Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].C(=O)([O-])[O-].[K+].[K+].C(OCCO)C>[Cu].[Cu]I.O>[F:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[F:12])[CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: Nc1ccccc1F
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCCO
Product: O=C(O)c1ccc(F)cc1Nc1ccccc1F
Temperature: 135 °C
Reaction time: 8 h
Yield: 113.4 %

Procedure:
In a 50 mL round bottom flask, 2-bromo-4-fluorobenzoic acid (12.78 g, 58.4 mmol), 2-fluoroaniline (7.33 mL, 75.9 mmol), potassium carbonate (9.68 g, 70.0 mmol), copper (0.371 g, 5.84 mmol) and copper (I) iodide (0.556 g, 2.92 mmol) were added to 2-ethoxyethanol (50 mL). The mixture was heated to 135° C. overnight. The mixture was cooled and 100 mL of water was added. The slurry was stirred at room temperature overnight. The slurry was filtered through a bed of celite and washed with 2-ethoxyethanol. The pH of the filtrate was adjusted to 2 using 4N HCl and the solid was filtered off. The solid was then dried in high vacuum to give 4-fluoro-2-(2-fluoro-phenylamino)-benzoic acid (16.5 g, >100% yield).
Reaction SMILES: Cl[C:2]1[N:11]2[C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:10]2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>[Pd].O>[C:15]1([N:13]2[C:12](=[O:21])[N:11]3[CH2:2][NH:3][C:4]4[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=4[C:10]3=[N:14]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1n(-c2ccccc2)nc2c3c(nc(Cl)n12)CCCC3
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1n(-c2ccccc2)nc2n1CNC1=C2CCCC1

Procedure:
A mixture of 5-chloro-2-phenyl-7,8,9,10-tetrahydro-1,2,4-triazolo[4,3-c]quinazolin-3-one (150 mg, 0.5 mmol), diisopropylethylamine (130 ml, 0.74 mmol) and 10% Pd-C (30 mg) was hydrogenated under H2 balloon for 1 hour. The reaction was filtered through Celite. NaBH4 (30 mg, 0.79 mmol) was added to the filtrate and the mixture was heated to reflux temperature. The reaction was poured into water and extracted with CH2Cl2 (3×50 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The residue was triturated with ethanol and filtered to afford 2-phenyl-5,6,7,8,9,10-hexahydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 31), m.p. 158-159° C.
Reaction SMILES: NC(=NO)C1C=CC(COCC(OC(C)(C)C)=O)=CC=1.[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][OH:27])#[N:22].Br[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:27][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])#[N:22]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: N#Cc1cccc(CO)c1
Agent: CC(C)(C)OC(=O)COCc1ccc(C(N)=NO)cc1
Product: CC(C)(C)OC(=O)CCOCc1cccc(C#N)c1

Procedure:
The title compound was prepared according the procedure described for Intermediate 15 Step 1, but starting from 3-cyanobenzyl alcohol and tert-butyl 3-bromopropionate. It was isolated as a colorless oil (630 mg, 32%). 1H NMR (DMSO-d6, 300 MHz) δ 7.76 (m, 2H), 7.65 (m, 1H), 7.57 (m, 1H), 4.53 (brs, 2H), 3.64 (t, J=6.3 Hz, 2H), 2.49 (t, J=6.3 Hz, 2H), 1.40 (s, 9H). LC/MS (Method B) 262.2 (M+H)+. HPLC (Method A) Rt 4.75 min (Purity: 99.9%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:21])([CH3:20])[CH2:15][CH2:16]C[Mg]Br>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:16][CH2:15][C:14]([CH3:21])([CH3:20])[CH3:13])=[CH:6][CH:5]=1
Reactant: CC(C)(C)CCC[Mg]Br
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(C(O)CCC(C)(C)C)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and 4,4-dimethylpentylmagnesium bromide following the general method of Preparation 1.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](C(=O)C)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)=[O:26].OO>C1(C)C=CC=CC=1>[OH:26][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: O=CO
Agent: OO
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
4-n-Octyloxy-4'-acetylbiphenyl (38.5 g, 0.119 mol), formic acid (23.8 g, 5.17 mols) and toluene (200 ml) were heated to 60° C., followed by dropwise adding a 35% H2O2 aqueous solution (160.7 g, 1.04 mol) over 1.5 hour while keeping the liquid temperature at 70°~75° C., thereafter heating at 60°~70° C. for 3 hours with stirring, cooling down to room temperature, extracting with toluene (1.5 l), washing with water till the washing water became neutral, drying, removing toluene, adding ethanol (200 ml), heating under reflux, somewhat cooling, adding a 40% NaOH aqueous solution (80 ml ), again heating under reflux for 2 hours, pouring the solution in 6N hydrochloric acid (1 l), stirring, collecting the resulting solids by suction filtering, adding toluene (300 ml), withdrawing water and recrystallizing to obtain 4-hydroxy-4'-n-octyloxybiphenyl (18.5 g). Yield: 50.6%. M.P.: 153.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[C:7]([S:11][CH3:12])[N:6]=[C:5]2Cl.[BH4-].[Na+].C(Cl)Cl>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[C:7]([S:11][CH3:12])[N:6]=[CH:5]2
Reactant: CSc1nc(Cl)c2cc(Br)cn2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CSc1ncc2cc(Br)cn2n1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Into a round bottom flask, 6-Bromo-4-chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (6.00 g, 21.5 mmoles) was suspended in Isopropyl alcohol (69 mL) at 55° C. Sodium borohydride (1.71 g, 0.0452 mol) was added and heated at 60° C. for 3 hours. The reaction was allowed to cool to RT. The solid was filtered and washed with DCM. The solvent was removed under vacuum to a viscous oil. Methylene chloride (100 mL, 2 mol) was added to the viscous oil. Dichlorodicyanoquinone (5.38 g, 0.0237 mol) was then added portion wise over 15 minutes. The mixture was stirred for 30 minutes. The solid was filtered through Celite and washed with DCM. The solvent was removed under vacuum. The reaction was purified via ISCO column chromatography with hexane and EtOAca as eluant (0 to 8% EtOAC). The collected fractions afforded 6-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a light yellow solid (1.46, 27%).
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:3]1[OH:23].S(=O)(=O)(O)O.[OH-].[Na+].C[O:32][CH2:33][CH2:34]O>>[CH3:15][C:13]1[N:14]=[C:7]2[C:6]3[NH:5][C@H:4]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C@@H:3]([OH:23])[C@H:2]([O:1][CH2:34][CH2:33][OH:32])[C:11]=3[CH:10]=[CH:9][N:8]2[C:12]=1[CH3:16]
Reactant: COCCO
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2c3c(ccn2c1C)[C@@H](OCCO)[C@H](O)[C@@H](c1ccccc1)N3
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.00 g (6.40 mmol) (7R,8R,9R)-7,8-Dihydroxy-2,3-dimethyl-9-phenyl-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in 2-methoxyethanol (100 ml) is added 1.26 g (12.8 mmol) sulfuric acid and the mixture is stirred for 3 h at 55° C. Subsequently the reaction is poured out into a of 0° C. cooled aqueous solution of sodium hydroxide (2N). The mixture is extracted with dichloromethane two times. The combined organic layer are washed with water four times, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (diethyl ether/2-propanol: 10/1) to give 0.35 g (0.99 mmol/16%) of the title compound as a colourless solid with a melting point of 107–109° C. (diethyl ether).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([S:14][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][CH:10]=2)[C:5]1=[O:25]>Cl.CO.O1CCCC1>[F:27][C:2]([F:1])([F:26])[CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([SH:14])=[CH:9][CH:10]=2)[C:5]1=[O:25]
Reactant: CC(C)[Si](Sc1ccc2ccn(CC(F)(F)F)c(=O)c2c1)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c2cc(S)ccc2ccn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2,2,2-trifluoroethyl)-7-((triisopropylsilyl)sulfanyl)isoquinolin-1(2H)-one was dissolved in a solution of hydrochloric acid in methanol (2 ml) and tetrahydrofuran (2 ml) and stirred at room temperature for 2 hours or until disappearance of starting material. Reaction mixture was concentrated to give the desired material (quant yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@H:10]([CH3:14])[CH2:11]C=O)=[CH:2]1.[CH:15](OC)([O:18][CH3:19])[O:16][CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH3:17][O:16][CH:15]([O:18][CH3:19])[CH2:14][CH:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:11]
Reactant: C[C@H](CC=O)c1c[nH]c2ccccc12
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(CC(C)c1c[nH]c2ccccc12)OC
Yield: 92.9 %

Procedure:
(R)-3-(1H-Indol-3-yl)-butanal (236 mg, 1.26 mmol) was dissolved in methanol (15 mL) and treated with trimethyl orthoformate (275 μl, 2.50 mmol) and a catalytic amount of p-TSA. The reaction was stirred at room temperature for 3 hours, at which time H2O (10 mL) was added and the reaction was extracted with ether (3×20 mL). The collected organics were rinsed with brine, dried over Na2SO4, and concentrated in vacuo to provide 3-(3,3-dimethoxy-1-methyl-propyl)-1H-indole (228 mg, 1.17 mmol). 3-(3,3-dimethoxy-1-methyl-propyl)-1H-indole (39.9 mg, 0.171 mmol) was dissolved in a KOH (38.4 mg, 0.684 mmol)/DMSO (2 mL) solution and allowed to stir at 0° C. for 10 min, at which time dimethyl sulfate (32.5 μl, 0.340 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was left to stir at room temperature until it appeared done by TLC. The reaction was quenched with H2O (1 mL) and brought to a neutral pH with dropwise addition of 1M HCl. The solution was extracted with Et2O (3×5 mL), and the collected organics were rinsed with brine, dried over Na2SO4, and concentrated in vacuo to provide 3-(3,3-dimethoxy-1-methyl-propyl)-1-methyl-indole. This crude residual material was dissolved in THF (5 mL) and 1M HCl (1 mL) to give (R)-3-(1-methyl-1H-indol-3-yl)-butanal (1.9 mg, 0.0094 mmol) after preparative TLC (25:75 EtOAc/hexanes). [α]D=−4.1 (c=1.0, CHCl3); reported rotation for (R)-3-(1-methyl-1H-indol-3-yl)-butanal [α]D=−4.2 (c=1.0, CHCl3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:9][CH:8]=2)=[O:27])[CH:22]=1
Reactant: O=C(O)c1cccnc1
Reactant: NCCCCCc1ccc(C2=NNC(=O)CC2)cc1
Product: O=C1CCC(c2ccc(CCCCCNC(=O)c3cccnc3)cc2)=NN1

Procedure:
By treating 6-[4-(5-aminopentyl)phenyl]-4,5-dihydropyridazin-3(2H)-one and nicotinic acid in the same manner as in Example 30, 6-[4-(5-(pyridin-3-ylcarbonylamino)pentyl)phenyl]-4,5-dihydropyridazin-3(2H)-one was obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH2:3][CH3:4].[C:10]1(=O)[O:14][CH2:13][CH2:12][CH2:11]1>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][C:13]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCCN
Reactant: O=C1CCCO1
Product: CCCCOCCCN1CCCC1=O
Temperature: 275 °C

Procedure:
360 grams of butoxypropylamine (2.75 moles) and 250 grams of butyrolactone (3.0 moles) were charged to a 1-liter stainless steel autoclave. After purging, the mixture was heated to 275° C. for six hours. The reactor was then cooled and the product discharged. The product was distilled with a simple Vigreux column, initially at atmospheric pressure to remove by-product water and then under vacuum (<1 mm) to recover the product. Butoxypropyl Pyrrolidone distills at about 135° C. to 145° C. under these conditions. The recovery was 391.2 grams of>98% pure Butoxypropyl Pyrrolidone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH:18]=O)=[CH:7]2.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1.[NH2:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[CH:44][CH:43]=[N:42]2>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH:38][C:39]1[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=1)[N:45]=[CH:44][CH:43]=[N:42]3)=[CH:7]2
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3)nc12
Reactant: Nc1ccc2nccnc2c1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc2cc(CNc3ccc4nccnc4c3)c(-c3ccccc3)nc12
Temperature: 100 °C
Yield: 37.4 %

Procedure:
To a solution of 8-methyl-2-phenylquinoline-3-carboxaldehyde (80 mg, 0.32 mmol) in THF (5 mL) was added di-n-butyltin dichloride (10 mg, 0.032 mmol), phenylsilane (70 mg, 0.64 mmol) and 6-aminoquinoxaline (46 mg, 0.32 mmol). The mixture was heated in a microwave at 100° C. for 3 h. Purification by preparative HPLC (Method 2) gave the title compound as an off-white solid (45 mg, 37%). δH (CDCl3) 8.61 (d, J 2.1 Hz, 1H), 8.51 (d, J 1.9 Hz, 1H), 8.24 (s, 1H), 7.84 (d, J 9.0 Hz, 1H), 7.71-7.76 (m, 1H), 7.61-7.66 (m, 1H), 7.40-7.58 (m, 6H), 7.10 (dd, J 9.2, 2.6 Hz, 1H), 6.88 (d, J 2.6 Hz, 1H), 4.64-4.69 (m, 2H), 4.52-4.60 (m, 1H), 2.82 (s, 3H). LCMS (ES+) 377.2 (M+H)+, RT 4.23 minutes (Method 4).
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH2:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].C([O-])([O-])=O.[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: CC(CF)(CF)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Yield: 103.3 %

Procedure:
According to the procedure described in Example 161C, to a solution of 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-amine (0.75 g, 2.98 mmol) in THF (25 mL) and K2CO3 (1.037 g, 7.5 mmol), was added phenyl chloroformate (0.548 g, 3.5 mmol). The crude product was purified by silica gel chromatography (with 10-25% EtOAc/hexane as eluants) to afford phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate as solid (1.143 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.5 (m, 3H), 7.4 (m, 4H), 7.2 (m, 4H), 6.6 (s, 1H), 4.75 (q, 2H), 4.55 (q, 2H), 1.4 (s, 3H); LC-MS (ESI) m/z 372 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1)[NH2:25].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([CH:8]([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=2)[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CC(C)C(O)c1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(O)C(C)C)n2)ccc1-n1cnc(C)c1
Temperature: 130 °C

Procedure:
1-(2-Chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)-2-methylpropan-1-ol (20 mg, 0.07 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (13.61 mg, 0.07 mmol), palladium(II) acetate (2.255 mg, 10.04 μmol),2-(dicyclohexylphosphino)biphenyl (3.52 mg, 10.04 μmol), and cesium carbonate (43.6 mg, 0.13 mmol) were mixed in dioxane (3 mL). The vial was flushed with nitrogen, capped and heated by microwave irradiation at 130° C. for 2.5 h. The mixture was filtered through a pad of silica gel, the pad was eluted with DCM and 5% MeOH in DCM. The solvents were evaporated. The residue was purified by preparative HPLC to give the title compound as a dry film, 9 mg (27%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([NH:37][C@H:38]([CH3:42])[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39](=[O:40])[C@H:38]([NH:37][C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:31])[CH3:33])[CH3:42])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)c1

Procedure:
Prepared as described in Example 83 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and (R)-2-(tert-butoxycarbonylamino)propanoic acid (32 mg, 0.17 mmol). Yield 25 mg (34%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:35]([NH2:37])=[S:36])[CH:32]=2)[NH:27][C:26]=1[C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:48][C:49](=O)[CH3:50]>>[C:1]([O:5][C:6](=[O:46])[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:35]3[S:36][CH:48]=[C:49]([CH3:50])[N:37]=3)[CH:32]=2)[NH:27][C:26]=1[C:38]1[CH:39]=[C:40]([CH3:45])[CH:41]=[C:42]([CH3:44])[CH:43]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:14][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(NC(N)=S)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OC(C)(C)C)c1
Reactant: CC(=O)CCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(Nc4nc(C)cs4)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of {2-[2-(3,5-dimethylphenyl)-5-thioureido-1H-indol-3-yl]ethyl}-[4-(4-methanesulfonylaminophenyl)butyl]carbamic acid tert-butyl ester (15 mg in 0.80 mL ethanol) was added 0.010 mL chloroacetone and the resulting suspension heated to reflux on an oil bath. After 5 hours, the mixture was cooled to room temperature and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (methylene chloride:methanol, 96:4) gave the title compound (15 mg).
Reaction SMILES: C(O)=O.C(N)CCC.[OH:9][C:10]([C:13]1[N:14]=[CH:15][C:16]([NH:19]C(=O)OCC=C)=[N:17][CH:18]=1)([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Na+].O.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.O>[NH2:19][C:16]1[N:17]=[CH:18][C:13]([C:10]([OH:9])([CH3:11])[CH3:12])=[N:14][CH:15]=1
Reactant: C=CCOC(=O)Nc1cnc(C(C)(C)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O=CO
Solvent: CCCCN
Solvent: O
Product: CC(C)(O)c1cnc(N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of formic acid (48 mg) and n-butylamine (76 mg) in THF (10 mL) was added tetrakistriphenylphosphinepalladium (30 mg) and allyl [5-(1-hydroxy-1-methylethyl)pyrazin-2-yl]carbamate (123 mg) at room temperature, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water, saturated aqueous sodium bicarbonate, and saturated brine at room temperature, followed by extraction with a solvent (chloroform:isopropyl alcohol=4:1). The organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by a thin layer silica gel chromatography (chloroform:methanol=10:1) to obtain 2-(5-aminopyrazin-2-yl)propan-2-ol (51 mg) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[CH2:12][CH2:11][CH2:10][O:9][C:6]2=[N:7][CH:8]=1.[Br:13]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C)C=O>[Br:13][C:8]1[N:7]=[C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]2=[N:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cnc2c(n1)CCCO2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc2c(nc1Br)OCCC2
Temperature: 60 °C

Procedure:
To a solution of 2-methoxy-6,7-dihydro-8H-pyrano[2,3-b]pyrazine (J. Chem. Soc. Perkin Trans. I 1988, 2585-2593; 3.16 g, 19.0 mmol) in N,N-dimethylformamide (95 mL) was added N-bromosuccinimide (5.08 g, 28.5 mmol) at room temperature, and then heated at 60° C. for 5 h. After being cooled to ambient temperature, the reaction mixture was diluted ethyl acetate, washed with 2% aqueous sodium sulfite, water, and saturated brine. The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give 3-bromo-2-methoxy-7,8-dihydro-6H-pyrano[2,3-b]pyrazine. MS (APCI): m/z 247 (M+H).
Reaction SMILES: O.[SH-:2].[Na+].Cl[C:5]1[N:10]([CH3:11])[C:9](=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[CH:6]=1>O.C(Cl)(Cl)Cl.C(O)C>[SH:2][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[CH:6]=1
Reactant: [SH-]
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1c(S)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A solution of sodium hydrosulphide hydrate (74.77 g, 1335.243 mmol) in water (125 ml) was added dropwise to a stirred solution of Step 1 (50.0 g, 286.532 mmol) in chloroform (250 ml) and ethanol (636 ml) in an ice water bath, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo at room temperature. The residue obtained was dissolved in water (100 ml) and extracted with dichloromethane (2×100 ml). The aqueous layer was acidified with 1 N HCl. Precipitated solid was filtered, washed with water (2×100 ml) and dried to obtain 49.22 g of the product as a pale yellow solid; 1H NMR (300 MHz, CDCl3) δ 3.33 (s, 3H), 3.74 (s, 3H), 4.17 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:10]=1[C:11](Cl)=[O:12].[CH:20]1([NH:25][C:26]([CH3:33])=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1>[CH:20]1([NH:25][C:26]([CH3:33])=[C:27]([C:11](=[O:12])[C:10]2[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:9]=2[F:8])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)C=C(C)NC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)c1cc(F)c(F)cc1F)=C(C)NC1CCCC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Under ice cooling, triethylamine and 2,4,5-trifluorobenzoyl chloride were added to a solution of ethyl 3-(cyclopentylamino)buta-2-enoate in dioxane, for stirring at ambient temperature for 30 minutes and at 65° C. for one hour, to obtain ethyl 3-(cyclopentylamino)-2-(2,4,5-trifluorobenzoyl)buta-2-enoate.