Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:46](OC1C(C(O)=O)=NC(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)=NC=1O)[C:47]1[CH:52]=CC=CC=1.[Si](OCCNCC1CC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:45][CH:52]1[CH2:47][CH2:46]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Product: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
This compound was prepared by following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from ‘5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (225 mg, 0.50 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amine (8i) (170 mg, 0.74 mmol). The yield was 307 mg, 93% of a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]1[CH2:11][CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O.[NH:24]1[CH2:29][CH:28]=[C:27]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[CH2:26][CH2:25]1.C(N(CC)CC)C.O>CS(C)=O>[NH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:27]2[CH2:28][CH2:29][N:24]([CH2:12][CH2:11][N:3]3[C:2](=[O:1])[N:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]4=[N:4]3)[CH2:25][CH:26]=2)=[CH:31]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCn2nc3ccccn3c2=O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=c1n(CCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12
Temperature: 85 °C
Yield: 30 %

Procedure:
Toluene-4-sulfonic acid 2-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2-yl)-ethyl ester 166 mg (0.5 mmol) was dissolved in 50 ml DMSO. To this solution was added 99 mg of 3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-1H-indole, (1 eq, 0.5 mmol) and 5 ml triethyl amine. The reaction media was heated under nitrogen at 85° C. for 18 hours. It was then cooled down to room temperature and poured into about 300 ml water and extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over magnesium sulfate and filtered and concentrated. Flash column chromatography using ethyl acetate and 20% methanol/ethyl acetate yielded 54 mg product (30%). mp: 170.4° C.; M+: 360.1; H-NMR: 8.28 (b, 1H, NH), 7.88 (d, 1H), 7.55(d, 1H), 7.30(d, 1H), 7.14(m, 5H), 6.47(m, 1H), 6.19 (m, 1H), 4.25 (m, CH2), 3.35 (d, CH2), 3.00 (t, CH2) 2.86 (t, CH2), 2.60(m, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-])=O)[C:14](I)=[N:15][CH:16]=1>>[NH2:18][C:13]1[C:14]([C:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[O:5])=[N:15][CH:16]=[C:11]([Cl:10])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1I
Reactant: O=Cc1ccccc1Cl
Product: Nc1cc(Cl)cnc1C(=O)c1ccccc1Cl

Procedure:
(3-Amino-5-chloro-pyridin-2-yl)-(2-chloro-phenyl)-methanone was prepared from 2-chlorobenzaldehyde and 5-chloro-2-iodo-3-nitro-pyridine in three steps according to the general procedure for synthesis of 3-Amino-5-chloro-pyridin-2-yl aryl ketones. MS m/z: 267.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][CH:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]([CH:9]([CH3:12])[CH2:10][OH:11])[C:24](=[O:25])[CH2:23][Br:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNC(C)CO)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(C(=O)CBr)C(C)CO)cc1

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(4-methoxybenzylamino)propan-1-ol (11 g, 56.41 mmol, 1.00 equiv) in dichloromethane (100 mL). This was followed by the addition of triethylamine (5.7 g, 56.44 mmol, 1.00 equiv). To this was added a solution of 2-bromoacetyl bromide (11.4 g, 56.44 mmol, 1.00 equiv) in dichloromethane (50 mL) dropwise with stirring at −17˜−25° C. The resulting solution was stirred for 1 h at −17˜−25° C. in a liquid nitrogen bath. The resulting mixture was washed with 3×100 mL of water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. This resulted in 16 g (90%) of N-(4-methoxybenzyl)-2-bromo-N-(1-hydroxypropan-2-yl)acetamide as yellow oil.
Reaction SMILES: [O:1]1CCCO[CH:2]1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[C:19]([F:28])[CH:18]=2)[CH2:11][CH2:10]1.C(O)C.C(O)=O>[Pd].C1(C)C=CC=CC=1>[F:28][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH:12]2[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][CH:2]=[O:1])[CH2:10][CH2:11]2)[CH:22]=[CH:21][C:20]=1[O:23][C:24]([F:26])([F:27])[F:25]
Reactant: Fc1cc(C=CC2CCC(CCC3OCCCO3)CC2)ccc1OC(F)(F)F
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: CCO
Product: O=CCCC1CCC(CCc2ccc(OC(F)(F)F)c(F)c2)CC1
Yield: 37.2 %

Procedure:
The above 1-(2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)vinyl-3-fluoro-4-trifluoromethoxybenzene (5.5 g, 13.7 mmol) was hydrogenated in the presence of 5% Pd/C catalyst (0.3 g) in an ethanol solution, followed by filtering off the catalyst, distilling off the solvent under reduced pressure, adding formic acid (2.8 g, 60.8 mmol) and toluene (50 ml) to the residue, refluxing the mixture for 5 hours, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over MgSO4, and distilling off the solvent, to obtain 3-(4-(2-(3-fluoro-4-trifluoromethoxyphenyl)ethyl)cyclohexyl)propanal (1.76 g, 5.1 mmol). The yield of this product from 1-(2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)vinyl-3-fluoro-4-trifluoromethoxybenzene was 37.2%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Li+].Cl>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.2 %

Procedure:
53 mg of (R)-methyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate, 1.5 mL of tetrahydrofuran, and 0.5 mL of water were added to 25 mL flask and the resulting reaction solution was cooled to 0° C. 7.32 mg of lithium hydroxide was added to the reaction solution and stirred for 6 hours while the reaction temperature was naturally increased to room temperature. After completing the reaction, 5 mL of ethyl acetate and 5 mL of water were added to the reaction solution and stirred for 10 minutes. An aqueous layer was isolated, cooled at 0° C., and 2 N hydrochloric acid aqueous solution was dropped to adjust to pH 3-4. The aqueous layer was extracted with methylene chloride:methanol=10:1 solvent, dehydrated with magnesium sulfate, and then concentrated under reduced pressure to obtain 40.8 mg of a title compound.
Reaction SMILES: Cl.Cl.[N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[NH:5][CH:4]=1.C([O-])(O)=O.[Na+].[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOC(C)=O.CO>[N:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:7][C:6]=2[NH:5][CH:4]=1
Reactant: c1nc2c([nH]1)CNCC2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCc2nc[nH]c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A mixture of 2.0 g of 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine dihydrochloride, 2.36 g of NaHCO3 and 2.45 g of N-(benzyloxycarbonyloxy)succinimide in 80 ml of dioxane/water mixture (50/50; v/v) is stirred for 16 hours at RT. The reaction mixture is extracted with EtOAc, the organic phase is washed with a saturated solution of NaHCO3, with a 0.1 M solution of HCl, with saturated NaCl solution, it is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is purified by silica gel chromatography, eluting with DCM/MeOH mixture. 1.9 g of the expected compound is obtained.
Reaction SMILES: C(O[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[OH-].[K+].C1CCCCC1.ClCCl.C(=O)=[O:25]>O>[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([OH:25])=[CH:9][CH:8]=1)=[CH2:5]
Reactant: O=C=O
Reactant: CC(=O)OC=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCCCC1
Product: C=Cc1ccc(O)cc1

Procedure:
The reaction is based on that described by Corson et al. J Org Chem (1958) 544–549; molar ratios acetoxystyrene:base 1:1.5. The base, KOH in water (30%) was immersed in an ice bath and the acetoxystyrene was added dropwise over 30 mins (all reaction carried under N2; the reaction was TLC monitored (20–80 cyclohexane-dichloromethane) until all acetoxystyrene disappeared, then the pH was brought down to 8 with CO2; the resulting precipitate was filtered and washed with water, then recrystallised from boiling hexane and NMR characterised.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:36])[C:33]([OH:35])=[O:34].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:33]([OH:35])(=[O:34])[CH3:32].[C:33]([OH:35])(=[O:34])[CH3:32].[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[C:32]([CH3:31])([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH3:36])=[CH:7][CH:6]=3)[C:16]=12
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC(=O)C(C)(C)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
A solution containing cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1 g, 0.000246 mol), α,α-dimethylphenylacetic acid (0.045 g, 0.000271 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.071 g, 0.000369 mol) and 1-hydroxy-7-azabenzotriazole (0.0037 g, 0.000271 mol) in anhydrous N,N-Dimethylformamide (5 mL) was stirred for 5 min., N,N-diisopropylethylamine (0.098 g, 0.00076 mol) was added dropwise and stirring under an atmosphere of nitrogen was continued for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-2-methyl-2-phenylpropanamide diacetate (0.014 g, 0.000021 mol) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1>>[CH3:28][C:26]1[N:27]=[C:23]([NH:22][C:2]2[N:3]=[CH:4][C:5]([C:17]3[S:18][CH:19]=[CH:20][N:21]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[S:24][CH:25]=1
Reactant: Brc1nccs1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3nccs3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=340.0 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 2-bromothiazole and 2-amino-4-methylthiazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH3:14])[C:7]=12.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[ClH:1].[CH2:13]([N:8]1[C:7]2=[C:2]([NH:21][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=3)[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]1[CH3:12])[CH3:14]
Reactant: Cc1ccc(CN)cc1
Reactant: CCn1c(C)c(C)c2ccnc(Cl)c21
Product: CCn1c(C)c(C)c2ccnc(NCc3ccc(C)cc3)c21
Product: Cl
Yield: 39 %

Procedure:
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 39%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]=[N+]=[N-])=[N:6][C:5]=1[Cl:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[N:6][C:5]=1[Cl:14]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])nc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CN)nc1Cl
Temperature: 45 °C

Procedure:
To a solution of 6-azidomethyl-2-chloro-nicotinic acid methyl ester (4.75 g, 21 mmol) in THF (189 mL) and water (3.6 mL) was added triphenylphosphine (11 g, 42 mmol), the reaction mixture was heated at 45° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue azeotroped with methanol. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) to afford the title compound as a yellow solid. LCMS (method B): RT=2.65 min, [M+H]+=201.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCO
Reactant: COc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCOc1ccsc1
Yield: 74.2 %

Procedure:
25 cm3 of 3-methoxythiophene (0.25 mole), 50 cm3 of 1-nonanol (0.28 mol) and 30 cm3 of toluene were heated to 120° C. together with 1 g of p-toluenesulfonic acid, and about 9.5 cm3 of a methanol/toluene mixture were distilled off over a period of 3 hours. The workup was carried out as described in Example 1. Fractionation through a 30 cm Vigreux column at 0.26 mbar gave 42 g of 3-n-nonyloxythiophene of boiling point 102° to 105° C., which corresponds to 74% of the theoretical yield. 1H-NMR and mass spectrum confirm the structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4].[NH:24]1[CH2:31][CH2:30]C[C@H:25]1[C:26](O)=[O:27].N1CCOCC1>CS(C)=O.O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:24]3[CH2:25][CH2:26][O:27][CH2:30][CH2:31]3)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Solvent: CS(C)=O
Solvent: C1COCCN1
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
The mixture of 4,4-dimethyl-2-(3-bromo-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester as prepared according to Example 1 (374 mg, 1 mmol), CuI (60 mg, 0.3 mmol), L-proline (70 mg, 0.6 mmol) and morpholine (440 mg, 5 mmol) in DMSO (5 mL) was stirred at 120° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3) and washed with brine (100 mL) and then dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-60% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (200 mg, 52.6%) as a white solid. MS (ESI+) [(M+H)+] 381.1.
Reaction SMILES: [ClH:1].NC(=O)[C@@H:4]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])[C:5]1[CH:10]=CC=C[CH:6]=1.[CH3:34]C(C)(C)CN>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][CH2:4][C:5]([CH3:10])([CH3:34])[CH3:6])=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)CN
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Agent: Cl
Product: CC(C)(C)CNC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Yield: 31.6 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with 2,2-dimethylpropan-1-amine (Aldrich, 12 mg, 0.2 mmol) in a manner similar to that which is described in Step C of Example 1 to give N1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N3-neopentylmalonamide, hydrochloride salt (13 mg, 32% yield). 1H NMR (DMSO-d6) δ 13.34 (s, 1H), 10.69 (s, 1H), 8.08 (m, 1H), 7.96 (d, 1H, J=7.0 Hz), 7.87 (m, 3H), 7.44 (m, 2H), 6.70 (m, 1H), 6.13 (d, 1H, J=2.0 Hz), 3.34 (s, 2H), 2.91 (d, 2H, J=6.5 Hz), 0.84 (s, 9H); MS (ESI+) m/z 375.32 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[O:9][CH2:10][CH:11]2[CH2:13][O:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>C(O)(C)C>[CH:1]1([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[O:9][CH2:10][CH:11]([OH:12])[CH2:13][NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:29][CH2:28][NH:27][C:26]3=[O:30])=[CH:23][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCNC2=O)cc1
Reactant: c1ccc(C2CCCCC2)c(OCC2CO2)c1
Solvent: CC(C)O
Product: O=C1NCCN1c1ccc(NCC(O)COc2ccccc2C2CCCCC2)cc1

Procedure:
A solution of 3.24 g o-(cyclohexyl)-phenoxymethyloxirane (see Example 3) and 2.65 g of 1-(4-aminophenyl)-2-imidazolidinone in 60 ml isopropanol is stirred at reflux for 18 hours. The reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is dissolved in 50 ml ethyl acetate and acidified to pH=1 with a solution of hydrogen chloride gas in ethyl acetate. The supernatant is decanted from the dark gum that forms and the residue is treated with ethyl acetate and 5% aqueous sodium carbonate. The ethyl acetate solution is separated, washed with 10% aqueous sodium carbonate and twice with water. After drying over anhydrous sodium sulfate the solution is treated with charcoal, filtered and concentrated in vacuo leaving a dark viscous gum. The gum is chromatographed by passing through a column of silica gel using methylene chloride/methyl alcohol as eluent to yield 1-{4-[3-(o-cyclohexylphenoxy)-2-hydroxypropylamino]-phenyl}-2-imidazolidinone, which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20](S(C4C=CC(C)=CC=4)(=O)=O)[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[OH-].[K+].C(O)(=O)C>CO>[NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 62.2 %

Procedure:
222 mg (0.397 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 5 mL methanol and 200 μL of a 50% w/v potassium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 5.5 hours and then neutralized with acetic acid. The material was filtered through a 0.45 μm syringe filter and purified by mass-triggered reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid). The clean fractions were lyophilized to afford 100 mg (0.247 mmol, 62% yield) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as an off-white powder. 1H NMR (500 MHz, DMSO-d6) δ 11.79 (d, 1H), 8.41 (d, 1H), 8.02 (d, 1H), 7.65 (d, 1H), 7.56 (dd, 1H), 7.45 (dd, 1H), 7.22 (t, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.99 (t, 1H), 5.17 (s, 2H), 3.75 (s, 3H), 2.90 (s, br., 6H); MS: m/z 405.1 (M+H+).
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[NH:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>O>[NH2:1][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1nccn1N
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of hydroxylamine-o-sulfonic acid (26.64 g, 235.8 mmol, 3.0 eq) in H2O (17 mL) at 0° C., ethyl 1H-imidazole-2-carboxylate (C-3) (11.0 g, 78.6 mmol, 1.0 eq) is added and the resulting mixture is stirred at 90° C. for 30 min. The mixture is cooled to RT and K2CO3 (3.6 g, 26.2 mmol, 1.0 eq) is added in portions. The resulting mixture is stirred at RT overnight, filtered and rinsed with H2O (10 mL×3). The filtrate is extracted with ethyl acetate (50 mL×5). The combined organic layer is washed with brine, dried over Na2SO4 and filtered. The filtrate is evaporated in vacuo and the residue is purified by flash column chromatography on silica gel (1% MeOH-DCM) to afford the product, ethyl 1-amino-1H-imidazole-2-carboxylate (C-4) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br.C(Cl)Cl>C(O)(=O)C.C(O)=O>[Br:20][C:6]1[C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[N:8][O:9][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: COC(=O)Nc1cc(C(C)(C)C)on1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=CO
Product: COC(=O)Nc1noc(C(C)(C)C)c1Br
Temperature: 70 °C
Yield: 99.1 %

Procedure:
To a solution of methyl 5-t-butyl-3-isoxazolylcarbamate (2.00 g) and anhydrous sodium acetate (1.1 mol equivalent) in glacial acetic acid (5 ml), bromine (1.0 mol equivalent) is added. The resultant mixture is heated at 50° C for 53 hours and mixed with glacial acetic acid (5 ml), anhydrous sodium acetate (0.91 g) and bromine (0.81 g). The mixture is heated at 70° C for 31 hours, mixed with several drops of formic acid, poured onto ice water (50 ml) and shaken with methylene chloride. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate and water in order and evaporated under reduced pressure to remove the solvent, whereby methyl 4-bromo-5-t-butyl-3-isoxazolylcarbamate (2.77 g) is obtained as an oil. I.R.: 1774, 1203 cm-1 (CCl4).