Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C=O.ClCCl>[CH2:40]([NH:47][C:7]([C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:9])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cc1ncsc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ncsc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of 4-methylthiazole-5-carboxylic acid (5.00 g, 34.92 mmol) in anhydrous N,N-dimethylformamide (75 mL) was added 1-hydroxybenzotriazole (5.66 g, 41.91 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (8.04 g, 41.91 mmol), N,N-diisopropylethylamine (18.23 mL, 104.76 mmol) and benzylamine (4.57 mL, 41.91 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (55 mL) and brine (45 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (35-45% ethyl acetate in hexanes) to afford N-benzyl-4-methylthiazole-5-carboxamide as a white solid (4.85 g, 60%): 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 7.36-7.33 (m, 5H), 6.17 (br s, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.72 (s, 3H); MS (ES+) m/z 233.2 (M+1).
Reaction SMILES: C1(NC=CP(=O)(OCC)[O:11][CH2:12][CH3:13])CCCCC1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([CH:33]=O)=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]3[NH:38][CH:39]=[CH:40][C:28]=23)=[CH:23][CH:22]=1.O.O.C(O)(=O)C(O)=O>O1CCCC1.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:32](/[CH:33]=[CH:13]/[CH:12]=[O:11])=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]3[NH:38][CH:39]=[CH:40][C:28]=23)=[CH:25][CH:26]=1
Reactant: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1C=O
Reactant: CCOP(=O)(C=CNC1CCCCC1)OCC
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1/C=C/C=O

Procedure:
A solution of 11 g (42 mmol) of diethyl 2-(cyclohexylamino)-vinyl-phosphonate in 60 ml of tetrahydrofuran are added dropwise under argon in the course of 10 min to a suspension of 2.52 g (84 mmol) of 80% strength sodium hydride in 60 ml of anhydrous tetrahydrofuran. 9.9 g (35 mmol) of the compound from Example VIII dissolved in 100 ml of tetrahydrofuran are added dropwise at reflux. The mixture is allowed to boil under reflux for 90 min and is cooled, treated with water and extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and concentrated in vacuo. The residue is dissolved in 300 ml of toluene and heated under reflux for 1 h with 22.9 g (182 mmol) of oxalic acid dihydrate in 350 ml of water. The mixture is cooled, the phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness in vacuo. The residue is dissolved in dichloromethane and filtered through 400 g of silica gel 230-400 mesh in a glass suction filter. The mixture is eluted without sucking dry using petroleum ether/ethyl acetate 1:1, the eluate is concentrated in vacuo and the residue is stirred thoroughly in ether.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=1[NH2:19].C([O-])([O-])=O.[Na+].[Na+].[CH3:26][C:27]1([CH3:36])[CH2:32][CH2:31][C:30](B(O)O)=[CH:29][CH2:28]1>C1(C)C=CC=CC=1.CCO.CCOC(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>[CH3:26][C:27]1([CH3:36])[CH2:32][CH2:31][C:30]([C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][S:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=2[NH2:19])=[CH:29][CH2:28]1
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1Br
Reactant: CC1(C)CC=C(B(O)O)CC1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2N)CC1
Temperature: 80 °C
Yield: 139 %

Procedure:
A solution of 40.0 mg (0.114 mmol) of 2-bromo-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (as prepared Example 26, step (e)) in toluene (4 mL) and EtOH (2 mL) was treated with 458 μL (0.229 mmol) of 2.0 M aqueous Na2CO3 and 29.8 mg (0.226 mmol) of 4,4-dimethyl-cyclohex-1-enylboronic acid. The mixture was degassed via sonication, placed under Ar, treated with 13.2 mg (0.0110 mmol) of Pd(PPh3)4, and heated to 80° C. for 5 h. The mixture was cooled to RT, diluted with EtOAc (10 mL), and washed with saturated aqueous NaHCO3 (1×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 60.0 mg of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C20H30N2O3S, 379.2 (M+H). found 379.1.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1I.[Br-].[CH:17]1([Zn+])[CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>>[CH:17]1([C:5]2[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:15])[CH2:20][CH2:19][CH2:18]1
Reactant: [Zn+]C1CCC1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1I
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(C(F)(F)F)cc1C1CCC1

Procedure:
In analogy to the procedure described for the synthesis of example B.10, the title compound was prepared from 2-iodo-4-trifluoromethyl-benzoic acid methyl ester and cyclobutyl zinc bromide followed by saponification with sodium hydroxide. MS (m/e): 243.0 (M−H)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Cl.Cl.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]1>>[CH2:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([NH:12][CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)[CH2:32][CH2:33][CH3:34]
Reactant: O=C(O)c1ccc(NCc2ccnc3ccccc23)cc1
Reactant: CCCCN1CCC(N)CC1
Agent: Cl
Product: CCCCN1CCC(NC(=O)c2ccc(NCc3ccnc4ccccc34)cc2)CC1

Procedure:
The title compound was prepared from 4-[(4-quinolinylmethyl)amino]benzoic acid and 4-amino-1-butylpiperidine bishydrochloride by the procedure described in Example 18, m.p. 189°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([C:12]([O:14][CH2:15]C)=[O:13])([CH3:11])[CH3:10])[C:5]([Cl:17])=[CH:4][C:3]=1[O:18]C(=O)C1C=CC=CC=1.[Na].Cl>CO>[CH3:15][O:14][C:12](=[O:13])[C:9]([O:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:18])=[CH:4][C:5]=1[Cl:17])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C(C)(C)Oc1cc(Cl)c(OC(=O)c2ccccc2)cc1Cl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C)(C)Oc1cc(Cl)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To an ice cold solution of 500 mg (1.3 mmol) benzoic acid 2,5-dichloro-4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl ester in 11.5 ml methanol was added a solution of 145 mg (6.3 mmol) sodium in 11.5 ml methanol within 5 min under an argon atmosphere. The solution was stirred for 4 h at ambient temperature, cooled to 0° C. and carefully neutralized with 1 N HCl. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and brine/ice water 1/1. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine/ice water 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 219 mg (0.8 mmol, 62%) of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C([SnH](CCCC)CCCC)CCC.[O:30]1CCC[CH2:31]1>CN(C)C=O.C1(C)C=CC=CC=1.[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>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:31]=[O:30])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1.0 g of 2-butyl-6-iodo-4(1H)-quinazolinone and 0.355 g of tetrakis(triphenylphosphine)palladium in 15 ml of tetrahydrofuran and 5 ml of N,N-dimethylformamide, heated to 55° C. under an atmosphere of carbon monoxide is added a solution of 1.40 g of tri-n-butyltin hydride in 2.5 ml of toluene over 6 hours via a syringe pump. After the addition is complete the reaction is allowed to cool to room temperature, diluted with brine and extracted with chloroform. The combined organics are concentrated in vacuo and the resulting residue triturated with ether. The precipitate is collected by filtration and purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes to give 0.35 g of the desired product, m.p. 242°-244° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cccc2oc(=O)[nH]c12
Product: Cc1cc(S(=O)(=O)Cl)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
1.10 g (6.60 mmol) 4-methyl-3H-benzoxazol-2-one in 5.0 mL (75 mmol) chlorosulphonic acid were stirred for 2 h at RT. Then the reaction mixture was very slowly added dropwise to a large amount of ice and stirred at RT. The precipitate formed was suction filtered and dried.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][CH:23]([CH3:27])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:15]([O:19][C:20](=[O:21])[NH:22][CH:23]([C:24](=[O:25])[NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:27])([CH3:16])([CH3:17])[CH3:18]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
N-Phenylbenzene-1,2-diamine (1.84 g, 0.01 mol), racemic (R/S)-2-tertbutoxycarbonylaminopropionic acid (1.89 g, 0.01 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.92 g), 4-methylmorpholine (1.0 g, 0.01 mol), HOBt (1.53 g, 0.01 mol) were suspended in THF (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 12 h at RT. After this period of time, additional amounts of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (500 mg×3) and of (R/S)-2-tertbutoxycarbonylaminopropionic acid (500 mg) were added and the mixture was stirred for further 4 h. The reaction mixture was then partitioned between water and EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC ISCO 24 g column, gradient 0-20% EtOAc in cyclohexane). The product containing fractions were combined and concentrated in vacuo affording [1-(2-Phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as a white crystalline solid (3.07 g, 86%). LCMS: RT 3.61 min [M+H-tBu]+ 300.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[C:11](OC)=[O:12].[I-].[Li+].[BH4-].[Na+].Cl>O.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:15]1[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:11][OH:12]
Reactant: COC(=O)C(Cc1ccc(Cl)cc1Cl)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: OCC(Cc1ccc(Cl)cc1Cl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 14.1 parts of methyl 2,4-dichloro-α-(2,6-dichlorophenyl)benzenepropanoate and 6.8 parts of lithium iodide in 120 parts of acetonitrile are added portionwise, during a 5-minutes-period, 2 parts of sodium borohydride. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is allowed to cool to room temperature. Then there are added successively 100 parts of a concentrated hydrochloric acid solution (carefully) and after stirring for 30 minutes, 1000 parts of water. The product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with water, dried, filtered and evaporated, yielding 11.2 parts of 2,4-dichloro-β-(2,6-dichlorophenyl)benzenepropanol.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([NH:15][CH3:16])=O)=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH3:24])=[O:22].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.O>C1(C)C=CC=CC=1>[F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([NH:15][CH3:16])=[S:35])=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CNC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=S)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Temperature: 25 °C
Yield: 10.1 %

Procedure:
A mixture of 3 g (0.009 mol) of product of Example 201 and 7.28 g (0.018 mol) of Lawesson's reagent in 100 ml of toluene was refluxed for 16 days. The reaction mixture was cooled to 25° C., poured into H2O, and extracted with ethyl acetate. The organic phase was dried (MgSO4), and concentrated in vacuo to 1.4 g of a brown oil. Chromatography using 10% ethyl acetate/cyclohexane as an eluting solvent afforded 0.35 g (11%) of product as a beige solid: mp 129°-131° C.
Reaction SMILES: N1C=CC=CC=C1.[Cl:8][CH:9]([CH3:37])[CH:10]([NH:22][C:23]([CH:25]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][C:35]#[N:36])[CH2:28][CH2:27][NH:26]1)=[O:24])[CH:11]1[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH:13]([S:20][CH3:21])[O:12]1.CCN(C(C)C)C(C)C.Br[CH2:48][C:49]1[O:50][C:51](=[O:55])[O:52][C:53]=1[CH3:54]>CN(C=O)C.CCOC(C)=O>[Cl:8][CH:9]([CH3:37])[CH:10]([NH:22][C:23]([CH:25]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][C:35]#[N:36])[CH2:28][CH2:27][N:26]1[CH2:48][C:49]1[O:50][C:51](=[O:55])[O:52][C:53]=1[CH3:54])=[O:24])[CH:11]1[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH:13]([S:20][CH3:21])[O:12]1
Reactant: CSC1OC(C(NC(=O)C2CCC(CCCC#N)CCN2)C(C)Cl)C(O)C(O)C1O
Reactant: Cc1oc(=O)oc1CBr
Agent: C1=CC=CNC=C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSC1OC(C(NC(=O)C2CCC(CCCC#N)CCN2Cc2oc(=O)oc2C)C(C)Cl)C(O)C(O)C1O

Procedure:
To a solution of azepine compound prepared in example 7′ (5-(3-cyano-propyl)-azepane-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide, 100 mg) in DMF (2.0 mL) was added DIEA (181 μL) followed by 4-bromomethyl-5-methyl-[1,3]-dioxol-2-one (194 mg, prepared as described in J. Alexander, et al. J. Med. Chem, 1996, 39, 480-486). After stirring overnight EtOAc (30 mL) was added, the organic solution washed with brine (20 mL), dried over Na2SO4 and the solvents removed under reduced pressure. The resulting residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, 6 μm particle size, 60 Å pore size, 20 mm ID×100 mm) to provide the title compound (6 mg) of as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:36][C:37]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[CH:41][C:38]=1[CH:39]=[O:40]>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.O1CCOCC1>[F:36][C:37]1[CH:44]=[C:43]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]4[C:19]5=[N:20][C:21]([C:24]6[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=6)=[CH:22][N:23]=[C:18]5[N:17]=[N:16]4)[CH2:9]3)=[N:6][CH:7]=2)[CH:42]=[CH:41][C:38]=1[CH:39]=[O:40]
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Reactant: CC1(C)OB(c2ccc(C=O)c(F)c2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(C=O)c(F)c6)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
In a pressure tube reactor, (S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (50 mg, 0.11 mmol) was added, and then 1M Na2CO3 (0.33 mL, 0.33 mmol) was added. Pd(PPh3)4 (6 mg, 0.005 mmol) was further added, and then 1,4-dioxane (1 mL) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzaldehyde (41 mg, 0.16 mmol) were added. The mixture was stirred at room temperature for 10 minutes under nitrogen gas, and then stirred at 105° C. for 13 hours. When the reaction was completed, the organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. Solid was generated using ether and hexane, followed by filtration, to give (S)-2-fluoro-4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)-methyl)morpholino)pyrimidin-5-yl)benzaldehyde (41 mg, 0.087 mmol) with a yield of 76%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:26][C:21]1[CH:20]=[C:19]([N:16]2[CH2:15][CH2:14][C:11]3([CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:18][CH2:17]2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(F)c(Cl)c1)CC2
Agent: O=C(O)/C=C/C(=O)O
Product: Fc1ccc(N2CCC3(CCNCC3)CC2)cc1Cl

Procedure:
Was prepared according to method C from 9-(3-chloro-4-fluoro-phenyl)-3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester as the fumaric acid salt. Mp. 201.4-202.2° C.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl-].[NH4+].[CH3:15][C@H:16]1[CH2:21][CH2:20][C@H](N)[CH2:18][CH2:17]1>>[CH3:15][C@H:16]1[CH2:21][CH2:20][C@H:12]([N:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:10]=[CH:11]2)[CH2:18][CH2:17]1
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Reactant: C[C@H]1CC[C@H](N)CC1
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)c1cn([C@H]2CC[C@H](C)CC2)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (Liebigs Annalen der Chemie, 1979, p. 1444) (1.52 g) was dissolved in trans-4-methylcyclohexylamine (3.07 g), and the solution was stirred at 70° C. for 4 hours. To the reaction solution, saturated aqueous ammonium chloride was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=2/1-1/2) to obtain the title compound (1.90 g).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[NH2:8][CH2:9][C@H:10]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C@H:11]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1.C(N(CC)CC)C.O>C1COCC1>[Cl:31][C:26]1[CH:25]=[C:24]([C@H:11]2[C@@H:10]([CH2:9][NH:8][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=S(=O)(Cl)CCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CS(=O)(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
2-Chloroethanesulfonyl chloride (390 mg) was added dropwise to a solution of tert-butyl (6R,7S)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (600 mg) and triethylamine (0.67 mL) in THF (5 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (235 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][N:12]=2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(Oc2ccccc2)cn1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(Oc2ccccc2)cn1
Yield: 18.4 %

Procedure:
5-Phenoxy-pyridin-2-ylamine (100 mg) was treated with 3-chloro-2-methylbenzenesulfonyl chloride (122 mg) in the presence of pyridine (3 mL) as described in example 172, step C] to give 3-Chloro-2-methyl-N-(5-phenoxy-pyridin-2-yl)-benzenesulfonamide (37 mg) as a white foam. MS (ESI): 375.1 (MH+).
Reaction SMILES: [CH:1]([N:4]([CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:5](=[O:7])[CH3:6])([CH3:3])[CH3:2].[ClH:21]>>[ClH:21].[CH:1]([N:4]([CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:5](=[O:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N(C(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CC(=O)N(C(C)C)C1CCNCC1
Yield: 45 %

Procedure:
A solution of tert-butyl 4-(N-isopropylacetamido)piperidine-1-carboxylate (0.880 g, 3.09 mmol) in hydrogen chloride (4.0 M solution in 1,4-dioxane, 10 mL) was stirred at room temperature overnight. The resulting solution was concentrated in vacuo, basified with aqueous saturated NaHCO3, and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2. The residue was further purified by flash chromatography on silica gel, eluting with 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford N-Isopropyl-N-(piperidin-4-yl)acetamide hydrogen chloride (0.260 g, 45%) as a clear liquid.