Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3Cl)[F:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[F:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(F)c4ccc(Cl)cc4Cl)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCC(F)c1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.5 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(2-(2,4-dichlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylate (0.161 g, 0.284 mmol) in 3:1 THF/ethanol (4 ml) was added sodium hydroxide (0.341 ml, 0.341 mmol), and the reaction was stirred for 3 days at ambient temperature. The reaction was concentrated, taken up in water, acidified with 1M hydrochloric acid, and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 121 mg of the title compound (79.7% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:13])([F:12])[CH:9]1[O:11][CH2:10]1>>[F:7][C:8]([F:13])([F:12])[CH:9]([OH:11])[CH2:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)C1CO1
Reactant: C1COCCN1
Product: OC(CN1CCOCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
To a round bottomed flask containing 3.136 g (36 mmol) of morpholine was added 3.362 g (30 mmol) of racemic 1,1,1-trifluoro-2,3-epoxypropane dropwise over 10 min (exothermic). The mixture was stirred at room temperature. After 90 min, the volatiles were removed under reduced pressure to give 5.837 g (98%) of 1,1,1-trifluoro-3-morpholin-4-yl-propan-2-ol as an oil.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:34]1([C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[NH:41][CH2:42][CH2:43][CH2:44]Br)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[O:19][CH2:44][CH2:43][CH2:42][NH:41][C:40]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2cc(-c3ccc(OCCCNC(c4ccccc4)(c4ccccc4)c4ccccc4)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1

Procedure:
360 mg (12 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced into a three-necked round-bottomed flask. A solution of 4.1 g (10 mmol) of methyl 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoate in 75 ml of DMF are added dropwise, under a nitrogen stream, and the mixture is stirred until the evolution of gas ceases. A solution of 42 g (11 mmol) of N-triphenylmethyl-3-bromopropylamine in 50 ml of DMF is then introduced dropwise and the mixture is stirred at room temperature for 8 h. The reaction medium is poured into water, extracted with ethyl ether, the organic phase separated after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by silica chromatography, eluted with a dichloromethane and hexane mixture (40-60). After evaporation of the solvents, 4.7 g (66%) of the expected product are recovered, which product melts at 168°-9° C.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[S:6][C:7]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.O.O.[Sn](Cl)Cl>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[S:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: Cc1ccc(Oc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2nc3cccc(N)c3s2)c(C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 114 %

Procedure:
A mixture of 2-(2,4-dimethylphenoxy)-7-nitro-1,3-benzothiazole (220 mg, 0.733 mmol) and tin(II) chloride dihydrate (694 mg, 3.66 mmol) in DMF (10 ml) was stirred at 80° C. for 15 h and diluted with saturated NaHCO3 solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine, dried over Magnesium sulfate, and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 226 mg of the title compound.
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[C:14](=[O:15])[C:13]2[C:12]([N+]#N)=[C:11]3[O:18]C[O:20][C:10]3=[CH:9][C:8]=2[N:7]([CH2:21][CH3:22])[N:6]=1)([OH:4])=[O:3].S(=O)(=O)(O)O>O>[Cl:1][C:12]1[C:11]([OH:18])=[C:10]([OH:20])[CH:9]=[C:8]2[C:13]=1[C:14](=[O:15])[C:5]([C:2]([OH:4])=[O:3])=[N:6][N:7]2[CH2:21][CH3:22]
Reactant: CCn1nc(C(=O)O)c(=O)c2c([N+]#N)c3c(cc21)OCO3
Reactant: [Cl-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCn1nc(C(=O)O)c(=O)c2c(Cl)c(O)c(O)cc21
Yield: 90.3 %

Procedure:
A solution of 3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-5-diazonium chloride (1.85 g, 5.68 mmol) in sulfuric acid (19.98 ml, 187 mmol) was heated at 95° C. for 20 h. Water was added, the precipitates were collected to provide 5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (1.46 g, 5.13 mmol, 90% yield). LCMS: (M+H)+: 285.2
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:31]2=[O:32])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCCCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 7-(pyridin-4-yl)heptanoate (2.0 eq., prepared in Synthetic Example 15) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[5-(pyridin-4-yl)pentyl]-1,8-naphthyridin-2(1H)-one, mp 188.8 to 189.6° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][CH2:19]I)([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].S(=O)(=O)(O)[OH:22]>>[C:1]([CH2:14][C:15]([CH2:18][CH2:19][OH:22])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=S(=O)(O)O
Reactant: FC(F)(CCI)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: OCCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
Ethylene (25 g) was introduced to an autoclave charged with C4F9CH2CF2I (217 g) and d-(+)-limonene (1 g), and the reactor heated at 240° C. for 12 hours. The product was isolated by vacuum distillation to provide C4F9CH2CF2CH2CH2I. Fuming sulfuric acid (70 mL) was added slowly to 50 g of C4F9CH2CF2CH2CH2I and mixture was stirred at 60° C. for 1.5 hours. The reaction was quenched with ice-cold 1.5 wt % Na2SO3 aqueous solution and heated at 95° C. for 0.5 hours. The bottom layer was separated and washed with 10 wt % aqueous sodium acetate and distilled to provide C4F9CH2CF2CH2CH2OH bp 54-57° C. at 2 mmHg (267 Pa).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([CH:12]3[CH2:29][CH:28]4[CH:14]([C:15](=[O:35])[N:16]([CH3:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]5[C:25]([C:31]([OH:33])=O)([NH:26][C:27]4=[O:30])[CH2:24]5)[CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:48]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]1([C:7]2[N:8]=[N:9][N:10]([CH:12]3[CH2:29][CH:28]4[CH:14]([C:15](=[O:35])[N:16]([CH3:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]5[C:25]([C:31]([NH:54][S:51]([CH:48]6[CH2:50][CH2:49]6)(=[O:53])=[O:52])=[O:33])([NH:26][C:27]4=[O:30])[CH2:24]5)[CH2:13]3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(n3nnc(-c4ccccc4)n3)CC2C1=O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(n3nnc(-c4ccccc4)n3)CC2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A mixture of 9 (50 mg, 0.104 mmol) and CDI (68 mg, 0.418 mmol) in dry THF (5 mL) was heated at reflux for 2 h under nitrogen. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (101 mg, 0.836 mmol) was added. Then, DBU (73 mg, 0.481 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, and then heated at 55° C. for 24 h. Solvent was evaporated, and the residue partitioned between AcOEt and acidic water (pH=3). The crude material was purified by column chromatography (AcOEt/CH2Cl2/Petroleum ether, 1:1:1). The residue was crystallized in Et2O, filtered to give the target compound contaminated with the cyclopropylsulfonamide. This material was triturated in 1.5 mL of water, filtered, washed with water and dried overnight in the high vacuum pump to give 28 mg (46%) of the target compound as a white powder: m/z=582 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C@H:8]1[NH:11][C:10](=[O:12])[C@H:9]1[NH:13][C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl[CH2:24][C:25]([CH:27]1[O:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29][CH2:28]1)=[O:26]>CN(C)C=O>[CH3:35][O:34][C:32]([CH:30]1[O:31][CH:27]([C:25]([CH2:24][S:7][C@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:26])[CH2:28][CH2:29]1)=[O:33]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N[C@@H]1S
Reactant: COC(=O)C1CCC(C(=O)CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(C(=O)CS[C@H]2NC(=O)[C@H]2NC(=O)Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
Potassium carbonate (2.0 g) was added to a stirred solution of (3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-one (2.31 g) and methyl (2RS,5SR)-5-(2-chloroacetyl)tetrahydro-2-furoate (2.02 g) in dimethylformamide (30 ml). The mixture was stirred at room temperature for 1.5 h and then partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed three times with water, then brine, dried over magnesium sulphate and evaporated. The title compound (2.208 g) was isolated by column chromatography of the residue (silica gel, ethyl acetate as eluent); νmax (CHCl3) 3410, 3335, 1777, 1736 and 1678 cm -1.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([N:11]([C:13]2[CH:14]=[C:15]([S:19](O)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)[CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:25]1C(Cl)=NC(Cl)=NC=1Cl.C(N(CC)CC)C.[OH-].[NH4+]>CC(C)=O>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([N:11]([CH3:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([NH2:25])(=[O:21])=[O:20])[CH:14]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CN(C(=O)c1ccc(C(C)(C)C)cc1)c1cccc(S(=O)(=O)O)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(C(C)(C)C)cc1)c1cccc(S(N)(=O)=O)c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A solution of 3-(4-tert-butyl-N-methylbenzamido)benzenesulfonic acid (12 mg, 35 μmol), cyanuric chloride (7.0 mg, 40 μmol), and triethylamine (6.0 μL, 40 μmol) in acetone (0.5 mL) was sealed in a glass tube and heated in a microwave oven at 120° C. for 10 min. Concentrated ammonium hydroxide (150 μL) was added, and the reaction was stirred for 6 h. The reaction was filtered, and the filtrate was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 4-tert-butyl-N-methyl-N-(3-(aminosulfonyl)phenyl)benzamide. LC/MS: m/z 347.3 (M+H)+ at 2.86 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CC1C=CC(C(OC)=O)=CC=1[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1.[CH:21]1([C:24]2[C:33](I)=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([CH3:35])[CH:25]=2)[CH2:23][CH2:22]1.IC1C=C(C=CC=1C)C(OC)=O>>[CH:21]1([C:24]2[C:33]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([CH3:35])[CH:25]=2)[CH2:23][CH2:22]1
Reactant: COC(=O)c1cc(I)c(C2CC2)cc1C
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: COC(=O)c1ccc(C)c(I)c1
Product: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.4, except methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound 267.2) was used in place of methyl 3-iodo-4-methylbenzoate (compound 5.3).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:9]=[N:8][NH:7][C:6]=1[NH2:10])([O-:4])=[O:3].[CH3:11][CH:12]([C:16](=O)[CH3:17])[C:13](=O)[CH3:14]>C(O)(=O)C>[CH3:14][C:13]1[C:12]([CH3:11])=[C:16]([CH3:17])[N:7]2[N:8]=[CH:9][C:5]([N+:2]([O-:4])=[O:3])=[C:6]2[N:10]=1
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Reactant: CC(=O)C(C)C(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc2c([N+](=O)[O-])cnn2c(C)c1C
Yield: 30.2 %

Procedure:
80 cc of acetic acid, 8.2 g of 4-nitro-2H-pyrazol-3-ylamine hydrochloride (prepared according to H. Dorn and H. Dilcher, Liebigs Ann. Chem., 707, 141, 1967) and 7.2 g of 3-methylpentane-2,4-dione were introduced into a 100 ml three-necked round-bottomed flask fitted with a magnetic stirrer, a condenser and a thermometer. The medium was refluxed for 3 hours. The medium was filtered at room temperature and the solid was washed with diisopropyl ether. This yielded 9.4 g of crude product. 3.5 g of this product was recrystallized in 23 cc of absolute ethanol. Drying under vacuum and over phosphoric anhydride yielded 3.1 g of 5,6,7-trimethyl-3-nitropyrazolo[1,5-a]pyrimidine (yield=80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([OH:21])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.[F:36][C:37]([F:43])([F:42])[S:38](Cl)(=[O:40])=[O:39]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:19])[CH3:20])[N:11]=[C:10]([O:21][S:38]([C:37]([F:43])([F:42])[F:36])(=[O:40])=[O:39])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(=O)(=O)C(F)(F)F)nc1C(C)C
Temperature: 0 °C
Yield: 66.3 %

Procedure:
In a 300 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 2.9 g (10.0 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 1.7 g (16.8 mmol.) of triethylamine, and 50 mL of toluene. The mixture in the flask was chilled to 0° C. in an ice bath. To the chilled mixture was slowly added 2.4 g (14.1 mmol.) of trifluoromethanesulfonyl chloride, and the resulting mixture was subjected to reaction for 3 hours at the same temperature. After the reaction was complete, to the reaction mixture was added 30 mL of water. From the aqueous reaction mixture, an organic liquid portion was separated. The organic liquid portion was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (8:2, volume ratio)). There was obtained 2.8 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine having the below-mentioned characteristics as a colorless oil. The yield was 66% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17]12([CH2:27][C:28](O)=[O:29])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N=C=NCCCN(C)C)C>>[NH2:12][C:11]1[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[N:7]([CH2:14][CH2:15][CH3:16])[C:8](=[O:9])[C:10]=1[NH:13][C:28](=[O:29])[CH2:27][C:17]12[CH2:26][CH:21]3[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]3)[CH2:24]1)[CH2:18]2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Product: CCCn1c(N)c(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(=O)n(CCC)c1=O
Yield: 112.8 %

Procedure:
At first 2.00 g (8.85 mmol) of 1,3-dipropyl-5,6-diaminouracil and 2.06 g (10.6 mmol) of 1-adamantaneacetic acid were condensed according to the procedure of Example 1 using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide to afford 4.02 g (yield: 100%) of amorphous 6-amino-5-(adamantan-1-yl)acetylamino-1,3-dipropyluracil as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([NH2:12])=O)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CCc1cccc(Br)c1
Solvent: C1CCOC1
Product: NCCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(3-bromophenyl)propionamide (94) (4.5 g, 19.7 mmol) in THF (50 ml) under argon was added BH3-THF complex (39.4 mL of a 1.0 M solution in THF, 39.4 mmol) and the mixture was stirred at room temperature for 18 h. The reaction was quenched with the cautious addition of 6 M HCl to pH 1. After stirring 4 h the solution was adjusted to pH>10 with the addition of 50% aqueous NaOH. This aqueous solution was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 3-(3-bromophenyl)propan-1-amine (95) as an oil. This material was used in the next synthetic step without purification. 1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.35 (dt, J=6.4, 2.4 Hz, 1H), 7.26 (br s, 1H), 7.18-7.24 (m, 2H), 6.75 (br s, 1H), 2.78 (t, J=7.6 Hz, 2H), 2.34 (t, J=7.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>C(OCC)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethane sulfonic anhydride (32.2 mmol) was added dropwise over 5 minutes to a −40° C. pyridine (70 mL) solution of (4-hydroxy-phenyl)-acetic acid methyl ester (5.35 g, 32.2 mmol). The reaction was stirred at −40° C. for 10 minutes and then at 0° C. for 2 hours. The reaction was diluted with diethyl ether and washed with water and 2N hydrochloric acid. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on a Biotage Flash 40M column eluting with ethyl acetate/hexanes (1:4) to provide the title compound as a clear, colorless oil, which crystallized upon standing 9.27 g, 97%). 1H NMR (400 MHz, CDCl3) δ7.37-7.34 (m, 2H), 7.24-7.21 (m, 2H), 3.70 (3H), 3.64 (2H).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].[ClH:43]>C1COCC1.O1CCOCC1>[ClH:43].[ClH:43].[ClH:43].[NH:11]1[CH2:12][CH2:13][CH:8]([N:6]2[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:21]3[CH:25]=[C:24]([C:26]4[C:27]5[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:28]=5[N:29]=[CH:30][N:31]=4)[CH:23]=[N:22]3)[CH2:7]2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate (3.2 g, 5.4 mmol) in 10 mL of THF was added 10 mL of 4 N HCl in dioxane. The reaction mixture was stirred at room temperature for 2 hours. Removing solvents under reduced pressure yielded 3.25 g (100%) of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a white powder solid, which was used directly in the next reaction. LC-MS: [M+H]+=493.3. 1H NMR (400 MHz, DMSO-d6): δ 9.42 (s 1H), 9.21 (s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 7.97 (s, 1H), 7.39 (d, 1H), 5.68 (s, 2H), 4.96 (d, 2H), 4.56 (m, 2H), 4.02-3.63 (m, 2H), 3.55 (s, 2H), 3.53 (t, 2H), 3.49-3.31 (3, 3H), 2.81 (m, 2H), 2.12 (d, 2H), 1.79 (m, 2H), 0.83 (t, 2H), −0.10 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13][N:17]([CH2:18][CH3:19])[CH2:15][CH3:16]
Reactant: CCNCC
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Solvent: O
Product: CCN(CC)Cc1c(Cl)ccc2cc(Cl)cnc12

Procedure:
24.6 parts of 3,7-dichloro-8-chloromethylquinoline and 30 parts of diethylamine were stirred at 55° C. for 6 hours. Water was added and the solid was filtered off with suction and dried. 25 parts of 3,7-dichloro-8-diethylaminomethylquinoline of melting point 54° C. were obtained. The yield corresponds to 89% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ccnc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromobenzenesulfonyl chloride (3.19 g, 12.5 mmol) was added to a solution of 4-amino-2-chloropyridine (642 mg, 5 mmol) in pyridine (5 ml) and dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue suspended in 2M NaOH (25 ml) and heated at 60° C. for 1 h. The reaction mixture was extracted with ethyl acetate (2×25 ml). The extracts were washed, dried and evaporated. The residue was suspended in methanol and filtered. Evaporation of the filtrate and trituration with diethyl ether afforded the title compound (D3), 1H NMR (DMSO) δ: 6.54 (1H, d), 6.62 (1H, s), 7.60-7.63 (4H, m), 7.66 (1H, d).