmol) and acetyl chloride (8.3 mg, 0.104 mmol), and the resulting mixture was allowed to stir at room temperature. After 18 h, the reaction mixture was quenched by addition of sat aq NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was separated and concentrated in vacuo to provide the crude amide, which was used without further purification: LCMS m/z 606.9 [M+1-1]+. To a solution of the amide in dioxane (1.5 mL) was added lithium hydroxide (0.75 mL, 2N aqueous, 1.5 mmol), and the mixture was stirred at 50° C. After 1 h, the reaction mixture was rendered acidic by addition of HCl (2N aqueous), then was diluted with acetonitrile and purified by reverse phase HPLC (40 to 100% acetonitrile/water, both 0.1% v/v TFA) to provide the title compound: LCMS m/z 578.9 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.10 (t, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.23-7.21 (m, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 1H), 5.16 (s, 2H), 4.52-4.49 (m, 1H), 3.91-3.87 (m, 1H), 3.12-3.07 (m, 1H), 2.77-2.70 (m, 1H), 2.58-2.53 (m, 1H), 2.27 (s, 3H), 2.01 (s, 3H), 1.78-1.72 (m, 2H), 1.59-1.51 (m, 1H), 1.44-1.35 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.CN(C)CCN.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([O:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[N:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCn2nc(OCc3ccccc3)cc21
Reactant: Fc1ccc(Br)cc1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1c2cc(OCc3ccccc3)nn2CCN1c1ccc(F)cc1
Temperature: 140 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
Copper (I) iodide (0.74 g, 3.88 mmol) was added to a stirred suspension of 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (1.5 g, 6.17 mmol), 4-bromofluorobenzene (2.03 mL, 18.5 mmol), N,N-dimethylethylenediamine (0.73 mL, 6.78 mmol) and K2CO3 (2.13 g, 15.42 mmol) in toluene (90 mL). The reaction mixture was stirred at 140° C. for 16 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 30/70). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with pentane to yield 2-(benzyloxy)-5-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (1.8 g, 86% yield) as a white solid. C19H16FN3O2. 1H NMR (500 MHz, CDCl3) δ ppm 4.07-4.17 (m, 2H), 4.32-4.40 (m, 2H), 5.22 (s, 2H), 6.35 (s, 1H), 7.07-7.16 (m, 2H), 7.27-7.33 (m, 2H), 7.32-7.36 (m, 1H), 7.36-7.42 (m, 2H), 7.45 (d, J=7.2 Hz, 2H).
Reaction SMILES: [C:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Pd].C(O)C>[CH:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cccc(C2=CCCC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cccc(C2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A mixture of 6-cyclopentenyl-pyridine-2-carboxylic acid (0.08 g, 0.42 mmol) and palladium on carbon (10% w/w, 0.04 g, 0.3 mmol) in ethanol (10 mL) was charged with a hydrogen balloon and stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to obtain the crude product as white solid (0.08 g, 99%) which was used directly in the next step without further purification; MS (EI): m/e=192.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>C1COCC1>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][S:8]([C:5]4[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc(I)cc4)cc23)CC1
Yield: 84.8 %

Procedure:
By a method similar to Example 31, using 4-Iodobenzenesulfonyl chloride (347 mg, 1.15 mmol) in THF (4 mL), 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (220 mg, 0.96 mmol) in 0.2 N sodium hydroxide (5.2 mL, 1.05 mmol) and THF (4 mL) gave 470 mg of an off white solid. The crude product was recrystallized from ethyl acetate/hexanes to give 404 mg (85%) of tan crystals: mp=174-176° C.; MS(m/e): 495 (M−1); Calculated for C20H21N2O3S: Calcd: C, 48.40; H, 4.26; N, 5.64. Found: C, 48.74; H, 4.20; N, 5.59.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](=O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]1([CH3:18])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3
Reactant: CC(=O)CCCCl
Reactant: OCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(CCCCl)OCCc2c1[nH]c1ccccc21
Reaction time: 1 h

Procedure:
To a solution of tryptophol (15 g, 0.09 M) in 150 ml of benzene, 5-chloro-2-pentanone (12 g, 0.10 M) is added. The mixture is heated in the presence of 200 mg of p-toluenesulfonic acid and hydrated alkali-aluminum silicate (Molecular Sieves No. 4). After 1 hr. of refluxing, 400 mg more of acid is added. After a total of 2 hr. the reaction is cooled, filtered and washed with 5% sodium bicarbonate, water and dried over sodium sulfate. Evaporation under reduced pressure affords an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentratio of the eluent gives 1-(3-chloropropyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (CDCl3) δ1.33 (3H); 1.93 (4H), 2.75 (2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:28]2[CH2:29][CH2:30][C:25]([F:31])([F:24])[CH2:26][CH2:27]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: FC1(F)CCNCC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Temperature: 65 °C

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.106 g, 0.301 mmol), 4,4-difluoropiperidine hydrochloride (0.0570 g, 0.362 mmol), palladium acetate (1 mg, 0.006 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6 mg, 0.009 mmol), and cesium carbonate (0.274 g, 0.843 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over sodium sulfate and evaporated to dryness. The resulting residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product. LCMS calculated for C16H16ClF2N2O (M+H)+: m/z=325.1; Found: 325.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:18])[C:7]=1[C:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:17][O:16][CH2:15]2)[CH2:12][CH:13]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>[F:18][C:6]1[C:7]([C:8]2[CH2:9][CH2:10][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:12][CH:13]=2)=[C:2]([NH:20][C:19](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=[N:4][CH:5]=1
Reactant: Fc1cncc(Cl)c1C1=CCN(C2COC2)CC1
Reactant: CC(C)(C)OC(N)=O
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Product: CC(C)(C)OC(=O)Nc1cncc(F)c1C1=CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.2 %

Procedure:
3-chloro-5-fluoro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]pyridine (572 mg, 2.129 mmol), tert-butyl carbamate (1.246 g, 10.64 mmol), sodium tert-butoxide (1.044 g, 10.86 mmol), BrettPhos pre-catalyst (84.78 mg, 0.1064 mmol) and BrettPhos (57.11 mg, 0.1064 mmol) were placed in a sealable tube and degassed by vacuum/nitrogen cycles (×5). Dry dioxane (10 mL) was added and the resulting mixture was placed into a pre-heated block at 100° C. and stirred at this temperature for 16 hours. The reaction mixture was cooled to ambient temperature and quenched with saturated NH4Cl. The mixture was passed through a pre-wetted (EtOAc) celite cartridge (2.5 g). The cartridge was washed with EtOAc/saturated NH4Cl and the layers of the filtrate separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl (5-fluoro-1′-(oxetan-3-yl)-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)carbamate as a pale yellow solid (180 mg, 24% Yield). Also isolate 197 mg of a mixture of SM and product. MS (ES+) 350.2.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31](/[CH:32]=[CH:6]/[CH2:5][C:2]([OH:4])=[O:3])=[CH:30][CH:29]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(/C=C/CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
The mixture of (2-carboxyethyl)triphenylphosphonium bromide (20.0 g, 54.0 mmol) and 4-methoxybenzaldehyde (6.5 g, 53.5 mmol) in anhydrous DMSO (64 mL) was added slowly to the suspension of 60% NaH in mineral oil (4.3 g, 107 mmol) in anhydrous tetrahydrofuran (32 mL). The reaction mixture was stirred at 0° C. for 30 minutes then warmed to room temperature over 4 hours. The reaction mixture was quenched with 1N HCl (150 mL) and extracted with ethyl acetate. The organic phase was washed with water, brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50% EtOAc in hexanes) to provide (E)-4-(4-methoxyphenyl)but-3-enoic acid (557) (5.7 g, 55.0%) as a yellow solid.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]2=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:7]2[N:6]=1)(=O)=O.[C-]#N.[K+].[CH3:25][N:26]1CCCC1=O.CCOC(C)=O>CO.C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[N:7]2[C:8]([CH:9]=[N:10][C:5]([C:25]#[N:26])=[N:6]2)=[CH:11][CH:12]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)(=O)=O)nn12
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1-c1ccc2cnc(C#N)nn12
Yield: 72.4 %

Procedure:
2-Methanesulfonyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (804 mg, 2.65 mmol) and Potassium cyanide (311 mg, 4.77 mmol) in N-Methylpyrrolidinone (8.0 mL, 84 mmol) was stirred under an atmosphere of Nitrogen at 80° C. for 7 h, reaching ˜90% conversion. Work up by partitioning between 50% brine (40 mL):EtOAc (60 mL); giving an emulsion, so DCM (20 mL) was added. The emulsion did not successfully break, so it was kept with the aq. The aq. and emulsion was ext. with EtOAc (3×40 mL), the emulsion was isolated by itself and solubilized with DCM:MeOH. Combining all the org. layers, the mix. was washed with satd. NaHCO3 (50 mL) and brine (2×50 mL), dried over sodium sulfate (two iterations) then conc. in vacuo. Purify on silica gel (ISCO 40 g, 0-40% EtOAc:Hex) to afford 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile (0.480 g, 72%). 1H-NMR (CDCl3): 8.95 (s, 1H), 7.73 (m, 1H), 7.48 (m, 1H), 7.42 (d, 1H, J=4.7 Hz), 7.1-7.2 (m, 3H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:29]1([CH2:28][NH:35][C:36](=[O:37])[O:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=[C:2]3[CH3:1])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCCN(c1ccncc1)n1cc(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1cc(C)c2cc(OC(=O)NCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution consisting of 3-methyl-1-(propyl-4-pyridinylamino)-1H-indol-5-ol (1.80 g) and tetrahydrofuran (43 ml) were added with stirring at room temperature milled potassium carbonate (0.93 g) and benzyl isocyanate (0.87 ml). Stirring was continued under nitrogen for 16 hours. The mixture was filtered through a pad of celite and the solids washed with ethyl acetate. Concentration followed by purification via flash column chromatography (silica gel, 2% Et3N/EtOAc) afforded 2.28 g of the desired carbamate. Recrystallization from ether gave a highly crystalline solid, m.p. 149°-151° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([F:49])[CH:48]=1)[C:44]#[N:45].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[CH3:12][C:7]1([CH3:13])[C:6]2[CH:14]=[C:2]([C:41]3[CH:42]=[C:43]([CH:46]=[C:47]([F:49])[CH:48]=3)[C:44]#[N:45])[CH:3]=[C:4]([O:15][CH3:16])[C:5]=2[NH:10][C:9](=[O:11])[O:8]1
Reactant: COc1cc(Br)cc2c1NC(=O)OC2(C)C
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(F)cc(C#N)c2)cc2c1NC(=O)OC2(C)C
Temperature: 85 °C
Yield: 32.8 %

Procedure:
A mixture of 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.6 g, 5.6 mmol), bis(pinacolato)diboron (1.6 g, 6.3 mmol), potassium acetate (1.5 g, 15.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol) in DMF (30 mL) was subject to a positive flow of nitrogen to remove oxygen and then heated at 85° C. under a blanket of nitrogen for 18 hours. The reaction mixture was allowed to cool to ambient temperature, treated with 3-bromo-5-fluoro-benzonitrile (1.2 g, 6 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol), and sodium carbonate (2 g, 19 mmol) in water (10 mL). The resulted solution was heated at 85° C. for 3 hours under a blanket of nitrogen, cooled to rt, and treated with brine (50 mL). Ethyl acetate (100 mL) was added, organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a flash silica gel column chromatography (THF:hexane/2:3) to yield 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile as a white solid (0.6 g, 33%): mp 252-253° C.; 1H-NMR (DMSO-d6) δ9.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, J=10.6 Hz), 7.82 (m, 1H), 7.39 (s 1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z 325 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21](CC3C=CC(OC)=CC=3)[C:20](=[O:32])[N:19]2[CH3:33])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>O>[CH2:1]([O:3][C:4](=[O:34])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:32])[N:19]2[CH3:33])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CNC(=O)N2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 118.5 %

Procedure:
A mixture of 2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (2.72 g, 5.78 mmol) and triethylsilane (1.34 g, 11.5 mmol) was treated with trifluoroacetic acid (70 mL) and stirred at room temperature under N2 for 5 h. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 98:2 CH2Cl2:MeOH to afford 2.40 g (100%) 2-methyl-2-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid ethyl ester. Rf=0.09 (1:1 hexanes:acetone); MS (ES+) Calc'd for C18H27N2O5 (M+1) 351. Found m/z 351 (100%). 1H NMR.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[N:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 75 °C
Yield: 142.6 %

Procedure:
A mixture of 2-benzyloxy-5-bromobenzaldehyde (20 g) and hydroxylamine hydrochloride (9.55 g) in pyridine (50 ml) was heated at 75° C. for 45 minutes. The solvent was evaporated and the residue purified by chromatography, eluting with dichloromethane, to give 2-benzyloxy-5-bromobenzaldehyde oxime (30 g) (mp 132°-134° C.).
Reaction SMILES: [Na].CS([C:6]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[S:8][N:7]=1)(=O)=O.[CH2:17]([OH:19])C>>[CH3:17][O:19][C:6]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[S:8][N:7]=1
Reactant: CS(=O)(=O)c1nsc(N2CCNCC2)n1
Reactant: CCO
Agent: [Na]
Product: COc1nsc(N2CCNCC2)n1
Temperature: 50 °C
Yield: 77 %

Procedure:
100 mg (4.0 mmol) of sodium were added to ethanol (20 ml). After reaction of the sodium was complete, 500 mg (2.0 mmol) of 1-(3-methanesulfonyl-[1,2,4]-thiadiazol-5-yl)piperazine were added and the mixture was subsequently stirred at 50° C. 2 h. The cooled reaction solution was poured into a satd aq. NaCI soln cooled to 0° C. This mixture was extracted with EA. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 310 mg (1.54 mmol, 77%) of 1-(3-methoxy-[1,2,4]-thiadiazol-5-yl)piperazine were obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]([N:26]1[CH2:33][CH:32]([O:34][CH2:35][O:36][CH3:37])[CH2:31][C@H:27]1[C:28]([OH:30])=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:38]1([CH2:44][NH2:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.ON1C(=O)CCC1=O>O1CCOCC1>[CH2:16]([O:23][C:24]([N:26]1[CH2:33][CH:32]([O:34][CH2:35][O:36][CH3:37])[CH2:31][C@H:27]1[C:28]([NH:45][CH2:44][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:30])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCOC1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: NCC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Product: COCOC1C[C@@H](C(=O)NCC2CCCCC2)N(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
13.4 g of dicyclohexylcarbodiimide was added, at room temperature, to a solution of 19.3 g of 1-benzyloxycarbonyl-4-methoxymethoxy-L-proline, 8.5 ml of cyclohexylmethylamine and 7.5 g of N-hydroxysuccinimide in 200 ml of dioxane. The mixture was stirred at the same temperature for 2 hours, then heated at 60° C. for 1 hour, and allowed to cool, followed by filtration. The solvent in the filtrate was removed by filtration. The resulting residue was purified by a silica gel column chromatography (eluant; 5% methanol/chloroform) to obtain 21.2 g of N-(1-benzyloxycarbonyl-4-methoxymethoxy-L-prolyl)-N-cyclohexylmethylamine as a light yellow oil.