Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(=O)c1c(C)cccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(C)cccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of methyl 2-hydroxy-6-methylbenzoate (prepared according to Doehner et al, WO 01/05739, 10.0 g), tert-butyldimethylsilyl chloride (11.0 g), N,N-di-isopropylethylamine (32 mL) and DMAP (0.75 g) in DCM (400 mL) was stirred at room temperature overnight. The mixture was washed with water and brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and pentane with a gradient of 0-10% to give methyl 2-(tert-butyldimethylsilyloxy)-6-methylbenzoate (11.9 g) as an oil.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[OH:13])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:21]1([C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([OH:13])[CH:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9][OH:8])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(C(O)(c2ccccc2)C(CCOCc2ccccc2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(O)cc1

Procedure:
The evaporation residue obtained in step (c) is dissolved in 300 ml of 94% ethanol. Then 2 g of 5% palladium-on-charcoal are added. The reaction mixture is stirred at room temperature under a hydrogen atmosphere until one equivalent of hydrogen is consumed. The catalyst is filtered off. The solvent is evaporated, and the residue is crystallized from toluene. The yield is 12.7 g (38% from desoxybenzoin) of a product having m.p. 192°-4° C.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]2[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[NH:9][C:8]=2[C:22]([F:25])([F:24])[F:23])[CH:3]=1.[Br:26]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[NH:9][C:8]([C:22]([F:23])([F:24])[F:25])=[C:7]([C:4]3[C:3]([Br:26])=[C:2]([Br:1])[S:6][CH:5]=3)[C:11]=2[N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1csc(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1csc(Br)c1Br

Procedure:
A solution of 3-(5-bromo-3-thienyl)-5-(p-chlorophenyl)-4-nitro-2-(trifluoromethyl)pyrrole (0.50 g, 1.1 mmol), bromine (0.20 g, 1.3 mmol) and sodium acetate (0.11 g, 1.3 mmol) in acetic acid (10 mL) is heated overnight at 50° C. and poured into water. The solids are collected and recrystallized from 1,2-dichloroethane to give the title product as a yellow solid, mp 241°-242° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:14][C:15]=3[N:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([C@@H]1CN2C(C3NC(C4(O)CCCC4)=NC=3N(CCC)C2=O)=N1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:12]1[C:11]2[C:10]3=[N:9][C@H:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:19][N:18]3[C:17](=[O:20])[N:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:15]=2[N:14]=[C:13]1[CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[N:14][C:15]=3[N:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C3(O)CCCC3)nc21
Agent: COC(=O)CN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C3CCCC3)nc21
Product: COC(=O)CN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C1CCCC1)n2Cc1ccccc1

Procedure:
Compound 66 (1.87 g, 4.21 mmol) obtained in Example 66 was dissolved in 1,4-dioxane (30 mL), to the solution was added 2 mol/L aqueous sodium hydroxide (15 mL), and the mixture was stirred with heating at 70° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and then the residue was neutralized by addition of concentrated hydrochloric acid. The deposited crystals were collected by filtration, washed with water and dried to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77a, 1.61 g, 90%). Compound 77a (500 mg, 1.08 mmol) was dissolved in N,N-dimethylformamide (5 mL), to the solution were added potassium carbonate (192 mg, 1.41 mmol, 1.2 equivalents) and bromoacetic acid methyl ester (140 μL, 1.41 mmol, 1.2 equivalents), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the concentrate, the mixture was extracted with chloroform, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=90:10) to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77b, 400 mg, 69%). From Compound 77b (850 mg, 1.71 mmol), (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77c, 220 mg, 29%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40. Compound 77c (200 mg, 0.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (1 mL), to the solution was added lithium hydroxide hydrate (0.04 g, 0.98 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH 3 with 1 mol/L hydrochloric acid, and the resulting solid was washed with ethanol and collected by filtration to obtain the title compound (180 mg, 93%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:17])=[CH:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]([CH3:14])=[C:8]([CH3:15])[C:7]=1[OH:16].O=O>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([CH3:17])=[CH:4][CH2:5][C:6]1[C:7](=[O:16])[C:8]([CH3:15])=[C:9]([CH3:14])[C:10](=[O:13])[C:11]=1[CH3:12]
Reactant: CC(=CCc1c(C)c(O)c(C)c(C)c1O)CCl
Agent: O=O
Solvent: ClC(Cl)Cl
Product: CC(=CCC1=C(C)C(=O)C(C)=C(C)C1=O)CCl
Reaction time: 4 h

Procedure:
2-(1-Chloro-2-methylbut-2-en-4-yl)-1,4-dihydroxy-3,5,6-trimethylbenzene (5.6 g, 22.0 mol) was suspended in chloroform (100 ml) at room temperature. Oxygen [O2 (g)]was passed in. After 4 hours, the addition of oxygen was stopped, the reaction mixture was filtered and the mother liquor was concentrated. This gave 2-(1-chloro-2-methylbut-2-en-4-yl)-3,5,6-trimethyl-1,4-benzoquinone (5.6 g, 99 percent). Data regarding the product was:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][NH:17][C:18](OC3C=CC([N+]([O-])=O)=CC=3)=[O:19])[O:14][CH2:13][CH2:12][N:11]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:38][O:39][C:40](=[O:44])[CH2:41][NH:42][CH3:43].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][NH:17][C:18](=[O:19])[N:42]([CH2:41][C:40]([O:39][CH3:38])=[O:44])[CH3:43])[O:14][CH2:13][CH2:12][N:11]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: CNCC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CN(C)C(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-({[(4-nitrophenoxy)carbonyl]amino}methyl)-1,4-oxazepane-4-carboxylate (94 mg) in THF (2.0 mL) were added sarcosine methyl ester hydrochloride (36 mg) and potassium carbonate (72 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (79 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH2:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]([CH3:48])([CH3:47])[CH:45]=O)[CH2:40][CH2:39]1)[CH3:37].N1CCCC1.Cl[Si](C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:48][C:44]([N:41]4[CH2:40][CH2:39][N:38]([CH2:36][CH3:37])[CH2:43][CH2:42]4)([CH3:45])[CH3:47])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCN1CCN(C(C)(C)C=O)CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: ClCCl
Product: CCN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@@H](n3nc(-c4ccc(Oc5ccccc5)cc4F)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To the solution of 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile (0.32 mL, 0.57 mmol DCM (20 mL), 2-(4-ethylpiperazin-1-yl)-2-methyl-propanal (211.84 mg, 1.15 mmol) and pyrrolidine (0.14 mL, 1.72 mmol) was stirred at room temperature for 10 minutes then added chloro(trimethyl)silane (0.29 mL, 2.3 mmol). The mixture was allowed to stirred at room temperature for 18 h. The mixture was worked up with saturated NaHCO3 (50 mL) and DCM (50 mL×2), washed with saturated sodium chloride, dried (MgSO4) and concentrated to yield an oil which was purified over silica gel (5%-50% iPA/DCM) to obtain 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-(4-ethylpiperazin-1-yl)-4-methyl-pent-2-enenitrile 265 mg (72.3% yield). MS (pos. ion) m/z: 638 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12]CC)=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([Cl:26])[CH:17]=2)[CH:3]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[C:18]([Cl:26])[CH:17]=2)[CH:3]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(C(F)(F)F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CNc1ccc(Cl)cc1Oc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product from step (ii) (0.5 g), methanol (5 ml), water (4 ml) and 2M NaOH (2 ml) were stirred at room temperature for 4 h then partitioned between ethylacetate/2 M HCl. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with diethylether/isohexane and filtered, yield 0.1 g.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][C:16]([S:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](=[N:21]\[S:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])/[CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)S(N)=O
Reactant: CCCCOc1ccc(C(C)=O)cc1
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(/C(C)=N\S(=O)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
To a stirred solution of 1-(4-butoxyphenyl)ethanone (3 g, 15.60 mmol) and 2-methylpropane-2-sulfinamide (2.84 g, 23.41 mmol) in THF (50 mL) was added tetraethoxytitanium (8.90 g, 39.0 mmol). The reaction was heated to 70° C. for 3 d. Cold water was added and the reaction was stirred vigorously for 20 min. The mixture was filtered through Celite® and the filtrated was diluted with EtOAc. The organic solution was washed with H2O, brine, dried over MgSO4, filtered and concentrated. The crude product was by silica gel chromatography (220 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (4 g, 87%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=8.80 Hz, 2H), 6.91 (d, J=8.80 Hz, 2H), 4.02 (t, J=6.46 Hz, 2H), 2.73 (s, 3H), 1.75-1.83 (m, 2H), 1.46-1.56 (m, 2H), 1.32 (s, 9H), 0.99 (t, J=7.43 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:28])[C:25]([NH2:27])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.CO>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:28])[C:25]([NH2:27])=[O:26])[C:13]([C:29]([F:31])([F:32])[F:30])=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C(C)C(N)=O)n2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C(C)C(N)=O)n2)cn1
Yield: 63 %

Procedure:
A solution of 2-(2-((2-((6-methoxypyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)propanamide A69 (0.198 g, 0.449 mmol) in EtOAc (20 mL) and MeOH (10 mL) was stirred over 10% Pd/C (wetted with ca. 53% water, 0.150 g) under an atmosphere of hydrogen for 16 hours. The mixture was filtered through Celite and the solvent was removed in vacuo. Purification by column chromatography (Biotage Isolera, 40 g SiO2, 0-80% EtOAc in petroleum benzine 40-60° C.) gave the title compound 61 as a white solid (0.126 g, 63%). LCMS-D: rt 3.43 min; m/z 446 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[CH3:14][N:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)=[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:11]=[N:12]1
Reactant: COc1ccc(-c2c(-c3ccncc3)nnn2C)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1nnc(-c2ccncc2)c1-c1ccc(O)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 4-(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine (170 mg, 0.64 mmol) in dichloromethane (5 mL) was treated at RT with boron tribromide (1.27 mL of 1M in dichloromethane) and the mixture was stirred overnight. Aqueous 1N NaOH (10 mL) was added, and after being stirred 1 h the mixture was extracted with dichloromethane (20 mL). The aqueous layer was acidified to pH 7 with 2N HCl, and extracted with ethyl acetate (2×15 mL). The extracts were dried with sodium sulfate and concentrated. giving a yellow solid (142 mg, 88%). 1H NMR (CDCl3, 400 mHz) δ 1H NMR (CDCl3, 400 mHz) δ 8.39 (d, 2H, J=5-6 Hz), 7.49 (d, 2H, J=5-6 Hz), 7.09 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=8.7 Hz), 3.87 (s, 3H). MS (AP−) 351 (M−H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:21](Br)[CH2:22][CH3:23]>CN(C=O)C>[CH2:21]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:6][CH2:7]1)[CH2:22][CH3:23]
Reactant: CCCBr
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-2-(4-hydroxycyclohexyl)-isoindole-1,3-dione (13 g, 53 mmol) in dry DMF (50 mL) was added molecular sieves (4 Å, 6 mL). The mixture was stirred for 30 min at rt. NaH (5.3 g 60% in oil, 132.5 mmol) was washed with hexanes before it was added in portions to the reaction mixture. The mixture was stirred for 30 min before propylbromide (48.1 mL, 530 mmol) was added. The reaction mixture was stirred for 16 hours before the reaction mixture was filtered. The filtrate was added water (100 mL) and extracted with Et2O (250 mL). The organic phase was washed with brine (3×50 mL) and dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, heptane-EtOAc (4:1). The first band was collected to give 6.6 g (43%) of trans-2-(4-propyloxycyclohexyl)-isoindole-1,3-dione.
Reaction SMILES: [Br-:1].[Br-:2].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[CH:24]=[CH:23]1.CC([OH:35])(C)C>>[Br:1][C:24]1([Br:2])[C:25]2[C:30](=[N:29][CH:28]=[CH:27][CH:26]=2)[NH:22][C:23]1=[O:35]
Reactant: CC(C)(C)O
Reactant: [Br-]
Reactant: c1cnc2[nH]ccc2c1
Agent: c1cc[nH+]cc1
Product: O=C1Nc2ncccc2C1(Br)Br
Reaction time: 3 h
Yield: 75 %

Procedure:
Technical (90%) pyridinium tribromide (220.4 g, 0.62 mol) was added portionwise over a period of 30 min to a stirred suspension of 7-azaindole (1, 27.13 g, 0.23 mol) in t-BuOH (1.36 L). The mixture was stirred at r.t for 3 h, and more pyridinium tribromide (73.3 g, 0.21 mol) was added in one portion. After additional stirring at r.t. for 2 h, the solvent was evaporated under reduced pressure. The residue was separated between water:AcOEt=1:1 (4.2 L). The aqueous layer was extracted with AcOEt (2×800 mL). Combined organic solutions were washed with water (2×500 mL), brine, dried (MgSO4) and concentrated to dyness in vacuum. The residue was triturated with CH2Cl2 (1500 mL) for 20 min. The solid was filtered off, washed with CH2Cl2 (250 mL) and dried in vacuum to afford 2 (49.85 g, 75%) as yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 7.16 (dd, J=7.4, 5.1 Hz, 1H), 7.98 (dd, J=7.4, 1.5 Hz, 1H), 8.19 (dd, J=5.1, 1.5 Hz, 1H), 11.97 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:39])[C:22]([C:24]1[N:33]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:27]2[N:28]=[C:29](Cl)[N:30]=[CH:31][C:26]=2[CH:25]=1)=[O:23]>>[CH:34]1([N:33]2[C:27]3[N:28]=[C:29]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([N:8]5[CH2:12][C:11]6([CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]6)[O:10][C:9]5=[O:19])=[CH:6][N:7]=4)[N:30]=[CH:31][C:26]=3[CH:25]=[C:24]2[C:22]([N:21]([CH3:39])[CH3:20])=[O:23])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: Nc1ccc(N2CC3(CCCNCC3)OC2=O)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5(CCCNCC5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 50.4 %

Procedure:
Following general N—C coupling procedure 1, 3-(6-Amino-pyridin-3-yl)-1-oxa-3,8-diaza-spiro[4.6]undecan-2-one (0.100 g, 0.276 mmol) was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.081 g, 0.276 mmol, 1.0 eq) which gave 7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide as white solid (0.075 g, 0.139 mmol) in 50% yield. 1H NMR (400 MHz, CDCl3) 6 ppm 1.58-1.82 (m, 4H) 1.97-2.27 (m, 14H) 2.47-2.65 (m, 2H) 2.86-3.11 (m, 4H) 3.16 (s, 7H) 3.80-3.88 (m, 2H) 4.80 (qd, J=8.95, 8.78 Hz, 1H) 6.46 (s, 1H) 8.06 (s, 1H) 8.13 (dd, J=9.03, 3.01 Hz, 1H) 8.21-8.32 (m, 1H) 8.50 (d, J=9.03 Hz, 1H) 8.72 (s, 1H); HRMS calc for m/z=531.2832 and found m/z=531.2858 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([C:8]1[C:13]([CH3:14])=[C:12](Cl)[N:11]=[C:10]([CH3:16])[N:9]=1)[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH3:17][C:18]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:19]=1[NH2:20].C(N(C(C)C)CC)(C)C>>[CH2:1]([N:5]([CH2:6][CH3:7])[C:8]1[C:13]([CH3:14])=[C:12]([NH:20][C:19]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:18]=2[CH3:17])[N:11]=[C:10]([CH3:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)c1nc(C)nc(Nc2c(C)cc(C)cc2C)c1C
Temperature: 220 °C
Yield: 103.1 %

Procedure:
A mixture of butyl-(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-ethylamine (398 mg, 1.65 mmol), 2,4,6-trimethylaniline (4.04 g, 30 mmol) and diisopropyl-ethyl-amine (200 mg, 1.55 mmol) was heated at 210 to 230° C. overnight. The mixture was quenched with water and dilute hydrogen chloride, and extracted with ethyl acetate. The organic layer was neutralized with saturated potassium carbonate, washed with brine, dried and concentrated to give a dark oil. The oil was distilled to give 579 mg of dark oil which was then purified through silica gel column chromatography using 1:1 hexane to chloroform as eluent to give 327 mg of title compound as a yellow solid. 1H NMR (CDCl3) δ 0.92 (t, 3H), 1.14 (t, 3H), 1.2–1.4 (m, 2h), 1.45–1.60 (m, 2H), 1.85 (s, 3H), 2.16 (s, 6H), 2.30 (s, 3H), 2.33 (s, 3H), 3.2–3.4 (m, 4H), 5.8 (brs, 1H), 6.90 (s, 2H) ppm.
Reaction SMILES: [NH2:1][CH:2]([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>O.C(#N)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH:2]([NH:1][C:17](=[O:19])[CH3:18])[CH3:11])=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)NC(C)Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
1.88 g (10.0 mmol) 4-(2-amino-propyl)-phenol*HCl and 1.80 g (21.0 mmol) NaHCO3 are combined in 50 mL water and cooled down to 0° C. 0.95 mL (10.0 mmol) acetic anhydride, dissolved in 50 mL ACN, are dropped into the mixture over a period of 1.5 h. The reaction mixture is stirred at r.t. for 72 h. The ACN is evaporated in vacuo and the aq. residue is acidified with HCl (1N). The mixture is extracted several times with EtOAc. The organic layers are combined, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH 95/5).
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH:5]=[CH:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]#[CH:4].[H][H]>CO.[Pd].[Zn]>[CH3:1][C:2]([OH:11])([CH:5]=[CH:6][CH:7]([CH3:10])[CH2:8][CH3:9])[CH:3]=[CH2:4]
Reactant: C#CC(C)(O)C=CC(C)CC
Reactant: [H][H]
Agent: [Pd]
Agent: [Zn]
Solvent: CO
Product: C=CC(C)(O)C=CC(C)CC
Reaction time: 6 h
Yield: 94 %

Procedure:
154 g (1 mole) of 3,6-dimethyl-oct-1-yn-4-en-3-ol are dissolved in 100 ml of methanol, 1 g of an 0.1% strength palladium/calcium carbonate catalyst, which has been poisoned with zinc ions, is added, and hydrogen is passed in at 15°-20° C. under atmospheric pressure. After 6 hours, the mixture is worked up similarly to Example 2. 145 g of 3,6-dimethyl-octa-1,4-dien-3-ol, of boiling point 38°-39° C./0.01 mbar and nD25 =1.4502, are obtained. This corresponds to a yield of 93% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:17]3[O:16][C:15](=O)[NH:14][C:13](=[O:19])[C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[NH4+:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:17]3[NH:21][C:15](=[O:16])[NH:14][C:13](=[O:19])[C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)c(F)c1)CC2
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1ccc(F)c(F)c1
Yield: 100 %

Procedure:
A solution of 7-(3,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (1.05 g, 3.96 mmol) in concentrated ammonium hydroxide (0.154 mL, 3.96 mmol) was stirred at 100° C. in a high-pressure vessel (75 mL) for 6 h. The formation of white precipitate was observed during the heating. The solvent was removed in vacuum to provide 7-(3,4-difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (1.046 g, 3.96 mmol, 100% yield) as a off-white solid. LC-MS (M+H)+=265.2.