Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CC#N>[N:28]1([CH2:27][CH2:26][NH:15][C:12]2[CH:13]=[CH:14][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: ClCCN1CCCCC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(NCCN3CCCCC3)cc2)OC1(C)C

Procedure:
N-(2-(piperidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine was prepared by heating 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (0.219 g, 1 mmol), potassium iodide (0.006 g, 0.03 mmol), potassium carbonate (0.060 g, 0.4 mmol) and 1-(2-chloroethyl)-piperidine (0.050 g, 0.3 mmol) in MeCN (2 ml) to 110° C. by microwave irradiation for 10 minutes. The crude reaction was purified by preparative HPLC to give the product as a white solid (0.009 g, 0.027 mmol). LCMS (3) 2.50 min; m/z (ES+) 331.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:31]=[CH:30][C:11]([CH2:12][N:13]2[C:17]3([CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]3=[O:28])[CH2:16][C@@H:15]([OH:29])[CH2:14]2)=[CH:10][CH:9]=1.[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1(C)C=CC=CC=1.C(O)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>[CH:22]1([N:19]2[CH2:20][CH2:21][C:17]3([N:13]([CH2:12][C:11]4[CH:30]=[CH:31][C:8]([C:35]5[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=5)=[CH:9][CH:10]=4)[CH2:14][C@H:15]([OH:29])[CH2:16]3)[C:18]2=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(Br)cc1
Reactant: OB(O)c1ccncc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(-c2ccncc2)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A solution of sodium carbonate (10.0 mg, 0.0000943 mol) in water (0.1 mL) was added to a mixture of (3R)-1-(4-bromobenzyl)-7-cyclohexyl-3-hydroxy-1,7-diazaspiro[4.4]nonan-6-one (19.0 mg, 0.0000466 mol; prepared as Example 37), 4-pyridinylboronic acid (8.60 mg, 0.0000700 mol) and tetrakis(triphenylphosphine)palladium(0) (1.6 mg, 0.0000014 mol) in toluene (200 μL, 0.002 mol) and ethanol (100 μL, 0.002 mol). After stirring the mixture at 120° C. for 6 h, the inorganics were separated by filtration and the filtrate was diluted with methanol and adjusted to a pH of ˜2.0 with TFA. The crude product was purified by prep. HPLC to afford the desired product. LC/MS 406.2 (M+1H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:26][OH:27])=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:27][CH2:26][C:20]2[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1cnc(CO)c(C)c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(COc2nc(N)nc(-c3ccco3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (3,5-dimethylpyridin-2-yl)methanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:25])([F:24])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:23])[CH2:14][C@@H:15](OS(C)(=O)=O)[CH2:16][CH3:17])=[CH:8][CH:7]=1.O>O1CCCC1>[CH2:16]([C@H:15]1[N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]([F:25])([F:24])[F:4])=[CH:7][CH:8]=2)[C:13](=[O:23])[CH2:14]1)[CH3:17]
Reactant: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
31.8 mg (0.589 mmol) of sodium methoxide was suspended in tetrahydrofuran (1 mL) and a tetrahydrofuran solution (1 mL) containing 200 mg (0.589 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-methanesulfonyloxypentanoic acid amide produced in Example 3 was added dropwise thereto at room temperature for 5 minutes. After stirring at room temperature for further 3.5 hours, water (5 mL) was added and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone as a brown solid (141.6 mg). The reaction yield of the product was determined by HPLC analysis (column; NACALAI COSMO SEAL 5C18-AR packed column 4.6×250 mm: eluent; acetonitrile/5 mM phosphate buffer solution (pH=3)=1/1: flow rate; 1.0 mL/min: column temperature; 30° C: detector; UV 210 nm) to be 60%.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:19]C(=O)C)([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[CH2:7][CH2:8][CH3:9])(=O)C.[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[ClH:32].NC(CCC1C=CC=CC=1OCCCCCCC)(CCC)CO>>[ClH:32].[NH2:19][C:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=1)([CH2:7][CH2:8][CH3:9])[CH2:5][OH:4]
Reactant: CCCCCCCCBr
Reactant: CCCC(CCc1cccc(O)c1)(COC(C)=O)NC(C)=O
Agent: CCCCCCCOc1ccccc1CCC(N)(CO)CCC
Agent: Cl
Product: CCCCCCCCOc1cccc(CCC(N)(CO)CCC)c1

Procedure:
2-Acetamido-2-[2-(3-hydroxyphenyl)ethyl]pentyl acetate and octyl bromide were used in the same manner as working example 52 (9) and (10) to give the subject compound as a yellowish oily substance.
Reaction SMILES: Cl.N[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18](CC(OCC)=O)[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1>C1COCC1>[C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:27]([OH:33])=[O:34])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1)#[N:3]
Reactant: CCOC(=O)CN1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2=NOC3(CCN(C(=O)CCCC(=O)O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.5 g (6.22 mmol) of the intermediate from Example 5. Step B in 40 ml dry THF were added 0.71 g (6.22 mmol) glutaric anhydride and 76 mg 4-N,N-dimethylaminopyridine (DMAP). It was stirred for 1 h at room temperature followed by 2 h heating with reflux. The solvent was removed under reduced pressure, and the title compound was obtained by chromatography on silica gel with dichloromethane containing 4% ethanol. It was recrystallized from ethyl acetate/ether, and the crystals were collected by filteration and dried in vacuo.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][C:8]1[N:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]2=[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)[N:9]=1.Cl[C:31]([O:33][CH2:34][CH2:35][Cl:36])=[O:32]>N1C=CC=CC=1.ClCCl>[NH2:25][C:19]1[C:20]([NH:24][C:31](=[O:32])[O:33][CH2:34][CH2:35][Cl:36])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[N:9]=[C:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:12]3[C:11]=2[CH:16]=[CH:15][CH:14]=[N:13]3)[N:18]=1
Reactant: O=C(Cl)OCCCl
Reactant: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1NC(=O)OCCCl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
247 mg (0.623 mmol) of the compound prepared in Example 9A were initially charged in pyridine (2.5 ml) and dichloromethane (2.5 ml), 64 μl (0.623 mmol) of 2-chloroethyl chloroformate were added at 0° C. and the mixture was stirred at 0° C. for 10 min. After 16 hours of stirring at 20° C., another 64 μl (0.623 mmol) of 2-chloroethyl chloroformate were added, and the mixture was stirred at 20° C. for 16 hours. The reaction mixture was then poured onto ice-water and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue (314 mg) was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12](=[S:15])SC)(=[O:10])=[O:9].CS.[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH3:27])[N:20]=1>C1(C)C(C)=CC=CC=1.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH3:27])[N:20]=1)=[S:15])(=[O:9])=[O:10]
Reactant: CSC(=S)NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(C)nc(N)n1
Agent: CS
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: COc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A solution of 5.0 g of methyl N-(2-chlorophenylsulfonyl)dithiocarbamate in 20 ml of xylene is stirred for 3.5 hours with heating at 145° C. During the heating, methylmercaptan gas is generated. After the reaction is completed, xylene is removed under reduced pressure to yield a pale yellow oil (IR: strong absorption band of -SO2NCS at 1900 cm-1). The oily substance is dissolved in 50 ml of acetonitrile, to which 2.8 g of 2-amino-4-methoxy-6-methylpyrimidine is added and stirred for 30 minutes at 50° C. The precipitated crystals are collected by filtration, and recrystallized from acetonitrile to give 5.6 g of the title compound as a white prism. mp 186.5°~187.5° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[N:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:47][CH2:48][CH:43]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:44][CH2:45]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27]
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Reactant: C1CC(N2CCOCC2)CCN1
Product: Cc1ccccc1-c1cc(N2CCC(N3CCOCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 40.6 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (47.6 mg) was reacted with 4-(morpholine-4-yl)piperidine (38.3 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (24.2 mg, 41%).
Reaction SMILES: ClC([O:4][CH2:5][CH3:6])=O.[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:23]=[C:19]([C:20]([OH:22])=[O:21])[C:18]([OH:24])=[C:17]([I:25])[CH:16]=1.[CH3:26]N(C)C1C=CC=CC=1.Cl>C1C=CC=CC=1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:16]=[C:17]([I:25])[C:18]([O:24][C:5]([CH2:6][CH3:26])=[O:4])=[C:19]([C:20]([OH:22])=[O:21])[CH:23]=1
Reactant: CCOC(=O)Cl
Reactant: CN(C)c1ccccc1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Agent: Cl
Solvent: c1ccccc1
Product: CCC(=O)Oc1c(I)cc(-c2ccc(F)cc2F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.928 g (0.0086 mmol) of ethyl chloroformate was added to a mixture of 2.5 g (0.0061 mmol) of 5-(2,4-difluorophenyl)-3-iodo-salicylic acid in 6 ml of benzene and 1.728 g (0.014 mmol) of dimethylaniline. The mixture was stirred at room temperature for 3 hr. Ice and a solution of 2.5 N of HCl were added. It was extracted with dichloromethane and the organic phase was dried over magnesium sulphate. The solvent was evaporated at low pressure and the crude was recrystalized from a chloroform-hexane mixture.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=4[N+:35]([O-:37])=[O:36])=[CH:21][CH:20]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:41])=O>C(Cl)Cl.O1CCCC1.CN(C)C=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([Cl:41])=[O:31])=[CH:28][C:27]=4[N+:35]([O-:37])=[O:36])=[CH:21][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.2 %

Procedure:
A suspension of the product of Example 19B (500 mg, 0.976 mmol) in anhydrous methylene chloride (10 mL) and tetrahydrofuran (5 mL) was treated with oxalyl chloride (2M in methylene chloride, 0.976 mL, 1.951 mmol) and N,N-dimethylformamide (3 drops), and the resulting solution was stirred under a nitrogen atmosphere for 2 hours at room temperature. The solvent was removed by rotary evaporation in vacuo and the residue dried on hi-vacuum to give the title compound as a yellow solid (0.571 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])[CH2:28][CH2:27]2)[C:19](=[O:38])[C:18]=1[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:42][CH:41]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH2:33][C:34]([OH:37])([CH3:35])[CH3:36])[CH2:28][CH2:27]2)[C:19](=[O:38])[C:18]=1[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]2[NH:3][C:4](=[O:7])[O:5][N:53]=2)=[CH:42][CH:41]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.49 g), sodium hydrogen carbonate (0.74 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C. for 30 min, 4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.31 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.27 g, 75%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:26]4[C@H:25]([CH3:24])[CH2:29][O:28][C:27]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)nc3)CC2)c(C)c1
Yield: 47.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (187.6 mg) described in Preparation Example 73 and (R)-4-methyloxazolidin-2-one (50.6 mg) described in Preparation Example 25, the title compound (94.5 mg) was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:31][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[S:26][C:19]3[C:18]([NH:17][C:13]4[CH:12]=[C:11]5[C:16](=[CH:15][CH:14]=4)[NH:8][CH:9]=[CH:10]5)=[N:23][CH:22]=[N:21][C:20]=3[CH:24]=2)=[CH:34][CH:33]=1
Reactant: NCc1ccco1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: c1coc(CNCc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)c1

Procedure:
The title compound was prepared from C-furan-2-yl-methylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 125-134° C.; LC-MS: 452 (MH+); HPLC RT: 4.51 minutes.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24](=[NH:28])OCC)[CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>>[OH2:9].[ClH:1].[NH2:29][N:28]=[CH:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:14][CH2:13][NH:12][C:10](=[O:11])[O:9][CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=N)c1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reactant: N
Agent: Cl
Product: NN=Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Product: O

Procedure:
A solution of the product of Stage (i) (0.1 g) in methanolic ammonia solution (25 ml) was stirred at room temperature for 72 h. The mixture was reduced to dryness and the residual oil triturated with a mixture of ethyl acetate and ethanol to give the title compound as a powder (0.06 g), m.p. 248°-250°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.IC1C=CC(N2C3CCCCC=3C(C(F)(F)F)=N2)=CC=1.C([Li])CCC.CN([O:56][CH3:57])[C:48]([C:50]1[N:51]([CH3:55])[CH:52]=[CH:53][N:54]=1)=[O:49].C1C[O:61]CC1>>[CH:57]([OH:56])=[O:61].[CH3:55][N:51]1[CH:52]=[CH:53][N:54]=[C:50]1[C:48]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1)=[O:49]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1nccn1C
Reactant: FC(F)(F)c1nn(-c2ccc(Br)cc2)c2c1CCCC2
Agent: FC(F)(F)c1nn(-c2ccc(I)cc2)c2c1CCCC2
Agent: [Li]CCCC
Product: Cn1ccnc1C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: O=CO
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirring mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (200 mg; 1.05 mmol), 4-bromoiodobenzene (297 mg; 1.05 mmol), K2CO3 (302 mg; 2.18 mmol), CuI (20 mg; 0.11 mmol) and N,N-dimethyl glycine (30 mg; 0.29 mmol) in DMSO (4 mL) was heated at 130° C. for 5 hours 30 minutes. The reaction mixture was partitioned between DCM and water, the organic phase filtered through silica (eluent—methanol), and concentrated in vacuo, giving a brown oil (411 mg). This was purified by column chromatography, giving a mixture of 1-(4-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and 1-(4-iodophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (205 mg). Under an inert atmosphere of argon, 95 mg of this mixture was dissolved in anhydrous THF (2 mL), cooled to −78° C., and n-butyl lithium (2.5 M in hexanes, 330 μL; 0.82 mmol) was added dropwise over 2 minutes. After stirring for 1 hour, N,1-dimethyl-N-(methyloxy)-1H-imidazole-2-carboxamide (93 mg; 0.55 mmol) was added in one portion to the cold (−78° C.) mixture and the reaction stirred at this temperature for a further 40 minutes. The reaction was warmed to 0° C. and stirred at this temperature for 5 hours 20 minutes. Additional N,1-dimethyl-N-(methyloxy)-1H-imidazole-2-carboxamide (58 mg; 0.34 mmol) was added in one portion, and the reaction stirred at 0° C. for a further 1 hour. The reaction was quenched with aqueous hydrochloric acid (1M, 2 mL), and purified by SCX column chromatography, yielding a white solid (32 mg). This was further purified by MDAP, giving the title compound as white solid (1.14 mg; 0.29% [2 steps]).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:27]1[S:28][CH:29]([CH2:32][N:33]3[CH2:38][CH2:37][S:36][CH2:35][CH2:34]3)[CH2:30][N:31]=1)=[CH:10]2.CO.[OH:41]OS([O-])=O.[K+].S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:27]1[S:28][CH:29]([CH2:32][N:33]3[CH2:34][CH2:35][S:36](=[O:41])[CH2:37][CH2:38]3)[CH2:30][N:31]=1)=[CH:10]2
Reactant: O=S([O-])OO
Reactant: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a mixture of N-{5-(3-methoxypropoxy)-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (110 mg), methanol (3 mL), water (3 mL) and tetrahydrofuran (3 mL) was added OXONE (registered trade mark, 60 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. Aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was stirred for 30 min, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-90:10, volume ratio). The obtained crystals were washed with diisopropyl ether to give the title compound (35 mg, yield 32%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 176-177° C.