Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8](O)=[O:9])([O-:3])=[O:2].S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([Cl:30])=[O:9])([O-:3])=[O:2]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Temperature: 67 °C

Procedure:
2-[2-Nitro-5-(2-Chloro-4-trifluoromethylphenoxy)phenoxy]propionic acid (100 grams) and toluene (40 ml) were charged into a glass reaction vessel equipped with a magnetic stirrer. The mixture was heated on a steam bath until a solution was obtained. The solution was allowed to cool and thionyl chloride (100 ml) was added dropwise with stirring. After the addition was completed the mixture was warmed to 67° C. with continued stirring for a period of about 21/2 hours. After this time the mixture was stripped of solvent in a rotary evaporator under reduced pressure leaving as the residue 105 grams of the desired product, 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride as a burgundy colored viscous oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>COC1C=CC([Mg]Br)=CC=1C>[CH3:28][O:29][C:30]1[CH:14]=[CH:15][C:6]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH:7]=2)=[O:5])=[CH:4][C:26]=1[CH3:27]
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Reactant: C1CCOC1
Agent: COc1ccc([Mg]Br)cc1C
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 168 mg (0.50 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2.5 mL THF and 2.5 mL 0.5M 4-methoxy-3-methylphenylmagnesium bromide. Yield: 107 mg of a white solid. LC-MSD, m/z for C25H22N2O3 [M+H]+=399.1; HPLC retention time: 2.1 min.
Reaction SMILES: C(OC(=O)C1C=CC([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[Cl:29])[N:13]=2)=CC=1)C.[CH2:31]([O:33][C:34](=[O:49])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37](CC2ON=C(CO)N=2)[CH:36]=1)[CH3:32]>>[CH2:31]([O:33][C:34](=[O:49])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[Cl:29])[N:13]=2)[CH:36]=1)[CH3:32]
Reactant: CCOC(=O)c1cccc(Cc2nc(CO)no2)c1
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)cc1
Product: CCOC(=O)c1cccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)c1

Procedure:
The title compound is prepared essentially as described for 4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester, employing 3-(3-Hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester (71%). LC-MS (m/e): 429 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Br)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
The mixture of 6-bromonicotinic acid (700 mg, 3.5 mmol), morpholine (391 mg, 4.5 mmol), HATU (220 mg, 0.59 mmol) and DIPEA (0.3 mL) in 10 mL of dry THF was stirred at room temperature for 14 hours. The reaction solution was evaporated to dryness. To the residue was added 20 mL of 0.5N hydrochloride, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was dried over sodium sulfate and concentrated to give (6-bromopyridin-3-yl)(morpholino)methanone (750 mg, 79%). LC-MS: 271, 273 [M+H]+, tR=1.290 min.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([N:15]=[C:16]=[S:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.O>[C:18]1([N:24]2[C:25](=[S:26])[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:7])[NH:15][C:16]2=[S:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(N=C=S)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ccccc2)NC(=S)N(c2ccccc2)C1=S
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
15.1 g (122 mmol) of potassium tert-butoxide are dissolved in 200 ml of tetrahydrofuran in a 500 ml, three-necked, round-bottomed flask under a dry argon atmosphere. The solution is cooled to -70° C. A solution containing 20 g (122 mmol) of alpha-methylbenzyl isothiocyanate, 16.55 g (122 mmol) of phenyl isothiocyanate and 50 ml of tetrahydrofuran is run in dropwise while keeping the temperature of the mixture below -60° C. On completion of addition, the mixture is held for 0.5 hour at -70° C. and then is left to return to room temperature. The mixture is poured into 500 ml of water. The mixture is acidified to pH=1 by addition of N hydrochloric acid. The product is extracted with ethyl acetate (2 extractions, each with 150 ml of solvent). The solution is dried over magnesium sulfate. The solution is concentrated under reduced pressure. The product is crystallized from 50 ml of ether. The precipitate is filtered. 21 g (yield: 58%) of 3,5-diphenyl-5-methyldithiohydantoin are thus obtained as a yellow powder melting at 157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>O1CCCC1>[CH:19]1([CH2:18][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (81.7 mg, 0.26 mmol) in tetrahydrofuran (10 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) and nicotinoyl chloride hydrochloride (47 mg, 0.26 mmol). The resulting reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 90/10 ethyl acetate/heptane) afforded N-{4-[2-cyclopentyl-1-(pyridin-2-ylcarbamoyl)-ethyl]-phenyl}-nicotinamide (40.9 mg, 21.7%) as a yellow solid: mp 160-163° C.; EI-HRMS m/e calcd for C25H26N4O2 (M+) 414.2055, found 414.2056.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]2[C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=1.[NH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]2[C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[N:20]=1
Reactant: CC(C)(CN)CO
Reactant: Cc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3F)nc12
Solvent: CC#N
Product: Cc1nccn2c(-c3ccnc(NCC(C)(C)CO)n3)c(-c3ccc(F)cc3F)nc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
To a mixture of 2-(2,4-difluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methyl-imidazo[1,2-a]pyrazine (1.4 g, 3.5 mmol) in ACN (30 mL) was added 3-amino-2,2-dimethyl-propan-1-ol (Lancaster, 0.79 g, 7.7 mmol). The mixture was heated to about 80° C. After about 16 h, the mixture was treated with additional 3-amino-2,2-dimethyl-propan-1-ol (Lancaster, 0.20 g, 1.9 mmol) and heated at about 80° C. for about another 4 h. The mixture was filtered through a pad of silica gel and eluted with EtOAc. The solution was evaporated, triturated with ether, and then filtered. The solid was dissolved in hot methanol (˜10 mL). The solution was cooled and the solvent evaporated. The resulting solid was dried at 100° C. under vacuum to yield the title compound as a white solid (0.88 g, 59%): LC/MS (Table 1, Method g) Rt=2.38 min; MS m/z: 425.2 (M+H)+, mp 173.8-174.5° C.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([O:13][S:14](C1CC1)(=[O:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[CH3:2][C:3]1([S:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:15])=[O:16])[CH2:5][CH2:4]1
Reactant: [Li]CCCC
Reactant: O=S(=O)(OCc1ccccc1)C1CC1
Solvent: C1CCOC1
Solvent: CI
Product: CC1(S(=O)(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (0.78 g, 12.25 mmol) was added drop-wise at −78° C. to a solution of Benzylcyclopropane sulfonate (2.0 g, 11.2 mmol) in THF (20 mL) and continued stirring at the same temperature for 10 min. CH3I (3.98 g, 28.0 mmol) was added at −78° C., allowed the reaction to warm to 0° C. with stirring for 30 min. The reaction mixture was quenched with ice cold water, diluted with ethylacetate (100 mL), organic layer collected was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude. The crude was purified by column chromatography (using silica gel and 4% ethyl acetate in Hexane as eluent) to afford benzyl 1-methylcyclopropane-1-sulfonate (Int-25). 1H NMR (300 MHz, CD3OD) δ ppm 4.2-4.1 (2H, t), 1.7-1.6 (2H, m), 1.4 (3H, s), 1.5-1.3 (2H, m), 1.3-1.2 (2H, m), 1.0-0.9 (2H, m), 0.9 (3H, t).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])(=[O:35])=[O:34])[CH2:12][CH2:11]2)=[N:2]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Product: O=S(=O)(Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1)c1ccccc1F

Procedure:
N-{2-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-fluoro-benzenesulfonamide was prepared according to the procedure outlined in Example 44, starting with 2-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (150 mg) and 2-fluorobenzenesulfonyl chloride (55 mg). The resultant white solid was purified using an ISCO autocolumn eluting with 100% ethyl acetate. N-{2-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-fluoro-benzenesulfonamide was isolated in 100% purity @ 254 nm; LCMS (APCI): 511 [M+H]+.
Reaction SMILES: [Mg].[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1Br)[CH3:3].[CH2:14]=[O:15].Cl>II.BrCCBr.O1CCCC1>[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1[CH2:14][OH:15])[CH3:3]
Reactant: CCc1cc(C)cc(CC)c1Br
Reactant: C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1CO
Temperature: 60 °C

Procedure:
Under a nitrogen atmosphere, 11.24 g of magnesium, 200 g of tetrahydrofuran, 0.1 g of iodine and 1.0 g of 1,2-dibromoethane were mixed. This mixture was heated to 60° C. To this mixture, a small amount of 2,6-diethyl-4-methylbromobenzene was added. To this mixture, 0.1 g of iodine and 1.0 g of 1,2-dibromoethane were added. Then, 2,6-diethyl-4-methylbromobenzene (the total amount including the amount added first: 100.12 g) was added dropwise over 2.5 hours. After completion of addition, the resultant mixture was stirred at 50° C. for 1.5 hours. This mixture was cooled to 30° C. To this mixture, 14.84 g of paraformaldehyde was added portionwise in five additions over 30 minutes. The resultant mixture was stirred at 30° C. for 2 hours. To the reaction mixture, 143 g of 10% hydrochloric acid was added, followed by extraction with 300 g of tert-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain 77.56 g of 2,6-diethyl-4-methylbenzyl alcohol as a yellow crystal.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([N:28]=[CH:29][N:30]=4)[C:24]([Br:27])=[CH:25][N:26]=3)=[CH:16][CH:15]=2)[C:10](=[O:31])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:27][C:24]1[N:23]2[N:28]=[CH:29][N:30]=[C:22]2[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3=[O:31])=[CH:15][CH:16]=2)=[N:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Yield: 77.3 %

Procedure:
A solution of 4-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (0.252 mg, 0.6 mmol) in 2:1 DCM:TFA (4.8 mL) is stirred for 1 hour at room temperature. The mixture is then diluted with DCM and basified with sat. NaHCO3. The aqueous layer is extracted with DCM (3×) and the organic layers are combined, dried over MgSO4, filtered and concentrated to afford the title compound as a solid (180 mg, 78%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[N:22]1([C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])=[O:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (200 mg), pyrrolidine (65 μL), 1H-1,2,3-benzotriazol-1-ol (150 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (210 mg, yield 90%) as pale-yellow needle crystals. melting point 248-249° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12](Cl)(=[O:14])=[O:13])[N:11]=[C:4]2[N:3]=1.[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH2:19].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12]([NH:19][C:18]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:17]=3[CH3:16])(=[O:14])=[O:13])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(C)cccc3C)nc2n1
Yield: 97.7 %

Procedure:
A solution of 2.2 g (8.9 mmol) of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride, 1.01 ml (8.4 mmol) of 2,6-dimethylaniline, 0.7 ml (8.4 mmol) of dry pyridine and 4 mg of DMAP in 20 ml of CH2Cl2 was stirred at room temperature for 17 hours. The solvent was removed by evaporation and the residue was taken up in 0.5M NaOH. The solution was extracted with diethyl ether and the aqueous phase was acidified with 3N HCl to precipitate a solid. The solid was collected by filtration and dried in vacuo to yield 2.72 g (97 percent) of the desired product as a white solid, m.p. 263°-266° C. (decomp.): 1H NMR (DMSO-d6)δ10.4 (1H, broad S), 7.55 (1H, s), 7.2 (3H, s), 2.7 and 2.8 (3H each, s) and 2.1 (6H, s); IR (KBr) 3100, 2980-2780, 1628, 1540 and 1355 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (728 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromo-2-(2-ethoxyethoxy)ethane (496 mg), and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=9/1→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl>[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH:5][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of leucine methyl ester (5 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml) was cooled to 0° C. and treated dropwise with allyl chloroformate. After addition, the solution was stirred at ambient temperature for 2 h, diluted with dichloromethane, washed successively with 1N HCl and aqueous NaHCO3, dried over Na2 SO4, and concentrated to give the desired compound.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[C:9]([F:31])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:34][CH2:33][CH2:32][N:6]1[C:7]2[C:12](=[CH:11][C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:18][CH2:19]3)=[O:16])=[C:9]([F:31])[CH:8]=2)[CH:13]=[C:5]1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of tert-butyl 2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6-fluoro-1H-indol-1-yl)ethylcarbamate (137.5 mg, 0.24 mmol) in dichloromethane (1.8 mL) was added trifluoroacetic acid (444 μL, 5.8 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution (3 mL) and brine (3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a white solid (93.7 mg, 82%). ESI-MS m/z calc. 473.19. found 474.5 (M+1)+. Retention time 1.61 minutes.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].[Cl-].[Na+]>C(Cl)Cl>[C:28]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: NC1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 Grams of 6-(4-amino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril and 3.06 ml of triethylamine were dispersed in 40 ml of methylene chloride, then under ice-cooling conditions, 0.78 ml of acetyl chloride was added dropwise thereto, and stirred at room temperature for 4 hours. The reaction mixture was poured into an aqueous solution saturated with sodium chloride, then extracted with chloroform. The extract was dried with anhydrous sodium carbonate, the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=10:1), then recrystallized from methanol-diethyl ether to yield 0.3 g of 6-(4-acetylamino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.1/4-hydrate. White powdery substance. Melting point: 228°-229° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC(N(C)C)=O.CCOC(C)=O>[O:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N2CCOCC2)cc(N2CCOCC2)n1
Temperature: 150 °C
Yield: 71.1 %

Procedure:
4,6-dimorpholinopyrimidin-2-amine was prepared using the following procedure: 2-amino-4,6-dichloropyrimidine (1 g, 6.10 mmol) and morpholine (5.33 ml, 60.9 mmol) were dissolved in DMA (1.1 ml) and sealed into a microwave tube. The mixture was heated to 150° C. over a period of 20 minutes in the microwave reactor. The reaction mixture was diluted with AcOEt, filtered and the filtrate concentrated to give an oil. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford 4,6-dimorpholinopyrimidin-2-amine (1.15 g, 71%) as a white foam.