Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1([Cl:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:3]1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)C1C=CC=CC1(Cl)Cl
Yield: 101.2 %

Procedure:
To a cold (5° C.) mixture at 55.0 g (0.423 mole) of ethyl acetoacetate, 70 ml. of benzene, 18.3 ml. of 33% sodium hydroxide, and 141 ml. of water was added simultaneously with vigorous stirring 80.0 g (0.457 mole) of o-chlorobenzoyl chloride and 76 ml. of 33% sodium hydroxide in 1 hour as described in Example 4. The aqueous solution of sodium salt of ethyl o-chlorobenzoylacetoacetate was stirred with 22.5 g (0.424 mole) of ammonium chloride for 18 hours. The aqueous solution was then saturated with 25.0 g of sodium chloride. At this moment, some precipitate formed which was filtered. The analysis indicated this material was mainly the sodium salt of ethyl o-chlorobenzoylacetoacetate. The sodium salt and the aqueous filtrate were combined and acidified with dilute hydrochloric acid. The oil which separated was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was Kugelrohr distilled to give 30.0 g of oil which contained mainly ethyl o-chlorobenzoylacetoacetate. This material was stirred with a mixture of 7.2 g of ammonium chloride, 14 ml. of concentrated ammonium hydroxide and 150 ml. of water and worked up as described in Example 4 to give 16.6 g (15%) of crude ethyl o-chlorobenzoylacetate which was about 92% pure. A mixture of 15.0 g (0.065 mole) of ehtyl o-chlorobenzoylacetate, 9.5 g (0.070 mole) of sulfuryl chloride and 20 ml. of chloroform was held at reflux for 6 hours and concentrated to give 17.3 g of crude ethyl 2-chloro-o-chlorobenzoylacetate. A mixture of 17.0 g (0.065 mole) of ethyl 2-chloro-o-chlorobenzoylacetate, 4.94 g (0.065 mole) of thiourea and 65 ml. of ethanol was held at reflux for 2 hours and worked up as described in Example 4 to give 15.0 g of solid, m.p. 114°-136° C. which was recrystallized twice from ethanol to give 5.8 g (31%) of ethyl 2-amino-4-(o-chlorophenyl)-5-thiazolecarboxylate, m.p. 162°-164° C. Part (1.0 g) of this material was recrystallized from toluene to give 0.75 g of pure ethyl 2-amino-4-(o-chlorophenyl)-5-thiazolecarboxylate, m.p. 165°-166° C. A solution of 4.2 g (0.015 mole) of ethyl 2-amino-4-(o-chlorophenyl)-5-thiazolecarboxylate in 50 ml. of 85% phosphoric acid and 15 ml. of nitric acid was diazotized with 1.12 g (0.016 mole) of sodium nitrite as described in Example 4. The diazonium salt solution was poured into a solution of 1.50 g (0.015 mol) of cuprous chloride in 7.5 ml. of concentrated hydrochloric acid and 7.5 ml. of water. The reaction mixture was worked up as described in Example 4 to give 4.0 g of oil which was Kugelrohr distilled (150° C. at 0.3 mm) to give 2.0 g of oil. The material was purified to give 0.66 g (15%) of ethyl 2-chloro-4-(o-chlorophenyl)-5-thiazolecarboxylate as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C1CCC(Oc2ncc(Br)cn2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3ncc(Br)cn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(5-bromo-pyrimidin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)[O:8][C:4]=2[CH:3]=1.Cl.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][N:13]([C:23]([C:22]4[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=4[O:20][CH3:19])=[O:24])[CH2:12]3)[O:8][C:4]=2[CH:3]=1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: Clc1ccc2nc(NCC3CCNC3)oc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)N1CCC(CNc2nc3ccc(Cl)cc3o2)C1
Yield: 22.3 %

Procedure:
A mixture of 20 mg (0.07 mmol) (6-chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride, 15 mg (0.77 mmol) 2,6-dimethoxybenzoyl chloride and 10 mg (0.1 mmol) NEt3 in 2 mL DCM was shaken at room temperature over night. After evaporation the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 6.5 mg (22%) of the title compound. MS (m/e): 416.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([CH3:23])[C:19](=[O:24])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:33]=[C:32]([NH:34][C:35]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[C:22]4[N:21]=[C:20]([CH3:23])[C:19](=[O:24])[NH:18][C:17]=4[N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1nc2c(Oc3ccc(N)c4ccccc34)ccnc2[nH]c1=O
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: Cc1nc2c(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c4ccccc34)ccnc2[nH]c1=O

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a slightly pink solid (56 mg, 71%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>[Cu](I)I.CN(C=O)C>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(Br)cc2n1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cc1ccc2ccc(C#C[Si](C)(C)C)cc2n1
Temperature: 110 °C
Yield: 80.8 %

Procedure:
In a sealed tube were introduced 7-bromo-2-methyl-quinoline (500 mg, 2.25 mmol, 1.0 eq), PdCl2(PPh3)3 (79 mg, 0.11 mmol, 5% mol), copper iodide (21 mg, 0.11 mmol, 5% mol), and triphenylphosphine (106 mg, 0.39 mmol, 20% mol). Then, DMF (5 mL) was added followed by diethylamine (3.5 mL, 34 mmol, 15 eq) and trimethylsilylacetylene (350 μL, 2.5 mmol, 1.1 eq). The mixture was heated at 110° C. overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-EtOAc 95:5) to afford 2-methyl-7-trimethylsilanylethynyl-quinoline as a white solid (435 mg, 81%).
Reaction SMILES: [F:1][C:2]([F:16])([CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[NH2:17][NH2:18]>>[F:1][C:2]([F:16])([CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:3]([NH:17][NH2:18])=[O:4]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccncc1
Reactant: NN
Product: NNC(=O)C(F)(F)C(O)c1ccncc1

Procedure:
α,α-difluoro-β-hydroxy-3-(4-pyridinyl)-propanoic acid, hydrazide (50) was prepared in the manner described in Example 10 on a 20 mmol scale using ethyl α,α-difluoro-β-hydroxy-3-(4-pyridinyl)-propanoate and hydrazine to yield 2.7 g (62%) of product. This product was used immediately in the manner described in Example 51, below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-])=O.C(=O)([O-])[O-].[K+].[K+].C(Br)CCCC>CN(C=O)C>[NH2:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCBr
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)O)cc1N
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 140.8 %

Procedure:
4Methoxy-3-nitrobenzoic acid (5 g, 25.4 mmol), DMF (30 ml), potassium carbonate (5.53 g, 40 mmol) and pentyl bromide (4 ml, 32.3 mmol) were mixed, and this solution was stirred at 100° C. for 1.5 hours. The reaction mixture was filtered to remove the inorganic salt, and DMF was evaporated under reduced pressure. Ethyl acetate (100 ml) was added to the obtained residue. The mixture was washed 3 times with saturated brine (30 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. Ethanol (150 ml) and 10% palladium-carbon catalyst (0.5 g) were added to the obtained residue, and the mixture was stirred at room temperature for 5.5 hours in a stream of hydrogen. The palladium-carbon catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=3/1) to give 3-amino -4-methoxybenzoic acid (5.98 g, 99% in 2 steps) as colorless crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([I:19])[C:5]=12.Cl[CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].[Li+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([I:19])[C:5]=12.[Cl:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[C:6]2[N:16]([CH2:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[N:17]=[C:18]([I:19])[C:5]=12
Reactant: O=C(CCl)N1CCCC1
Agent: Clc1c(-c2ccccc2)nnc2[nH]nc(I)c12
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
4-Chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazine was synthesized according to Example 1 through step 6. Sodium hydride (60% in mineral oil, 32 mg, 1.75 mmol) was added to a solution of 4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (400 mg, 1.12 mmol) and 2-chloro-1-(pyrrolidin-1-yl)ethanone (54 mg, 1.8 mmol) in dry DMF (7.5 mL) at room temperature. After 1.5 h at room temperature further sodium hydride (60% in mineral oil, 27 mg) was added and the suspension stirred for 2 h. 4% LiCl aq. solution and ethyl acetate was added. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was partially purified by column chromatography (silica gel, iso-hexanes/ethyl acetate 1:0 to 0:1). The resulting solid was dissolved in minimum CH2Cl2 and diethyl ether was added until a solid precipitated. The solid was collected by filtration to provide 2-(4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (246 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CNCCNC.[I-:18].[Na+].O>O1CCOCC1>[I:18][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: [I-]
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Ic1cnc2ccccc2c1
Reaction time: 18 h
Yield: 87.2 %

Procedure:
3-Bromoquinoline (64.00 g, 308 mmol), N,N′-dimethylethylenediamine (13.5 ml, 127 mmol), cuprous iodide (12.00 g, 63.0 mmol) and sodium iodide (112 g, 747 mmol) in dioxane (300 ml) was placed into a preheated oil bath at 100° C. After stirring for 18 h, the heterogeneous mixture was diluted water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with methylene chloride as the eluant to afford 68.47 g (87% yield) of 3-iodoquinoline as a yellow solid. Method [8] retention time 6.47 min by HPLC (M+=256).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([C:27]([N:29]3[CH2:32][CH:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:30]3)=[O:28])[N:23]=2)[CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:55][OH:56]>CN(C)C=O>[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([C:27]([N:29]3[CH2:32][CH:31]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[CH2:30]3)=[O:28])[N:23]=2)[CH2:18][C:19]([NH:55][OH:56])=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Reactant: NO
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1)NO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 12.4 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[3-(4-morpholinyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid trifluoroacetate (Preparation 28) (1173 mg, 2.70 mmol) and N-methylmorpholine (327 μl, 2.97 mmol) in N,N-dimethylformamide (25 ml) was cooled to 0° C., treated dropwise with isobutyl chloroformate (386 μl, 2.97 mmol) and stirred under a nitrogen atmosphere at 0° C. for 45 minutes. Hydroxylamine hydrochloride (564 mg, 8.11 mmol) was then added followed by further N-methylmorpholine (891 μl, 8.11 mmol) and the mixture was stirred for 18 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue dissolved in a saturated aqueous solution of sodium carbonate. The pH of the solution was adjusted to 9 by dropwise addition of acetic acid. Water was added (75 ml) and the product was then extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:0.88 ammonia (90:10:1) then dichloromethane:methanol:0.88 ammonia (80:20:2). The product was further purified by HPLC to afford the title compound as a white solid (151 mg)
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([Br:21])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30](=[O:32])[CH3:31].O.[Cl-].[Na+].O>CN(C=O)C.C1COCC1>[NH2:1][C:2]1[O:3][CH2:4][C:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH2:29][C:30](=[O:32])[CH3:31])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([Br:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: CC(=O)CCl
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1ncc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2′-amino-7-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-3-ol (0.570 g, 1.637 mmol) in 5 mL DMF was treated with potassium carbonate (0.283 g, 2.047 mmol) and was allowed to stir at RT for 15 minutes. The reaction mixture was then cooled to 0° C. and 1-chloropropan-2-one (0.151 g, 1.637 mmol) was added as a solution in 1 mL THF. After stirring for one hour the reaction mixture was allowed to warm to RT and stir for 4 hours. The reaction mixture was poured into 1:1 water/brine, extracted with EtOAc (3×25 mL). The combined organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography provided 1-(2′-amino-7-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yloxy)propan-2-one. MS m/z=404.0 [M+H].
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1([NH2:28])[CH2:27][O:26][CH2:25]1>>[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1([NH:28][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:27][O:26][CH2:25]1
Reactant: NC1(c2nccs2)COC1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Agent: Cl
Product: O=C(NC1(c2nccs2)COC1)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 3-(thiazol-2-yl)oxetan-3-amine hydrochloride (Example 32b) as starting materials and isolated (16 mg, 29%) as colorless oil; MS (ESI, m/z): 372.2 (M+H+).
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:10][O:9][C@@H:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[O:7][CH2:6]1)[CH2:2][CH2:3]C.C(C1C=CC(C2C=CC(C#N)=CC=2)=CC=1)C>>[CH2:1]([C@@H:5]1[CH2:6][O:7][C@@H:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[O:9][CH2:10]1)[CH2:2][CH3:3]
Reactant: CCCC[C@H]1CO[C@H](c2ccc(C#N)cc2)OC1
Agent: CCc1ccc(-c2ccc(C#N)cc2)cc1
Product: CCC[C@H]1CO[C@H](c2ccc(C#N)cc2)OC1

Procedure:
17.0% of 4-(trans-5-n-butyl-1,3-dioxan-2-yl)-benzonitrile 10.4% of 4-ethyl-4'-cyanobiphenyl
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)[C:6]2[CH:23]=[C:24]([C:28]3[N:32]([CH3:33])[C:31]4[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:30]=4[N:29]=3)[CH:25]=[C:26]([CH3:27])[C:5]=2[N:4]=1)[CH3:2].[Cl-].[NH4+].[N-:41]=[N+:42]=[N-:43].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:43][N:42]=[N:41][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:23]=[C:24]([C:28]3[N:32]([CH3:33])[C:31]4[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:30]=4[N:29]=3)[CH:25]=[C:26]([CH3:27])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A solution of 1.9 g (3.8 mMol) of 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl, 4.1 g (76 mMol) of ammonium chloride and 4.9 g (76 mMol) of sodium azide in 30 ml of dimethylformamide is heated to 140° C. for 15 hours, then a further 2.0 g of ammonium chloride and 2.4 g of sodium azide are added and the mixture is heated for another 4 hours to 140° C. Then the solution is stirred into about 80 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (150 g of silica gel; eluant: methylene chloride/ethanol=19:1).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[C:15]([F:20])=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25].[NH4+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[C:15]([F:20])=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:27]#[C:26][C:24]([OH:28])([CH3:25])[CH3:23])=[CH:9][CH:10]=1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1cc(F)c(O)cc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(O)c(F)cc1O2
Temperature: 80 °C

Procedure:
A vial charged with (S)-2-amino-7′-bromo-3′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.225 g, 0.616 mmol), Pd(PPh3)4 (0.071 g, 0.062 mmol), and copper(i) iodide (0.012 g, 0.062 mmol), was treated with 3 mL DMF followed by DIPA (1.317 mL, 9.24 mmol). The solution was purged with argon for 2 minutes then 2-methylbut-3-yn-2-ol (0.301 mL, 3.08 mmol) was added and the vial was sealed and heated to 80° C. overnight. The reaction mixture was poured into saturated NH4Cl (50 mL) and was extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (9:1:0.1—CH2Cl2:MeOH:NH4OH)/CH2Cl2] provided (R)-2-amino-3′-fluoro-7′-(3-hydroxy-3-methylbut-1-ynyl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol. MS m/z=369.3 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[CH2:10][CH2:9][C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][C:6]=2[CH:23]=1.B([O-])([O-])O[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O>[CH2:36]([O:35][CH2:34][CH2:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH2:13][O:14][CH3:15])[CH2:10][CH2:9][C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][C:6]=3[CH:23]=2)=[CH:31][CH:30]=1)[CH2:37][CH2:38][CH3:39]
Reactant: COCCN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3CCOC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
In toluene/ethanol/water (=10/1/1, 62.4 ml) was dissolved tert-butyl 7-bromo-1-(2-methoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.8 g). To the solution were added 4-(2-butoxyethoxy)phenyl borate (1.68 g) and potassium carbonate (1.55 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinpalladium (0.22 g), and the mixture was heated to reflux for 16 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/1) to give tert-butyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.4 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.Cl[C:32]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[O:33]>>[CH3:38][O:37][CH2:36][CH2:35][O:34][C:32](=[O:33])[NH:1][CH2:2][C@H:3]1[CH2:4][C@@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:6]1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: COCCOC(=O)Cl
Product: COCCOC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamic acid 2-methoxy-ethyl ester is prepared as described in Example 22 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and 2-methoxyethyl chloroformate (TCI America, Portland, Oreg., U.S.A.). Analytical HPLC: tR=7.02 min (Grad 2); ES-MS: m/eo=502.0.