Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3N)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2].C[Si]([Br:33])(C)C.C(ON=O)(C)(C)C.C([O-])(O)=O.[Na+]>BrCBr.C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[Br:33])[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: BrCBr
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(Br)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
To a solution of (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-yl acetate (2.00 g, 4.91 mmol) in dibromomethane (98.2 mL) were added trimethylsilylbromide (0.717 mL, 5.55 mmol) then t-butylnitrite (3.98 mL, 33.44 mmol). The reaction mixture was stirred at room temperature for approximately 3 hours before being slowly poured into a 1:1 mixture of saturated NaHCO3:CH2Cl2. The organics were washed with water then brine. After drying over Na2SO4, the solvent was removed in vacuo. The crude product was purified by flash chromatography (0% to 30% EtOAc/Hex) to obtain the title compound as a yellow oil (1.26 g, 55%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:38]=[CH:37][C:12]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[N:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1.O.[OH-].[Na+]>C(OCC)(=O)C>[F:8][C:9]1[CH:38]=[CH:37][C:12]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[N:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cncc3ccccc23)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2cncc3ccccc23)cc1Nc1ccc(F)cc1
Yield: 52.6 %

Procedure:
Trifluoroacetic acid 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-(isoquinolin-4-yl)benzoate 110 mg was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and it was adjusted to pH6.0 with 1.0 mol/L sodium hydroxide aqueous solution. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-(isoquinolin-4-yl)benzoic acid 50 mg of pale green solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].Cl[CH:9]([C:15]([C:17]([F:20])([F:19])[F:18])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(Cl)Cl>[CH3:2][CH:1]([NH:4][C:5]1[O:6][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([C:17]([F:18])([F:20])[F:19])[N:7]=1)[CH3:3]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CC(C)NC(N)=O
Solvent: ClCCl
Product: CCOC(=O)c1oc(NC(C)C)nc1C(F)(F)F
Yield: 47.3 %

Procedure:
By the procedure of Example 4, 6.1 g (60 mmol) of isopropyl urea was reacted with 10.9 g (50 mmol) ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product mixture was treated with methylene chloride, washed with water, dried and concentrated. The residue was recrystallized from methylcyclohexane to yield 6.3 g of crystal product (m.p.=51°-52° C.) identified in Table I.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6]1)=[O:4].CN(C)C=O.Cl.Cl.[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:35]#[N:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:35]([C:34]1[CH:37]=[CH:38][C:39]([N:40]2[CH2:45][CH2:44][N:43]([C:11]([C@H:10]3[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])[CH2:6][C@@H:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:13])[CH2:42][CH2:41]2)=[C:32]([CH3:31])[CH:33]=1)#[N:36]
Reactant: Cc1cc(C#N)ccc1N1CCNCC1
Reactant: COC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (3R,4S)-piperidine-1,3,4-tricarboxylic acid 1-benzyl ester 3-methyl ester (0.554 g, 0.00172 mol) in N,N-dimethylformamide (8.500 mL, 0.1098 mol) was added 3-methyl-4-piperazin-1-ylbenzonitrile dihydrochloride (0.6146 g, 0.002241 mol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.017 g, 0.001896 mol), and, N,N-diisopropylethylamine (1.509 mL, 0.008620 mol). The reaction mixture was stirred overnight at room temp. Reaction quenched with KH2PO4(sat solution). Layers separated and aq layer extracted with ethyl acetate 3×. Organic layers were washed with brine and dried over magnesium sulfate. Filtered and concentrated. The residue was purified by Combiflash with 40-70% EtOAc/Hex to give the product (75% in yield). MS (ESI): (M+H)+=505.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[O:19][N:20]=[CH:21][C:11]=3[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(N(CC)CC)C>O1CCCC1.O1CCOCC1.O1CCOCC1>[O:19]1[C:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[CH3:24])=[CH:3][CH:4]=3)=[O:7])[CH2:9][CH2:10][C:11]=2[CH:21]=[N:20]1
Reactant: Nc1ccc(C(=O)N2CCc3cnoc3-c3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cnoc3-c3ccccc32)cc1
Reaction time: 4.5 h

Procedure:
A partial solution of 0.250 g of 5,6-dihydro-6-(4-aminobenzoyl)-4H-isoxazolo[4,5-d][1]benzazepine in 4 ml of tetrahydrofuran-dioxane (1:3) under argon is treated with 160 μl of 2-methylbenzoyl chloride in 1.5 ml of dioxane followed by 114 μl of triethylamine and stirring continued for 4.5 hours at room temperature. The volatiles are evaporated in vacuo to a residue which is dissolved in methylene chloride containing methanol, washed with 10% NaHCO3 and brine, then treated with activated carbon. The mixture is filtered through MgSO4 and the filtrate filtered through silica gel with 15% ethylacetate in methylene chloride. The filtrate is evaporated in vacuo to a residue which is dissolved in methylene chloride, filtered through glass wool, evaporated to a residue which is dissolved in ethyl acetate by warming to give 0.25 g of the desired product as tan crystals, m.p. 257°-260° C. HR FABMS: (M+H)=424.1657.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[C:7]([CH:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]([CH3:20])=[CH:5]2.[CH:21]1[C:34]2C=C(O)C3C(=CC=CC=3)C=2C=C[CH:22]=1>>[OH:19][CH:13]([C:7]1[C:6]2[C:5]([C:4]3[CH:3]=[CH:2][CH:11]=[CH:10][C:9]=3[C:8]=1[OH:12])=[CH:34][CH:21]=[CH:22][CH:20]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(Br)ccc2c1O
Reactant: Oc1cc2ccccc2c2ccccc12
Product: CCOC(=O)C(O)c1c(O)c2ccccc2c2ccccc12

Procedure:
Prepared by the similar method to make ethyl 2-(6-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate in Example 20, using phenanthren-9-ol instead of 6-bromo-3-methylnaphthalen-1-ol. 1H-NMR: 400 MHz, (CDCl3) δ: 8.90 (s, 1H), 8.66-8.62 (m, 2H), 8.40 (d, J=4.2 Hz, 1H), 7.97-7.94 (m, 1H), 7.71-7.49 (m, 4H), 6.23 (s, 1H), 4.14-4.08 (m, 2H), 3.81 (bs, 1H), 1.11 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:8][CH:7]=[C:6]([C:9]2[C:13]3[C:14]([O:20]C)=[N:15][CH:16]=[C:17]([C:18]#[N:19])[C:12]=3[N:11]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:10]=2)[CH:5]=1)#[N:2].[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[C:1]([CH2:3][C:4]1[S:8][CH:7]=[C:6]([C:9]2[C:13]3[C:14](=[O:20])[NH:15][CH:16]=[C:17]([C:18]#[N:19])[C:12]=3[N:11]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:10]=2)[CH:5]=1)#[N:2]
Reactant: COc1ncc(C#N)c2c1c(-c1csc(CC#N)c1)cn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCc1cc(-c2cn(C3CCCC3)c3c(C#N)c[nH]c(=O)c23)cs1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 3-(5-(cyanomethyl)-3-thienyl)-1-cyclopentyl-4-methoxy-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (220 mg) in acetonitrile (5 mL) were added sodium iodide (182 mg) and chloro(trimethyl)silane (0.388 mL), and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was allowed to be cooled to room temperature, and filtered, and the obtained solid was washed with acetonitrile and water, and dried under reduced pressure to give the title compound (146 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:23])([F:14])[F:24])=[CH:21][N:20]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(C(F)(F)F)cn1

Procedure:
2,6-Dichlorobenzoyl isocyanate (1.1 grams; 0.005 mole) and 5-(trifluoromethyl)-2-aminopyridine (800 mg; 0.005 mole) were mixed in 50 ml. of ethyl acetate at room temperature and stirred overnight (about 18 hours) at room temperature. Solvent was then evaporated and the product recrystallized from ethanol, m.p. 228°-230° C., yield 200 mg. Elemental analysis showed:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([O:23][CH3:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O.O.[OH-].[K+]>C(OCC)C>[CH2:16]([N:13]1[CH2:14][CH2:15][C:11]([CH2:9][OH:8])([O:23][CH3:24])[CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C1(OC)CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COC1(CO)CCN(Cc2ccccc2)C1
Reaction time: 2 h

Procedure:
6.5 g Lithium aluminum hydride are suspended in 250 ml of dry diethylether. 42 g (0.16 mol) 1-benzyl-3-methoxypyrrolidine-3-carboxylic acidmethylester are added dropwise. The mixture is stirred for 2 hours under reflux. Thereafter 6.5 ml of water, 6.5 ml 15% proof KOH and 6.5 ml of water are added, the inorganic salts are removed by filtration and washed twice with tetrahydrofurane. The organic solvents are removed from the filtrate in vacuo and the resedue is destilled.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([OH:10])=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:11](O)[CH:12]([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: Oc1cccc2sccc12
Reactant: CC(C)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)COc1cccc2sccc12

Procedure:
Benzo[b]thiophen-4-ol (200, 4.3 g, 28.9 mmol) and iso-butanol (3.2 ml, 34.7 mmol) are dissolved under argon in 150 ml of toluene. After addition of triphenylphosphine (9.1 g, 34.7 mmol) and a 40% solution of DEAD in toluene (16.8 ml, 34.7 mmol), the mixture is stirred at 120° C. over night. After cooling down, the reaction mixture is subsequently washed with saturated aqueous NaHCO3 solution and NaCl solution, dried over Na2SO4 and evaporated under reduced pressure. Triphenylphosphinoxid is removed by crystallization from ethyl acetate and hexane and the crude product is further purified by flash chromatography (silica gel, hexane/ethyl acetate 9:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C>ClCCl.CS(C)=O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CCO)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC(CC=O)C1CCCCC1
Reaction time: 2 h

Procedure:
To a solution of (1-cyclohexyl-3-hydroxypropyl)carbamic acid tert-butyl ester (500 mg; 1.9 mmol) and N,N-diisopropylethylamine (1.35 mL; 7.8 mol) in dichloromethane (5 mL) was added a solution of pyridine sulfur trioxide complex (1.25 g; 7.8 mmol) in dimethyl sulfoxide (5 mL) at −20° C. The reaction mixture was stirred for 2 h and diluted with dichloromethane (20 mL). The reaction mixture was washed with 10% acetic acid in water (2×15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude oil was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=O)[C:3]([OH:5])=[O:4].O=C1CCCC1CC(NC(N)=O)C(O)=O.N.[H][H]>O.[Pd]>[NH:1]1[C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]12
Reactant: N[C@@H](CC1CCCC1=O)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: N
Agent: NC(=O)NC(CC1CCCC1=O)C(=O)O
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Yield: 100 %

Procedure:
(S)-2-amino-3-(2-oxocyclopentyl)propanoic acid as obtained in Example 3 (130 mg, 0.76 mmol) was dissolved in water (2 mL) and the pH was adjusted to 9 with 25% aqueous NH3 solution. Then, 10% Pd/C (5 mg) was added and hydrogenation was performed under 5 bar of hydrogen gas for 16 h. At the end of the reaction, the catalyst was filtered off on a pad of celite under suction and the product (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid was isolated after evaporation of the water layer in vacuo at 80° C. Weight 118 mg. 100% yield. Diastereomeric excess >95% (determined by chiral HPLC). 1H NMR: (DMSO-d6, 300 MHz): δ 10.54 (br s, 1H), 8.71 (br s, 1H), 4.22 (dd, 1H), 3.98 (t, 1H), 2.86-2.76 (m, 1H), 2.49-2.42 (m, 1H), 2.00-1.96 (m, 1H), 1.80-1.40 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:32])[C@H:13]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:14][N:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[O:17])[C:3]=1[F:33].Cl.[NH2:35][C@@H:36]([CH2:42][CH3:43])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:27]1([CH2:26][C@H:13]([CH2:14][N:15]([CH:16]=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([NH:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([NH:35][C@@H:36]([CH2:42][CH3:43])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:3]=2[F:33])=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC[C@H](N)C(=O)N(C)C
Reactant: COc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1nc(OC)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F)C(=O)N(C)C
Temperature: 80 °C
Reaction time: 168 h
Yield: 22.4 %

Procedure:
[(2R)-3-{2-[6-Chloro-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.133 g, 0.28 mmol), (2S)-2-amino-N,N-dimethylbutanamide, hydrochloride salt (Example 83) (0.075 g, 0.45 mmol) and diisopropylethylamine (0.1 mL, 0.62 mmol) were stirred in DMSO (2 mL) overnight at 65° C. Then additional diisopropylethylamine (0.2 mL) was added, and the reaction was stirred for 7 days at 80° C. Purified by RP-HPLC to provide (2S)-2-{[6-{2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]hydrazino}-5-fluoro-2-(methyloxy)-4-pyrimidinyl]amino}-N,N-dimethylbutanamide (0.036 g, 23%). LCMS: (M+H)+=574.3.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[O:20]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:28]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4cccc(Oc5ccccc5)c4)ccc3o2)C1

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.034 g, 0.131 mmol), 3-phenoxy-benzoic acid (0.042 g, 0.196 mmol), HATU (0.050 g, 0.131 mmol), polystyrene-bound diisopropylamine (0.327 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (10 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Concentrate the solution to yield a yellow residue. Dilute with CH2Cl2 and wash with 1.0M NaOH (2×25 mL), dry over Na2SO4, filter, and concentrate in vacuo after adsorption onto silica gel. Subject the mixture to flash column chromatography on an ISCO Companion (4 g column, 10% 2M NH3 in MeOH/CH2Cl2) to yield the desired compound as a white oil. Dilute with CH2Cl2 and n-hexane and concentrate in vacuo. Pump for 2 h to yield the desired compound as a white solid (0.027 g, 45%). mass spectrum (m/e): 457.3 (M+1), 455.3 (M−1). 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.51-7.45 (m, 2H), 7.41 (t, J=8.0 Hz, 1H), 7.37-7.29 (m, 3H), 7.20-7.10 (m, 3H), 7.04-7.00 (m, 2H), 3.59-3.48 (m, 2H), 3.18 (s, 3H), 2.74-2.50 (m, 4H), 2.38-2.33 (m, 1H), 2.35 (s, 3H), 2.05-1.95 (m, 1H), 1.59-1.49 (m, 1H).
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:18])[CH:8]=1.C([Li])CCC.C(N1CCOCC1)=O>C(OCC)(=O)C.O>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[CH:8][C:9]=1[F:18]
Reactant: Fc1cc(Br)ccc1C1OCCO1
Reactant: C1CCOC1
Agent: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(C2OCCO2)c(F)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a tetrahydrofuran (600 mL) solution of 2-(4-bromo-2-fluoro-phenyl)-[1,3]dioxolane (12.5 g, 50.7 mmol) described in Manufacturing Example 204-1-1 was added dropwise n-butyl lithium (28.5 mL, 2.67 M hexane solution, 76.1 mmol) over 15 minute. The system was stirred for 5 minutes at −78° C., after which a THF solution of N-formylmorpholine (5.61 mL, 55.8 mmol) was added to this reaction solution, which was stirred for another 2.5 hours at room temperature. Water and ethyl acetate were added to this mixture, which was partitioned. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (9.99 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][OH:23]>>[CH2:1]([Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([O:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[O:18][Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Reactant: CC(C)CCO
Product: CCCCCCCC[Sn](CCCCCCCC)(OCCC(C)C)O[Sn](CCCCCCCC)(CCCCCCCC)OCCC(C)C
Reaction time: 0.67 h
Yield: 99 %

Procedure:
700 g (1.94 mol) of dioctyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 1700 g (19.3 mol) of 3-methyl-1-butanol (made by Kuraray Co., Ltd., Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to 143° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational stirring and heating were carried out for approximately 40 minutes at normal pressure, whereupon the liquid mixture boiled, and hence distilling off of a low boiling component began. This state was maintained for 7 hours, and then the purge valve was closed, and the pressure in the system was gradually reduced, and residual low boiling component was distilled off with the pressure in the system at from 76 to 32 kPa. Once low boiling component stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 864 g of reaction liquid was obtained in the flask. According to 19Sn—, 1H—, and 13C-NMR analysis results, the product 1,1,3,3-tetraoctyl-1,3-bis(3-methylbutyloxy)-distannoxane was obtained at a yield of 99% based on the dioctyltin oxide. The same procedure was carried out so as to produce 1,1,3,3-tetraoctyl-1,3-bis(3-methylbutyloxy)-distannoxane to be used in the following step B.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: Cc1cc2c(NCc3ccccc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[NH:21][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:20]=[CH:19][C:14]4[NH:15][C:16](=[O:18])[S:17][C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:2]2[NH:21][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:20]=[CH:19][C:14]5[NH:15][C:16](=[O:18])[S:17][C:13]=5[CH:12]=4)[C:4]=3[CH:3]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: O=c1[nH]c2ccc(Nc3ncnc4[nH]c(Br)cc34)cc2s1
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)c2cc3c(Nc4ccc5[nH]c(=O)sc5c4)ncnc3[nH]2)cc1

Procedure:
50 mg (138 μmol) 6-[(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1,3-benzothiazol-2(3H)-one (prepared according to example 8) were transformed in analogy to intermediate example 23 using sodium 4-methylbenzenesulfinate to give after working up and purification 6.7 mg (11%) of the title compound.