Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:29][C:30]2[C:31]([CH2:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:20][CH:19]4[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.[SH:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]>>[CH2:36]([C:31]1[C:30]([O:29][C:4]2[C:5]([NH:8][C:9]3[S:13][N:12]=[C:11]([CH:14]4[CH2:20][CH:19]5[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]5)[CH2:15]4)[N:10]=3)=[N:6][CH:7]=[C:2]([S:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH:3]=2)=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:37]
Reactant: COC(=O)CCS
Reactant: CCc1ncccc1Oc1cc(Br)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Product: CCc1ncccc1Oc1cc(SCCC(=O)OC)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Yield: 89.6 %

Procedure:
Following the procedure in Example 52, tert-butyl 3-(5-(5-bromo-3-(2-ethylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.2042 mmol) and methyl 3-mercaptopropanoate (24.34 μL, 0.2247 mmol) afforded tert-butyl 3-(5-(3-(2-ethylpyridin-3-yloxy)-5-(3-methoxy-3-oxopropylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (115 mg, 0.183 mmol, 89.8% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19](OC)=[C:18](OC)[CH:17]=3)[C:12]3[CH:26]=[CH:27][C:28]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:31])=[CH:29][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2].N>C(OCC)(=O)C.C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:7][CH2:8][CH2:3][CH2:4][CH2:5][CH3:6])[C:12]3[CH:26]=[CH:27][C:28]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:31])=[CH:29][C:11]=3[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C#N)cc1)n2CCc1ccc(OC)c(OC)c1
Agent: N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCn1c(-c2ccc(C#N)cc2)nc2cc(C(=O)NCCC(=O)OC)ccc21

Procedure:
The same procedure is used as in (1) Rf value: 0.60 (silica gel; ethyl acetate/ethanol/conc. ammonia=50:2:0.02)
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:16][CH:15]=[CH:14][CH:13]=2.Cl.N1C=CC=CC=1>ClCCl>[CH2:2]([C:1]1[N:19]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: CCOC(=O)CCCNc1c(N)cnc2cccnc12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Valeryl chloride (1.8 mL, 15.3 mmol, 1.1 eq) was added dropwise to a solution of ethyl 4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyrate (3.8 g, 13.9 mmol, 1 eq) in dichloromethane (55 mL) and stirred for one hour. The reaction mixture was concentrated under reduced pressure and was dissolved in pyridine (55 mL). Pyridine hydrochloride (0.16 g, 1.39 mmol, 0.1 eq) was added and the reaction mixture was heated to reflux for 18 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (75 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organics were dried over magnesium sulfate, stirred over decolorizing charcoal, filtered through CELITE filter aid, concentrated under reduced pressure, and dried at 35° C. under high vacuum to afford 4.18 g of ethyl 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyrate as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1.[OH-].[Na+]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH2:24][CH3:25])=[C:2]([NH:1][C:32]([C:31]5[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: CCc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of N-[6-(3-amino-4-ethylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (202 mg, 0.60 mmol) in N-methylpyrrolidone (3 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (143 mg, 0.90 mmol), and the mixture was stirred at room temperature for 8 hr. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→80/20) and recrystallized from a mixed solvent of ethyl acetate/diisopropyl ether to give the title compound (167 mg, yield 61%) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](N(OC)C)=[O:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:28]=[C:29]([Mg]Br)[CH3:30]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](=[O:23])[C:29]([CH3:30])=[CH2:28])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(C)[Mg]Br
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 5, 30.79 g, 76.48 mmol) in THF (200 mL) at 0° C. was added prop-1-en-2-ylmagnesium bromide (0.5M in THF) (300 mL, 149.90 mmol). The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with 200 mL 10% citric acid, diluted further with 100 mL water and extracted with ether. The organics were concentrated and the resulting oil was dissolved in ether and washed with water and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product (26.2 g, 89%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=O.C(#N)C.C([BH3-])#N.[Na+].Cl>O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1
Reactant: N#Cc1ccc2[nH]cc(C(=O)CCCO)c2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc2[nH]cc(CCCCO)c2c1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
3-(4-Hydroxybutyryl)-1H-indole-5-carbonitrile (50 g) was added to acetonitrile (750 ml) at 25-30° C., followed by the addition of sodium cyanoborohydride (75 g) at the same temperature. The resulting mixture was cooled to 0-5° C., followed by drop-wise addition of a mixture of concentrated HCl (112.5 ml) and water (112.5 ml) for a period of 15 minutes at the same temperature. After completion of the reaction, water (750 ml) was added to the reaction mass at 0-5° C., followed by stirring for 5 minutes at the same temperature. The layers were separated and the aqueous layer was extracted two times with toluene (2×1000 ml). The resulting organic layers were combined, washed two times with water (2×1000 ml), and then distilled off the solvent under vacuum to produce 42 g of the titled compound as a residue. Dichloromethane (420 ml) was added to the residue at 25-30° C. to form a clear solution, followed by filtration to remove undissolved particles. The resulting filtrate was cooled to −5° C. to 0° C. and then stirred for 1-2 hours at the same temperature. The separated solid was filtered, washed with chilled dichloromethane (42 ml) and then dried at 50-55° C. to produce 31 g of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile (Purity by HPLC: 99%). The mother liquors were taken and distilled off the solvent under vacuum to give 11 g of the titled compound as a residue (Total yield: 86%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][Cl:10].[Se:11]1(=[O:20])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1>CN(C)C=O>[Cl:10][CH2:9][CH2:8][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Se:11](=[O:20])[CH2:12]1
Reactant: O=[Se]1C=Nc2ccccc21
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[Se]1CN(CCCl)c2ccccc21
Temperature: 50 °C
Reaction time: 6 h

Procedure:
0.06 mol of potassium carbonate and then 0.015 mol of 1-bromo-2-chloroethane are added to a solution of 0.015 mol of benzoselenazolinone in 30 cm3 of dimethylformamide. The mixture is heated to 50° C. with stirring for six hours. The inorganic precipitate is drained and then washed with dimethyl formamide. The DMF is evaporated off under reduced pressure and the residue is taken up with water. An extraction with ether is then carried out. The organic phase is dried over sodium sulfate and then filtered. The ether phase is evaporated to dryness under reduced pressure and the product is recrystallized in petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1>C1COCC1.C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCOCCCCOCCCN
Reactant: O=C1CCC(=O)O1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOCCCCOCCCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(tert-Butoxycarbonylamino)-4,9-dioxa-12-dodecanamine (5.0 g, 16.45 mmol) was dissolved in THF (30 mL), succinic anhydride (1.81 g, 18.1 mmol) in acetonitrile (10 mL) was added and the mixture was heated to 60 C for 4 h, and subsequently stirred at RT overnight.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1.C([O-])([O-])=[O:22].[K+].[K+].OO.O>CS(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:22])=[CH:15][N:14]=2)=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ncc(Oc2ccc(C#N)cn2)c2ccccc12
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ncc(Oc2ccc(C(N)=O)cn2)c2ccccc12

Procedure:
To a solution of 6-(1-methylisoquinolin-4-yloxy)nicotinonitrile (Preparation 18) (200 mg, 0.77 mmol) in DMSO (5 mL) was added K2CO3 (53 mg, 0.38 mmol) and H2O2 (30% w/v, 120 μL, 1.1 mmol). After 1 h water (20 mL) was added and the mixture extracted with EtOAc (3×50 mL). The organic phase was washed with water (2×30 mL), NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (0.5 NH3: 5 MeOH: 95 DCM) to give the title compound: RT=2.11 min; m/z (ES+)=280.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])=[C:4]([F:22])[CH:3]=1.S(OC)(O[CH3:27])(=O)=O>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[N:12]([CH3:27])[C:11]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Product: COc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, m.p. 128°-130° C.;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].C(O)C.[CH2:21]([NH2:23])[CH3:22]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:23][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Yield: 69 %

Procedure:
27.9 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) are dissolved in 100 ml. of ethyl alcohol and 12 g. of triethylamine. At reflux temperature a solution of 4.5 g. of ethylamine in 50 ml. of alcohol is slowly added dropwise with continual stirring. After the addition is completed, the reaction mixture is refluxed for an additional 30 minutes. The solvent is then removed in vacuo and the residue is dissolved in 300 ml. of petroleum ether. The triethylamine hydrochloride is filtered off and the filtrate cooled to 0°; 6-chloro-4-ethylamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester crystallizes, yield: 69%, m.p. 36°-37° (methanol).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26][CH2:27]C>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:26][CH3:27]
Reactant: CCCI
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Product: CCCCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 1-iodopentane for 1-iodopropane while making non-critical variations the title compound was obtained as 361 mg (71%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.83 (br s, 1H), 7.36-7.28 (m, 3H), 7.17-7.13 (m, 1H), 7.05-7.01 (m, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 3.95-3.85 (m, 2H), 3.12-3.10 (m, 1H), 3.06-3.04 (m, 1H), 2.98-2.93 (m, 2H), 2.88-2.85 (m, 1H), 2.81-2.79 (m, 1H), 2.42-2.37 (m, 2H), 1.59-1.52 (m, 2H), 1.21-1.13 (m, 4H), 0.79 (t, J=7.0 Hz, 3H); HRMS (FAB) calcd for C23H28N2O+H1: 349.2280 found 349.2280.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH:27]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:28][C:29]([OH:31])=[O:30]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH:27]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: CC(C)CC(CN)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)CC(=O)O
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmole) and 3-(aminomethyl)-5-methylhexanoic acid (249 mg, 1.6 mmole, AK Scientific) in 0.5 M sodium methoxide in methanol (2.5 ml) was refluxed for two days before it was cooled to room temperature, concentrated and dissolved in water, extracted with dichloromethane. The remaining aqueous layer was acidified with 1N hydrochloric chloride, extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and ethyl acetate to give the title compound as a white solid (35 mg). LC-MS ESI+: 448 (M+1)+; ESI−: 446 (M-1)−.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:17]=[C:10]2[C:11]([O:13]C(=O)[NH:15][C:9]2=[CH:8][CH:7]=1)=O)(=[O:5])=[O:4].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:11](=[O:13])[C:10]2[C:9](=[CH:8][CH:7]=[C:6]([S:3](=[O:4])(=[O:5])[NH:2][CH3:1])[CH:17]=2)[NH2:15])[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: CNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Product: CNS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-methylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-methylsulfamoyl)-anthranilic acid (4-methyl)-piperazide in the form of an oil (melting point of the methanesulfonate: 120°-123°).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:15]1[C:20]2[CH2:21][CH2:22][CH2:23][C:19]=2[C:18]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:39])[CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:27][CH:26]=2)=[N:17][CH:16]=1>CC(C)=O>[N:15]1[C:20]2[CH2:21][CH2:22][CH2:23][C:19]=2[C:18]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31](=[O:39])[CH2:32][CH:33]3[CH2:34][CH2:35][N:36]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:37][CH2:38]3)=[CH:29][CH:30]=2)=[N:17][CH:16]=1
Reactant: O=C(CC1CCNCC1)c1ccc(Nc2ncnc3c2CCC3)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 ml of acetone, 1.14 g of potassium carbonate and 0.4 ml of benzyl bromide were added to 1.34 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]aniline, and the mixture was stirred at room temperature for 4 hours. After separating the solid by filtration and removing the solvent by distillation under reduced pressure, the obtained residue was applied to silica gel column chromatography to obtain 1.05 g of the title compound as yellowish white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Cl:7].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][C@@H:45]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]([F:68])([F:67])[F:66])[CH2:46][N:47]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]1=[O:57]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:44][C@@H:45]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:66])[F:67])[CH2:46][N:47]2[C:55](=[O:56])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:57])=[O:10])[S:5][C:6]=1[Cl:7]
Reactant: O=C(O)c1cc(Br)c(Cl)s1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1cc(Br)c(Cl)s1
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-5-chloro-2-thiophenecarboxylic acid (1.3 g, 5.42 mmol), PyBrOP (3 g, 6.5 mmol) and diisopropylethyl amine (4.7 mL, 27.1 mmol) in DCM (54 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (2.0 g, 5.42 mmol) [prepared in Preparation 6]. After 1 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and used directly: LCMS (ES) m/z=572 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]([OH:14])=O)[S:8][C:6]=2[N:7]=1.[CH3:21][C:22]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH2:23][OH:24].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>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]([N:29]3[CH2:30][CH2:31][N:26]([C:22]([CH3:25])([CH3:21])[CH2:23][OH:24])[CH2:27][CH2:28]3)=[O:14])[S:8][C:6]=2[N:7]=1
Reactant: O=C(O)Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CC(C)(CO)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)N1CCN(C(=O)Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 57.1 %

Procedure:
A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)acetic acid (80 mg, 0.25 mmol), 2-methyl-2-piperazin-1-ylpropan-1-ol (48 mg, 0.31 mmol), HATU (116 mg, 0.31 mmol) and DIPEA (133 μL, 0.76 mmol) in DMF (3 mL) was stirred at r.t. for 65 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an orange solid (65 mg, 56%)._LCMS (method H): RT 2.02 min [M+H]+ 455.3
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8](P(=O)(OCC)OCC)[CH2:9][CH3:10])=[O:7])[CH3:4].COC(=O)/C=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][CH:25]=1.C(O)(=O)C>O1CCCC1>[CH2:3]([O:5][C:6](=[O:7])/[C:8](/[CH2:9][CH3:10])=[CH:23]/[C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:28][CH:29]=1)[CH3:4]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccc(Cc2cccnc2)cc1)CC
Reaction time: 0.25 h
Yield: 113.6 %

Procedure:
To a suspension of 46 mg of sodium hydride(content 63%) in 3 ml of tetrahydrofuran was added dropwise 0.33 g of diethyl 1-ethoxycarbonylpropylphosphonate at room temperature, and the mixture was stirred at that temperature for 15 minutes. To it was added a solution of 206 mg of the aldehyde (prepared as described in Reference Example 1) in one ml, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was acidified with acetic acid, and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 273 mg of the title compound having the following physical characteristics: