Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[C:17]1(=[O:27])[N:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)[C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CCCCCCCBr)cc(C)n1
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1cc(CCCCCCCN2C(=O)c3ccccc3C2=O)cc(C)n1
Temperature: 125 °C

Procedure:
A mixture of compound (14) (3.54 g, 12.5 mmol), potassium phthalimide (2.54 g, 13.7 mmol) and dimethylformamide (25 ml) was heated at 125° C. for 6 h. DMF was evaporated and the residue coevaporated twice with n-butanol and twice with toluene. The dry crude product was purified by flash chromatography. Yield: 3.54 g (81%) viscous oil Rf=0.46 (System A) H1NMR (60 MHz, CDCl3): 7.60-7.95 (m, 4H), 6.76 (s, 2H), 3.68 (t, 2H, J=7 Hz), 2.48 (s, 6H), 2.36-2.60 (m, 2H), 1.23-1.77 (m, 10H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(CN([C@H]2CCCCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 3 %

Procedure:
The titled compound (6.4 mg) was prepared in 3% yield from cis-2-(4-chlorobenzenesulfonylamino)-cycloheptanecarboxylic acid amide (150 mg, 0.45 mmol) and 4-bromomethyl-benzonitrile according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.84 (m, 3 H), 7.69 (m, 4 H), 7.50 (d, 1 H, J=8.0 Hz), 7.31 (s br, 1 H), 6.65 (s br, 1 H), 4.60 (AB2,2 H,Δv=16,Jab=96 Hz), 3.93 (m, 1 H), 2.79 (m, 1 H), 2.24 (m, 1 H), 1.72 (m, 2 H), 1.31 (m, 7 H).
Reaction SMILES: B(Br)(Br)Br.[C:5]1([C:11]2[N:12]=[C:13]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35]C)[CH:30]=3)[O:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:5]1([C:11]2[N:12]=[C:13]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=3)[O:14][C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(CN2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(CN2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 3 h
Yield: 91.2 %

Procedure:
A 1.0M solution of boron tribromide in methylene chloride (2.08 ml) was added dropwise to a solution of 2-(4,5-diphenyl-2-oxazolyl)-1-(3-methoxybenzyl)piperidine (440 mg) in methylene chloride (2.5 ml) under ice cooling. The resulting mixture was stirred at the same temperature for 3 hours and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 2-(4,5-diphenyl-2-oxazolyl)-1-(3-hydroxybenzyl)piperidine (388 mg) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[Br:11]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:11])[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.3 %

Procedure:
5-Aminoindan (3.0 g, 22.5 mmol) was dissolved in 10 ml of anhydrous dimethylformamide. A solution of N-bromosuccinimide (4.0 g, 22.5 mmol) in 10 ml anhydrous dimethylformamide was added, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the separated organic layer washed twice with H2O, then with brine. Drying over Na2SO4 followed by filtration and evaporation of solvent gave a dark brown oil as the crude product. Purification by flash chromatography (50% EtOAc/hexane) provided 5-amino-6-bromoindan (3.26 g, 68% yield), a compound of Formula 2 where X is bromo, as a brown oil which crystallized into a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:25][CH2:24][C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: CC(C)(C)OC(=O)CCOCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
2-(4-Bromophenyl)ethanol (5 g) was treated with benzyltrimethylammonium hydroxide (Triton B®) (0.3 mL) and the resultant mixture was stirred in vacuo for 30 minutes. The mixture was then cooled to 0° C. and treated with t-butyl acrylate (3.5 g). The reaction was warmed to room temperature and stirred for 5 hours. The mixture was filtered through aluminium oxide (15 g) eluting with ether (75 mL). The collected filtrate was concentrated and purified by flash chromatography eluting with ethylacetate:iso-hexane (1:8) to give the sub-titled compound (5.42 g) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N:25]2[C:29]([NH2:30])=[CH:28][C:27]([CH3:31])=[N:26]2)=[CH:17][N:16]=1>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:30][C:29]2[N:25]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[N:16][CH:17]=3)[N:26]=[C:27]([CH3:31])[CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N)n(-c2cncc3ccccc23)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2cncc3ccccc23)n1
Temperature: 80 °C
Yield: 33.3 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.10 g, 0.43 mmol) and 1-(isoquinolin-4-yl)-3-methyl-1H-pyrazol-5-amine (0.080 g, 0.36 mmol) in pyridine (5 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 50-100% ethyl acetate in hexanes) to give the title compound as a white solid (0.18 g, 0.12 mmol, 27%). 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.02 (s, 1H), 8.87 (dd, J=1.6, 6.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.58 (s, 1H), 7.56 (s, 1H), 7.39-7.35 (m, 3H), 6.25 (s, 1H), 2.34 (s, 3H), 1.32 (s, 9H); MS: (ES) m/z calculated for C23H25N4O2S [M+H]+ 421.2. found 422.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:11]([CH3:12])=[N:10][N:9]2[CH:13]=[CH:14][CH:15]=[C:8]2[C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH3:2].[Cl:24]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:11]([CH3:12])=[N:10][N:9]2[C:13]([Cl:24])=[CH:14][CH:15]=[C:8]2[C:7]=1[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1c(C)nn2cccc2c1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of ethyl[4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (100 mg) in tetrahydrofuran (2 ml) was added N-chlorosuccinimide (43 mg) and the mixture was stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous ethyl acetate, water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (34 mg) as an yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@H:21]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:24])[CH3:22].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:24])[CH3:22])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccccc1
Reactant: C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1cc2ccccc2n1Cc1ccccc1)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Yield: 56.1 %

Procedure:
1-Benzylindole-2-carboxylic acid (477 mg, 1.9 mmol) and 3(S)-(alaninyl)amino-4-oxobutanoic acid, t-butyl ester semicarbazone (581 mg, 1.9 mmol) were dissolved in methylene chloride (8 mL) and both DMAP (232 mg, 1.9 mmol) and EDAC (498 mg, 2.6 mmol) were added to the solution under a nitrogen atmosphere at 0° C. The resultant solution was stirred for 1 hour at 0° C. and an additional 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated to give a yellow foam. Flash column chromatographic purification of the foam (silica gel, methanol/methylene chloride 2-5%) afforded the title product as a white powder (570 mg, 56%). TLC(methanol/methylene chloride:1/9, silica gel): Rf =0.38; 1H-NMR (CDCl3): δ 8.60 (bs, 1H), 7.67 (dd, J=8.0, 1.1, 1H), 7.50 (d, J=8.0, 1H), 7.33-7.01 (m, 8H), 6.79 (d, J=7.4, 1H), 5.78 (s, 2H), 4.87-4.83 (m, 1H), 4.67-4.62 (m, 1H), 2.73-2.43 (m, 2H), 1.46 (d, J=7.1, 3H), 1.39 (s, 9H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][CH:8]([CH3:9])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: CCC(=O)CC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(=O)C(C)Br
Reaction time: 0.67 h

Procedure:
Methyl 3-oxopentanoate (1 g, 7.68 mmol) was dissolved in chloroform (30 mL). Bromine (0.4 mL, 7.80 mmol) was added under ice-cooling and the mixture was stirred for 40 minutes. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
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][CH3:35])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:35][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: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 50 mg (0.125 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 2 ml of dry dichloromethane are added at RT 12 μl (0.150 mmol) of methyl chloroformate (Fluka, Buchs, Switzerland) and 21 μl (0.150 mmol) of triethylamine. After stirring for 2 h at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo to provide trans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamic acid methyl ester. Analytical HPLC: tR=7.08 min (Grad 2); ES-MS: m/eo=458.0.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1.[Cu][C:19]#[N:20]>CN1CCCC1=O>[C:19]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1)#[N:20]
Reactant: N#C[Cu]
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Yield: 99.7 %

Procedure:
A mixture of 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (51.7 g, 0.168 mol), copper (I) cyanide (31.8 g, 0.35 mol) and N-methyl-2-pyrrolidinone (620 ml) was heated at reflux for 4 h, cooled, then partitioned between dilute aqueous ammonia (1.5 L) and dichloromethane (5×300ml). The combined organic extracts were dried (Na2O4) and evaporated in vacuo to give the title compound (42.6 g, 100%) as an oil.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([C:12]12[O:19][CH2:18][C:15]([CH2:20][CH2:21][CH3:22])([CH2:16][O:17]1)[CH2:14][O:13]2)[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].CI>O1CCCC1>[CH2:6]([C:12]12[O:17][CH2:16][C:15]([CH2:20][CH2:21][CH3:22])([CH2:14][O:13]1)[CH2:18][O:19]2)[CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH3:1]
Reactant: C#CCCCCC12OCC(CCC)(CO1)CO2
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC#CCCCCC12OCC(CCC)(CO1)CO2
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.7 ml, 1.6M solution in hexane) was added dropwise to a stirred solution of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane (0.65 g) in dry tetrahydrofuran (25 ml) at 0°, under a current of nitrogen. The mixture was stirred at 0° for 15 minutes and then methyl iodide (0.18 ml) was added. The reaction mixture was stirred at 0° for 1 hour and then evaporated in vacuo. The residue was partitioned between diethyl ether and water. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on alumina, eluting with 1:10 dichloromethane: hexane, saturated with ammonia. 1-(Hept-5-ynyl)-4-n-propyl-2,6,7trioxabicyclo[2.2.2]octane was obtained as a colourless crystalline solid (0.23 g) {contained 15% of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:28]=2[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([N:17]([CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:28]=2[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])[CH3:42])([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCCN(C(=O)OC(C)(C)C)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCCN(C(=O)OC(C)(C)C)C1
Yield: 89.3 %

Procedure:
1-(tert-Butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid (Isomer 1) (400 mg, 0.71 mmol) was dissolved in 5% acetic acid in dichloromethane (25 ml) and 37% aqueous formaldehyde (5 ml) added. The mixture was stirred rapidly and sodium triacetoxyborohydride (151 mg, 0.71 mmol) added. Over a period of 5 hours a further 3 equivalents of sodium triacetoxyborohydride were added. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, the layers separated and the organic phased dried (MgSO4) and concentrated under reduced pressure. Column chromatography on silica, eluting with 10% ammonia in methanol/dichloromethane gave 1-(tert-butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-3-carboxylic acid (Isomer 1) (364 mg, 85%) as a white solid; 1H NMR Spectrum: (DMSO d6 100° C.) 1.27 (s, 9H); 1.47 (m, 1H); 1.86 (m, 1H); 2.01 (m, 2H); 2.30 (s, 3H); 3.30 (m, 1H); 3.44 (m, 1H); 3.63 (d, 1H); 3.74 (d, 1H); 3.81 (d, 1H); 3.88 (d, 1H); 3.96 (s, 3H); 7.19 (s, 1H); 7.25 (t, 1H); 7.40 (t, 1H); 7.65 (m, 1H); 8.22 (s, 1H); 8.41 (s, 1H); Mass Spectrum: (M+H)+ 574.5.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCCC)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:26][CH:25]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 74.5 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.242 g, 1.22 mmol) was reacted with 2-azidoethanamine (0.105 g, 1.22 mmol) and triethylamine (0.246 g, 2.43 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-butylbenzamide (0.224 g, 75% yield). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.4 Hz, 2H), δ 7.39 (t, J=1.8 Hz, 1H), δ 7.17 (d, J=8.1 Hz, 2H), δ 3.55 (q, J=8.7, 5.7 Hz, 2H), δ 3.45 (t, J=5.7 Hz, 2H), δ 2.60 (t, J=7.8 Hz, 2H), δ 1.56 (m, 2H), δ 1.30 (m, 2H), δ 0.90 (t, J=4.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 147.2, 131.7, 128.8, 127.4, 50.9, 39.7, 35.7, 33.5, 22.5, 14.1 ppm; HRMS (ESI) calcd for C13H18N4O (M+) 246.1481. found 246.1476.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[BH4-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2C(O)c2cccc(F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccccc2Cc2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
The product of the Example 25b (140 mg, 0.393 mmol) was dissolved in anhydrous dichloromethane (10 mL) and under nitrogen atmosphere was added trifluoroacetic acid (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes and to the resulting dark orange solution was then added, in small portions sodium borohydride (290 mg, 7.86 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 5 minutes. The solvent and trifluoroacetic acid were evaporated under reduced pressure and the residue was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give the crude which upon trituration with hexane yielded the title compound as a white solid, (110 mg, 83%), mp 97-98° C. 1H NMR (CDCl3) δ7.97 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.45-7.15 (m, 5H), 6.98 (dt, J=8.4 and 2.2 Hz, 1H), 6.75 (d, J=7.6 Hz, 1 H), 6.63 (d, J=10 Hz, 1H); 13C NMR (CDCl3) δ164.4, 161.2, 147.2, 143.3 (d, J=7 Hz), 140.3, 139.2, 137.2, 130.7, 130.1 (2×C), 129.9, 129.7 (d, J=2.5 Hz), 128.6, 127.1 (2×C), 126.9, 124.3 (d, J=2.5 Hz), 115.4 (d, J=21 Hz), 112.9 (d, J=21 Hz), 44.5, 38.9; LRMS (APIMS) m/z 358 (M+NH4)+.
Reaction SMILES: [CH3:1][CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[NH2:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=1>C(O)(=O)C>[CH3:15][C:13]1[CH:14]=[C:10]2[N:9]=[C:3]([CH3:4])[C:2]([CH3:1])=[C:6]([CH3:7])[N:11]2[N:12]=1
Reactant: CC(=O)C(C)C(C)=O
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc2nc(C)c(C)c(C)n2n1
Yield: 86.6 %

Procedure:
12.6 g of 3-methyl-2,4-pentanedione, 30 cc of acetic acid and 9.6 g of 3-amino-5-methylpyrazole were introduced into a 100 ml three-necked round-bottomed flask fitted with a magnetic stirrer, a condenser and a thermometer. The medium was refluxed for 1 hour. The acetic acid was evaporated off and the product was taken up in 50 cc of petroleum ether. The solid was filtered off and washed with petroleum ether. Drying under vacuum and over phosphoric anhydride yielded 15 g of 2,5,6,7-tetramethylpyrazolo[1,5-a]pyrimidine (yield=85.7%).
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][SH:6].[CH2:7]1[O:16][C:10]([CH2:12][CH2:13][CH2:14]Cl)([CH3:11])[O:9][CH2:8]1>C1(C)C=CC=CC=1.CO>[CH2:7]1[O:16][C:10]([CH2:12][CH2:13][CH2:14][S:6][CH3:5])([CH3:11])[O:9][CH2:8]1
Reactant: CC1(CCCCl)OCCO1
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CSCCCC1(C)OCCO1
Yield: 100.7 %

Procedure:
To a solution of sodium methoxide prepared by slowly adding 2.4 g (54 mmol) of sodium to 40 mL of methanol was added 4.8 g (48 mmol) of methylmercaptan followed by 6.6 g (40 mmol) of 5-chloro-2-pentanone ethylene ketal. The mixture was refluxed for 4 h and an additional 50 mmol each of sodium and methylmercaptan was added and then refluxed an additional 4 hours to complete the reaction. 50 mL of toluene was added and the mixture washed twice with 10 mL of 1N sodium hydroxide. The toluene layer was dried over magnesium sulfate and evaporated to give 7.1 g of 5-methylthio-2-pentanone ethylene ketal. This was stirred in 60 mL of 70% trifluoroacetic acid for 24 h at room temperature. The mixture was neutralized with sodium carbonate and extracted with 200 mL of ether. The ether extract was dried and evaporated to yield 3.5 g of the desired ketone as an oil.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][N:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]([NH:12][C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])=[O:14])=[S:11].C(N(CC)CC)C>ClCCl>[C:25]1([N:9]2[CH2:8][CH2:7][S:11][C:10]2=[N:12][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])=[O:14])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NC(=S)N(CCO)c1ccccc1)c1cnccc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N=C1SCCN1c1ccccc1)c1cnccc1C(F)(F)F
Temperature: 20 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
Methanesulfonyl chloride (0.14 ml) was added to an ice-cooled solution of 1-(2-hydroxyethyl)-1-phenyl-3-(4-trifluoromethyl-3-pyridylcarbonyl)thiourea (0.60 g) and triethylamine (0.42 ml) in dichloromethane, and stirred for 3 hours at 20° C. The mixture was washed (water), dried (magnesium sulfate), evaporated and the residue recrystallized (ethanol) to give 3-phenyl-2-(4-trifluoromethyl-3-pyridylcarbonyl)iminothiazolidine (0.26 g, Compound D-60).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[NH:8][N:9]=[N:10][C:11]=1[C:12](=[O:29])[NH:13][C:14]1[CH:19]=[CH:18][N:17]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=[C:16]2[N:15]=1)=[O:6].Cl>CO.C1COCC1>[C:23]1([C:21]2[N:22]=[C:16]3[N:15]=[C:14]([NH:13][C:12]([C:11]4[N:10]=[N:9][NH:8][C:7]=4[C:5]([OH:6])=[O:4])=[O:29])[CH:19]=[CH:18][N:17]3[CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1[nH]nnc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccn2cc(-c3ccccc3)nc2n1)c1nn[nH]c1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
NaOH (3N, 1.47 ml) was added to a solution of 5-(2-phenyl-imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-3H-[1,2,3]triazole-4-carboxylic acid methyl ester (example 26, 800 mg, 2.2 mmol) in methanol/THF=1:1 (16 ml), and the mixture was stirred for 6 h at RT. The mixture was acidified (pH=3) with HCl (2N), the suspension was stirred for 15 min, and filtered. The precipitated title compound (590 mg, 77%) was dried under vacuum, and used in the next step without further purification.