Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[CH:9]=[C:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12])[C@H:2]1[O:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]>>[ClH:19].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:3][C@H:2]([OH:4])[CH2:1][O:5][C:6]3[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:10]3[CH2:15][CH2:14][O:13][C:11]3=[O:12])[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Clc1ccc(C2CCNCC2)cc1Cl
Reactant: O=C1OCCC1=Cc1cccc(OC[C@@H]2CO2)c1
Product: Cl
Product: O=C1OCCC1=Cc1cccc(OC[C@@H](O)CN2CCC(c3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
In the same manner as in Example 425, the title compound was synthesized from (S)-α-(3-glycidyloxybenzylidene)-γ-butyrolactone and 4-(3,4-dichlorophenyl)piperidine, melting point 147–149° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:26]1[O:27][C:21]2[CH:20]=[CH:19][C:24]([C:2]3[CH:3]=[CH:4][C:5]4[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:23][C:22]=2[O:25]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Yield: 90.8 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.5 g), 3,4-methylenedioxyphenyl borate (0.92 g) and potassium carbonate (1.39 g) in toluene/ethanol/water (50/5/5 ml) was stirred at room temperaturel hours. To the mixture was added tetrakistriphenylphosphine palladium (0.29 g), and the mixture was refluxed for 16 hours and cooled. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give pale yellow crystals of methyl 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzo-thiepine-4-carboxylate (1.55 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33]>>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Clc1ccccc1OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3Cl)cc2)C(O)C1

Procedure:
Analogously to Method I, 5.84 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 6.00 g of 1-(3-bromopropoxy)-2-chlorobenzene are reacted. The title compound is obtained as a white solid. Rf=0.62 (1:2 EtOAc-heptane); Rt=5.33.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][N:4]=[C:5]([NH2:28])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.O.NN>C(O)C>[F:30][C:2]([F:1])([F:29])[CH2:3][N:4]=[C:5]([NH2:28])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH2:17])[N:8]=1
Reactant: NC(=NCC(F)(F)F)Nc1ccnc(CSCCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Yield: 77.2 %

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (5.4 g.), ethanol (30 ml.) and 99% hydrazine hydrate (3 ml.) was heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with N hydrochloric acid and then filtered and the filtrate basified with 17N NaOH. The mixture was extracted with ether, and the ether extracts dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine (2.93 g.) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[N:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38](O)=[O:39])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.[CH:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[N:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:56][S:53]([CH:50]6[CH2:52][CH2:51]6)(=[O:55])=[O:54])=[O:39])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccc(F)cc3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccc(F)cc3)nc2c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
A solution of the acid (153) (92 mg, 0.15 mmol) and EDC (38 mg, 0.2 mmol) in dry DCM (2 ml) was stirred at room temperature overnight. Cyclopropylsulfonamide (48 mg, 0.4 mmol) and DBU (76 mg, 0.5 mmol) was added and the mixture was stirred at room temperature for 6 hours. 5% Citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with 5% citric acid and brine, dried with sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with ether-methanol which gave the title compound (70 mg, 65%), MS (M+H) 720.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:39]=[CH:38][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13][C@H:14]([O:23][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[O:16]([CH2:15][C@@H:14]([O:23][Si:24]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:29][CH3:30])[CH2:13][N:12]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:38]=[CH:39][C:3]([CH2:2][O:1][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:4][C:5]=2[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(CO)cc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(COS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyl-oxy)propyl]-tert-butoxycarbonylamine (1.93 g) and triethylamine (0.58 ml) in dichloromethane (40 ml) was added dropwise methanesulfonyl chloride (0.27 ml) under ice-cooling. After stirring at room temperature for 6 hours, the reaction mixture was washed successively with water, sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford crude N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-N-(3-methylsulfonyloxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (2.18 g), which was used without purification.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([O-:22])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:32](N(CC)CC)[CH3:33].O>C1(C)C=CC=CC=1>[CH2:24]([NH:31][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([O:22][CH2:32][CH3:33])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: O=C([O-])c1cn(C2CCOCC2)c2cc(F)c(F)c(F)c2c1=O
Reactant: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CCOCC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Temperature: 100 °C
Yield: 99 %

Procedure:
A suspension of 5,6,7-trifluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylate (95.0 mg, 0.267 mmol), benzylamine (0.032 mL, 0.292 mmol) and triethylamine (0.11 mL, 0.789 mmol) in toluene (2 mL) was heated at 100° C. for 2 h. The reaction mixture was poured into water and the whole mixture was extracted with CHCl3 two times. The combined extracts was dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. Flash chromatography of the residue (hexane: EtOAc=1:1) gave ethyl 5-benzylamino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylate (117 mg, 99%) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:5])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
Under nitrogen atmosphere, 50.0 g (0.216 mole) of 2-amino-4'-chlorobenzophenone was added in four portions at 15 min intervals to a stirred melt (105°-110° C.) of 35.9 g (0.227 mole) of 2-chloro-3-nitropyridine. The reaction temperature was increased to 120° C. for 3 hr and then to 150° C. for 2 hr. The stirred mixture was cooled to 115° C. and 100 ml of hot toluene was added. The cooled mixture (room temperature) was filtered. The filtrate was washed with 75 ml of 5% sodium hydroxide solution, 50 ml of water and 30 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate-isopropyl ether to give 43 g (56.4%) solid. Recrystallization from ethyl acetate-isopropyl ether gave 18.26 g* of bright-yellow solid, m.p. 138'-140° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].[CH3:11][C:12]#[C:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1>C(N(CC)CC)C.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>[F:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[C:11]#[C:12][CH2:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1
Reactant: CC#CN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Reactant: Fc1cc(F)c(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C

Procedure:
4.05 g of tetrakis(triphenylphosphine)palladium, 0.834 g of cuprous iodide and 7.9 cm3 of 1-bromo-2,3,5-trifluorobenzene are added at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 17.28 g of methyl (3R,4R)-1-(3-prop-2-ynyl)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 173 cm3 of triethylamine. After heating for 2 hours at a temperature in the region of 80° C., the reaction mixture is cooled to approximately 20° C., diluted with 100 cm3 of water and then extracted with 4 times 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 5 times 100 cm3 of water, dried over sodium sulfate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; diameter 7 cm; mass 600 g), elution being carried out with ethyl acetate. Fractions 3 to 11 are combined and then concentrated under the above conditions. 18.4 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate are obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[C:34]([C:36]1[CH:51]=[CH:50][C:39]([O:40][C:41]2[C:42]([C:47](O)=[O:48])=[N:43][CH:44]=[CH:45][N:46]=2)=[CH:38][CH:37]=1)=[O:35].C(N(C(C)C)CC)(C)C.[C:61]1([CH2:67][CH2:68][NH2:69])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[NH:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:25]=[C:26]1[C:34]([C:36]1[CH:37]=[CH:38][C:39]([O:40][C:41]2[C:42]([C:47]([NH:69][CH2:68][CH2:67][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[O:48])=[N:43][CH:44]=[CH:45][N:46]=2)=[CH:50][CH:51]=1)=[O:35]
Reactant: NCCc1ccccc1
Reactant: O=C(c1ccc(Oc2nccnc2C(=O)O)cc1)c1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(Oc2nccnc2C(=O)NCCc2ccccc2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (123 mg, 0.324 mmol) was added to a mixture of 3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazine-2-carboxylic acid (106 mg, 0.294 mmol) and diisopropylethylamine (102 μL, 0.588 mmol) in DMF (1 mL) and the mixture was stirred at RT for 10 min. 2-Phenylethylamine (55.8 μL, 0.441 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was purified by chromatography on silica gel to deliver 3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-phenethylpyrazine-2-carboxamide as a white solid. MS (ESI, pos. ion) m/z: 464.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:6])C([O-])=O.[Na+].[O:9]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>COCCOC>[O:9]([CH:16]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1([Cl:6])[Cl:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C=COc1ccccc1
Reactant: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1C(Oc2ccccc2)C1(Cl)Cl

Procedure:
The mixture of 20.9 g (113 mmol) sodium trichloroacetate, 15.4 g (80 mmol) ethyl 3-phenoxy-2-propenoate and 50 ml dry 1,2-dimethoxyethane is heated under reflux for 10 hr, under nitrogen. The mixture is filtered and solvent removed. The residue is purified by chromatography on silica gel, giving ethyl 3-phenoxy-2,2-dichlorocyclopropanecarboxylate, which is then hydrolyzed, as in Example 3, to give the corresponding carboxylic acid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH:26]=O)[CH:22]=[CH:21][CH:20]=3)=[C:11]2C=1CN[C:10]2=[O:35])(=[O:4])=[O:3].[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:59](#[N:61])[CH3:60]>>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH2:26][N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:60]=1[CH2:59][NH:61][C:10]2=[O:35])(=[O:4])=[O:3]
Reactant: COc1cc(-c2cc3c(C=O)cccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: CCNCC
Reactant: CC#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)Cc1cccc2c1cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 57 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-formylindol-2-yl]isoindolinone (0.226 g, 0.452 mmol) was dissolved in acetonitrile (15.0 mL) and the solution was treated with diethylamine (0.935 mL, 9.03 mmol), acetic acid (0.517 mL, 9.03 mmol) and sodium triacetoxyborohydride (0.479 g, 2.26 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=3/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-(diethylaminomethyl)indol-2-yl]isoindolinone (0.144 g, 57%).
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[C:7]([N:12]([CH3:14])[CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:2].[C:22]1([C:28]2([NH2:32])[CH2:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1>O1CCOCC1>[CH3:14][N:12]([CH3:13])[C:7]1[C:6]([NH:5][C:4]([NH:32][C:28]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30][CH2:31]2)=[N:3][C:1]#[N:2])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CN(C)c1ncccc1NC(=NC#N)Oc1ccccc1
Reactant: NC1(c2ccccc2)CCC1
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: CN(C)c1ncccc1NC(=NC#N)NC1(c2ccccc2)CCC1
Yield: 44.2 %

Procedure:
A stirred mixture of the product from Step 1 (3.23 g, 0.0115 mol), 1-phenylcyclobutylamine (1.73 g, 0.0126 mol) (A. Kalir and Z. Pelah, Israel J. Chem. 5:223 (1967)), N-methylmorpholine (2.74 ml, 0.0249 mol) and dioxane (40 ml) was refluxed, under nitrogen for 18 hours and concentrated in vacuo. The residue was mixed with EtOAc and concentrated to give a solid which was recrystallized from EtOAc-hexane to give 1.7 g, mp 204°-205° C. of the titled product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 525.5 %

Procedure:
A mixture of 3-pyridinesulfonic acid (1.0 g, 6.3 mmol), phosphorous pentachloride (1.6 g, 1.2 mmol), and phosphorous oxychloride (2.0 mL, 3.3 mmol) was combined and stirred at 100° C. for 18 h. The reaction was cooled to 25° C., diluted with CHCl3, and bubbled with HCl gas. The resulting precipitate was collected by filtration, washed with CHCl3, and dried in vacuo to yield 1.12 g of the title compound (84%).
Reaction SMILES: COC1[N:8]=[C:7]2C=CN[C:6]2=CC=1.[CH:12]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][NH:23][C:18]2=[CH:17][CH:16]=1)([CH3:14])[CH3:13].Br[CH2:25][CH2:26][CH2:27]CBr.BrCCCBr>>[CH:12]([C:15]1[CH:16]=[CH:17][C:18]2[N:23]3[C:22]([CH2:25][CH2:26][CH2:27]3)=[C:21]([CH2:6][CH2:7][NH2:8])[C:19]=2[N:20]=1)([CH3:14])[CH3:13]
Reactant: COc1ccc2[nH]ccc2n1
Reactant: BrCCCCBr
Reactant: CC(C)c1ccc2[nH]ccc2n1
Agent: BrCCCBr
Product: CC(C)c1ccc2c(n1)c(CCN)c1n2CCC1

Procedure:
The procedure is as for Preparation 8, in Step A replacing 5-methoxy-1H-pyrrolo[3,2-b]-pyridine by 5-isopropyl-1H-pyrrolo[3,2-b]pyridine and 1,4-dibromobutane by 1,3-dibromopropane.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)[CH3:2].C(N(CC)CC)C>CS(C)=O>[CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1)[CH3:2]
Reactant: CCNc1nc(CO)cs1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCNc1nc(C=O)cs1

Procedure:
The reaction described in Preparation 44 was repeated, but using 4.4 g of 2-ethylaminothiazol-4-ylmethanol, 13.3 g of sulfur trioxide pyridine complex, 8.4 g of triethylamine and 60 ml of dimethyl sulfoxide, giving the title compound as pale brown prisms.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6].C1(C)C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(=O)([O-])O.[Na+]>O>[CH2:26]([O:25][C:23]([NH:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)CCl
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Yield: 83 %

Procedure:
(3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (100 mg) was dissolved in water (4.3 ml), and a toluene solution (5.3 ml) of benzyl chloroformate (0.794 ml) was added thereto. An aqueous solution (1.0 ml) of sodium hydrogencarbonate (71.9 mg) was further added dropwise thereto while being stirred. After the mixture was reacted at room temperature for 50 minutes while being stirred, the aqueous layer was separated. The resulting toluene layer was analyzed by HPLC, and it was identified that (3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone (118 mg) was obtained in a yield of 83%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[O:13].Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[C:28]([C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][NH:36][CH2:37]4)=[CH:32][CH:31]=3)[N:27]=[C:26]([NH2:40])[N:25]=2)[CH2:20][CH2:19]1>>[NH2:40][C:26]1[N:27]=[C:28]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][N:36]([C:12]([NH:9][C:8]4[CH:10]=[CH:11][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=4)=[O:13])[CH2:37]3)=[CH:32][CH:31]=2)[CH:29]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)[N:25]=1
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=C(Cl)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CC(C)Oc1ccc(NC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)cc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 4-isopropoxyaniline (TCI, Cat. #10399), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=502.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[BH3-][C:15]#N.[Na+]>C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]1
Reactant: Brc1ccccc1N1CCNCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: CN1CCN(c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
1-(2-Bromophenyl)piperazine (200 mg) was dissolved in formaldehyde (36.5% in water, 0.603 mL) and the solution was stirred 3 h at RT. NaBH3CN (78.2 mg) was added and the mixture was stirred at RT overnight. NaBH3CN (78.2 mg) was added again and the mixture was stirred at RT for 6 h. The solvents were removed in vacuo and the residue was taken up in EA, washed with sat. NaHCO3, dried (Na2SO4) and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 18 for 4CV, 18 to 100 over 10CV, 100 for 2CV, then MeOH flush for 4CV) to afford 1-(2-bromophenyl)-4-methylpiperazine (111 mg, colorless oil). LC-MS (B): tR=0.57 min; [M+H]+: 255.05.