Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12(Br)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[SnH4]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: [SnH4]
Product: C1C2CC3CC1CC(C2)C3
Yield: 90 %

Procedure:
Adamantyl bromide was cleanly reduced over approximately 3 hours with 1.2 equiv of fluorous tin hydride reagent 3 in refluxing BTF (stoichiometric procedure). After evaporation of the BTF and liquid-liquid extraction (PFMC-CH2Cl2) to separate the tin products, adamantane was isolated in 90% yield (as determined by GC integration). Under the stoichiometric procedure, fluorous tin hydride reagent 3 reduces a number of other functional groups besides halides, as shown in FIG. 1. In these substrates, the nitro, phenylseleno, or xanthate groups are replaced by hydrogen.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH3:12])C.CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].C(Cl)Cl>C1COCC1>[CH3:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:6]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])=[CH:5][CH2:4][OH:3]
Reactant: CCOC(=O)C=C(c1sccc1C)c1sccc1C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccsc1C(=CCO)c1sccc1C
Reaction time: 2 h

Procedure:
To a solution of 3,3-bis-(3-methyl-thiophen-2-yl)-acrylic acid ethyl ester (2.12 g, 7.27 mmol) in THF (20 ml) was added a solution of DIBAL-H (1.5 M in toluene, 33 ml, 49.5 mmol) at −20° C. The reaction mixture was stirred for a further 2 h. A solution of ammonium chloride was added followed by methylene chloride (150 ml) and decalite. The mixture was filtered and the filter was washed with additional methylene chloride (500 ml). The combined organic phases were evaporated to give crude product. Purification on column chromatography gave 3,3-bis-(3-methyl-thiophen-2-yl)-prop-2-en-1-ol in 376 mg (21%) yield.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23]([O:29]C)=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].[ClH:31]>CO>[Cl:31][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7]
Reactant: Cl
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NOCCBr)c2n1
Solvent: CO
Product: O=C(NOCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 90 °C

Procedure:
A mixture of (R)-N-(2-bromoethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (70 mg, 0.146 mmol) and HCl (4 N dioxane, 3.65 mL, 14.6 mmol) was sealed in a pressure tube and heated at 90° C. for 3 hours. The reaction mixture was then cooled, diluted with MeOH, concentrated, and dried on high vacuum to obtain the desired product which was used in the next step directly without further purification, assuming quantitative conversion.
Reaction SMILES: O1CCCOB1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Br[C:16]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[C:23]([C:21]1[CH:22]=[CH:16][C:17]2[C:19](=[C:7]3[C:8](=[C:9]([NH2:10])[N:18]=2)[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:20]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N)c(Br)c1
Reactant: N#Cc1ccccc1B1OCCCO1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc2nc(N)c3ccccc3c2c1
Yield: 35.4 %

Procedure:
35.7 g (190 mmol) 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 31.9 g (158 mmol) 2-bromo-4-(tertbutyl)aniline, 3.6 g (3.16 mmol) tetrakis(triphenylphosphine) palladium(0) and 59.0 g (427 mmol) K2CO3 were heated to reflux in a 2 L flask containing 400 ml toluene and 300 mL ethanol. The reaction mixture was heated for 19 hours under constant N2 purge. HPLC of the reaction mixture indicated consumption of the starting aniline. The mixture was cooled and then filtered to remove the base. The base was washed with EtOAc to remove trace organic. The combined filtrate was evaporated down to give impure oil. The oil was purified on a column of silica using 95/5/0.05 CH2Cl2/MeOH/NH4OH as eluent to obtain separation. The product fractions were evaporated of solvent and the resultant residue recrystallized from CH2Cl2/hexanes to yield 14.0 g of the target compound as white solids (35.5% yield, confirmed by GC-MS).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=[O:21])C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:21])=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ncccc2OCC2CC2)cc1
Reactant: CC(=O)O
Solvent: O
Product: [O-][n+]1cccc(OCC2CC2)c1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 65.19 %

Procedure:
To a solution of 5 g 2-(4-chloro-phenyl)-3-cyclopropylmethoxy-pyridine in 15 mL acetic acid, 3 mL hydrogenperoxyde (30% in water) was added. The reaction mixture was then stirred at 70° C. for 15 h. The reaction mixture was diluted with water and quenched with sodium carbonate. The mixture was washed with methylene chloride. The organic phase was washed with water; then dried over MgSO4 and purified by chromatography on silica gel with a gradient of ethyl acetate to ethyl acetate:methanol 4:1 to yield 3.46 g (65.19%) of the title compound as white solid, MS 276.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.C(=O)=O.CC(C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C1COCC1>[CH2:35]([O:34][C:32]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1)=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C(O)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Indole-3-acetic acid (13 g, 74 mmol) was taken up in 130 mL anhydrous THF in a flame-dried, 2-necked 1 L round-bottomed flask, under an inert atmosphere, and cooled to −78° C. (dry ice/acetone bath). A 1.0 M THF solution of LHMDS (163 mL, 0.163 mol) was added via syringe over 30 minutes, and the reaction mixture allowed to stir for an additional 30 minutes at −78° C. once the addition was complete. Next, benzyl chloroformate (11.7 mL, 13.9 g, 81.6 mmol) was added dropwise via syringe. Stirring was then continued for 1 hour. To work up the reaction mixture, it was quenched with 2 M HCl, and partitioned between 2 M HCl and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers washed with brine, dried over anhydrous MgSO4, filtered, and evaporated to give a white solid with a pinkish tinge (22.49 g, 98% yield): 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 2H) 5.47 (s, 2H) 7.27 (t, J=7.2 Hz, 1H) 7.32-7.47 (m, 4H) 7.54 (d, J=6.8 Hz, 2H) 7.58 (d, J=7.6 Hz, 1H) 7.68 (s, 1H) 8.08 (d, J=8.1 Hz, 1H) 12.43 (s, 1H); HRMS (ESI+) calcd for C18H16NO4 (MH+) 310.1074, found 310.1080.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.Cl.ClCCl.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: Cc1nc(OCCCC(C)C)c(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(OCCCC(C)C)c(Br)cc1N
Temperature: 25 °C
Yield: 131.6 %

Procedure:
In a 50 ml single-necked round-bottomed flask equipped with a condensor, 1.36 g of crude 3-bromo-6-methyl-2-(4-methyl-pentyloxy)-5-nitro-pyridine is dissolved in 3.15 ml of methanol and the resulting solution stirred. Under cooling using an ice/water bath, 3.15 ml of concentrated aqueous HCl is added dropwise by syringe (precipitation is observed). The ice bath is removed and 2.23 g anhydrous SnCl2 is added in portions. Stirring is continued under heating to reflux for 5.5 h (yellow suspension). After cooling this mixture to ambient temperature, it is concentrated in vacuo to give a yellow solid. After adding dichloromethane, 10 ml of a 4 M aqueous NaOH solution is added (pH 12). After extraction, the organic phase is dried over Na2SO4, filtered and the solvent removed in vacuo to give 1.62 g of a yellow oil. Purification is done by flash chromatography [silica gel cartridge (50 g, 150 ml) of a solid deposition with heptane/ethyl acetate 4:1 (v:v)] to give 490 mg of the compound in the form of a yellow oil. RP HPLC: Retention time of compound: 2.12 minutes.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4].C1(=O)[NH:22]C(=O)C2=CC=CC=C12.[K]>CN(C)C=O.O>[NH2:22][CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4]
Reactant: OC(CBr)C1=CC2(CCCC2)c2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: NCC(O)C1=CC2(CCCC2)c2ccccc21

Procedure:
Crude 2-bromo-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (7.3 g; prepared as described in Example 3) in dimethylformamide (100 g) is stirred at 40° C. for 4 hours with potassium phthalimide (5.0 g), then diluted with water and extracted three times with chloroform. The combined extracts are dried and evaporated to dryness. The crude 2-phthalimido-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is added to ethanol (100 ml) containing hydrazine hydrate (1.5 g). The reaction mixture is stirred under reflux for 4 hours, concentrated hydrochloric acid (2 ml) is added, and the mixture is heated for 15 minutes. The solution is cooled, filtered from the solid precipitate and concentrated to a small volume. The concentrate is made alkaline with 2 N sodium hydroxide solution and repeatedly extracted with diethyl ether. Evaporation of the ether and crystallization of the residual product from cyclohexane gives 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, m.p. 76°-78° C.
Reaction SMILES: N.[C:2]([OH:13])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[N+]([O-])([O-])=O.[Ag+:18]>O>[C:2]([O-:13])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:9])([CH3:10])[CH3:11].[Ag+:18]
Reactant: CC(C)(C)CCCCCC(=O)O
Agent: [Ag+]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CC(C)(C)CCCCCC(=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
Ammonia liquor (SG 0.88, 36 ml, 0.6 mole) was added dropwise to neodecanoic acid (95%, 103.2 g, 0.6 mole; Exxon purified by vacuum distillation) in ice-cooled distilled water (200 ml). The resulting ammonium neodecanoate soap was stirred at ambient temperature for 90 minutes, and then silver nitrate (101.94 g. 0.6 mole) in distilled water (120 ml) was added dropwise. The resultant white semi-solid was tritrated 4 times each with cold and warm (50° C.) distilled water, slurried in methanol (400 ml), filtered off and dried overnight at 40° C. under vacuum. Contains 30 wt% silver; yield 64% w.r.t. silver.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1.Cl>ClCCl>[ClH:19].[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3([CH3:18])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:17])=[N:9]3)[CH:3]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC1(c2cccc(Br)c2)N=C(N)c2ccccc21
Agent: Cl
Solvent: ClCCl
Product: CC1(c2cccc(-c3cc(Cl)cc(Cl)c3)c2)N=C(N)c2ccccc21
Reaction time: 1 h
Yield: 61.7 %

Procedure:
The title compound was prepared as described for Example 78 (Scheme #14, N) starting from 1-(3-bromophenyl)-1-methyl-1H-isoindol-3-amine (Example 90) (71.4 mg, 0.237) and (3,5-dichlorophenyl)boronic acid (47.4 mg, 0.249 mmol) with the exception that the hydrochloride was made by dissolving the product in dichloromethane (1 mL) and adding hydrochloric acid (0.71 mL, 1 M in diethyl ether). The solution was stirred for 1 h and was then concentrated to afford 31.0 mg (32% yield) of the title compound: 1H NMR (DMSO-d6) δ 8.23 (d, J=7.78 Hz, 1 H), 7.91-7.87 (m, 1 H), 7.84-7.74 (m, 4 H), 7.71 (d, J=7.78 Hz, 1 H), 7.67-7.62 (m, 2 H), 7.47 (t, J=7.78 Hz, 1 H), 7.43-7.38 (m, 1 H), 2.06 (s, 3 H); MS (ES) m/z 367, 369, 371 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([CH3:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>O1CCOCC1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:7]2[C:3]([C:2]([F:1])([F:10])[F:11])([CH3:9])[CH2:4][CH2:5][C:6]2=[O:8])=[O:28])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1(C(F)(F)F)CCC(=O)N1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2C(=O)CCC2(C)C(F)(F)F)cc1

Procedure:
5.0 g (0.03 mol) of 5-(trifluoromethyl)-5-methylpyrrolidin-2-one in 10 ml of dioxane are stirred with 3.3 g of triethylamine and 6.8 g (0.04 mol) of anisoyl chloride for 16 h at 110°-120° C. The solid which precipitates is filtered off with suction and the salt is washed with a little dioxane. The dioxane solution is stirred into 50 ml of water and the organic phase is separated off with the addition of a little methylene chloride. After stripping off the solvent, the residue is a brownish solid which is recrystallized from ligroin.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][N:27]([CH3:36])[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]1[CH2:29][CH2:28][N:27]([CH3:26])[CH3:36])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CN(C)CCC1CCCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CCN(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(2-dimethylaminoethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.01 minutes; C26H31Cl2N5O2 (516.47); mass spectrum: (M−H)−=515/517 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=2)[C:33]([O:35][CH2:36][CH3:37])=[O:34])O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=3)[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Reactant: CCOC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cccc(-c2cc(Nc3ccc(OC)c(OC)n3)c3nccn3n2)c1
Temperature: 125 °C
Yield: 33.8 %

Procedure:
6-Chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (611 mg, 2 mmol), ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (828 mg, 3.00 mmol), potassium phosphate (1.06 g, 5.00 mmol) and X-phos (381 mg, 800 μmol) were combined with dioxane (29.4 ml) and water (2.94 ml) to give a light yellow suspension. The mixture was evacuated and back-filled with argon three times, then Pd2(dba)3 (183 mg, 200 μmol) was added and the mixture heated to 125° C. in a microwave for 60 min. The mixture was filtered and the filtrate concentrated. The residue was purified by chromatography (silica, 160 g, 20% to 50% EtOAc in hexanes, gradient over 20 min) to give ethyl 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (284 mg, 677 μmol, 34%) as an off-white powder. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.55-8.68 (m, 2H) 8.20 (dd, J=13.79, 7.74 Hz, 2H) 7.96 (d, J=1.51 Hz, 1H) 7.52-7.71 (m, 2H) 7.19 (d, J=8.31 Hz, 1H) 6.73 (d, J=8.31 Hz, 1H) 4.45 (q, J=7.18 Hz, 2H) 4.20 (s, 3H) 3.82-3.97 (m, 3H) 1.44 (t, J=7.18 Hz, 3H); LC/MS: 420.2 [MH]+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)[CH2:4][CH2:3]1.OO>O1CCCC1.O>[OH:1][C@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCC(=O)[C@H]2C1
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H]2CC[C@@H](O)[C@H]2C1
Temperature: -78 °C
Yield: 81.8 %

Procedure:
Under an inert atmosphere, 1.00 g (4.44 mmol) of tert-butyl (3aR,6aS)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate is dissolved in 15 mL of anhydrous tetrahydrofuran; the medium is cooled to −78° C. and 6.66 mL (6.66 mmol) of a solution of lithium tri-sec-borohydride (L-Selectride) at 1N in tetrahydrofuran are then added dropwise. The medium is allowed to warm to room temperature over three hours with stirring, and then cooled to 0° C., followed by dropwise addition of 35% aqueous hydrogen peroxide solution until the evolution of gas has ceased. The medium is diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. 0.826 g (82%) of the expected product is obtained in the form of a colourless oil.
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N+:20]([O-])=O)[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>C(OCC)(=O)C>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[C:12]([NH2:20])[CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(S(C)(=O)=O)c(N)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
Tin(II)chloride dihydrate (2.73 g, 12.1 mmol) was added to a solution of the above sulfone (777 mg, 3.02 mmol) in ethyl acetate (15 mL). The mixture was heated to reflux for 0.5 h then cooled to room temperature and poured onto aqueous 2.0 M NaOH. The aqueous phase was extracted with diethyl ether and the combined organic layers were washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated in vacuo to provide pure 5-tert-butyl-2-methanesulfonyl-phenylamine (618 mg, 90%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)(=[O:33])=[O:32])=[CH:27][C:26]=2[OH:41])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CC(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)(=[O:33])=[O:32])=[CH:27][C:26]=2[O:41][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2O)C1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.6 %

Procedure:
Methyl bromoacetate (47 L, 0.495 mmol), followed by potassium carbonate (136.7 mg, 0.99 mmol) were added to a solution of 3-[4-(3-fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (198.7 mg, 0.471 mmol) in acetone (5 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 4 hours, then filtered and the solvent was evaporated under reduced pressure to give 240.9 mg of 3-[4-(3-fluoro-benzenesulfonyl)-2-methoxycarbonylmethoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester, which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl.N1C=CC=CC=1>[NH2:19][C:17]1[C:18]2[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)=[CH:11][N:12]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(-c2cn(C3CCCC3)c3ncnc(N)c23)cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-c2cn(C3CCCC3)c3ncnc(N)c23)cc1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A solution of 5-(3-amino-4-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40 mg, 0.124 mmol) in dichloromethane (1 ml) and pyridine (1 ml) was cooled to 0° C. and then treated with benzyl chloroformate (32 mg, 0.186 mmol) while maintaining a temperature of less than 5° C. The solution was stirred for another 1 hour at 0° C. then the solvents were removed under reduced pressure. Purification by preparative C-18 RP-HPLC then lyophilization provided benzyl N-[5-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (25 mg) as a white powder: 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.1-7.4 (m, 8H), 6.2 (bs, 2H), 5.15 (s, 2H), 5.07 (m, 1H), 3.8 (s 3H), 1.6-2.2 (m, 8H), RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=18.63 min.; MS: MH+458.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15].CS(C)=O>O>[F:1][C:2]1[C:7]2[C:8](=[O:9])[N:14]([CH3:16])[CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: CNCC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CN1CC(=O)Nc2cccc(F)c2C1=O
Temperature: 100 °C

Procedure:
7.2 g (0.04 mol) of 6-fluoroisatoic acid anhydride and 3.9 g (0.044 mol) of sarcosine are added to 10 ml of dimethyl sulphoxide and the mixture is heated at 100° C. for 30 minutes. After cooling and diluting with 15 ml of water, the separated substance is filtered off. After drying, there is obtained 6-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 214°-217° C. (decomposition).