Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25](=[O:59])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]3[N:36]=[CH:37][N:38](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:39]=3)=[CH:30][N:29]=2)[CH:27]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25](=[O:59])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]3[N:36]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:4]=4)[CH:37]=[N:38][CH:39]=3)=[CH:30][N:29]=2)[CH:27]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)cc1OCCCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-(3-phenyl-propoxy)-benzonitrile from step 3 (35 mg, 0.13 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (70 mg, 0.13 mmol) in CH2Cl2 (650 μl) was added DIEA (50 μl, 0.27 mmol) followed immediately by the addition of Tf2O (33 μl, 0.19 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (650 μl) and heated to 60° C. for 14 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2) to yield the final product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].S(Cl)([Cl:20])(=O)=O.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([Cl:20])[C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(Cl)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-oxo-5-phenyl-pentanoic acid ethyl ester (1.6 g, 7.76 mmol) in methylene chloride (18 mL) is added sulfuryl chloride (1.15 g, 8.53 mmol) dropwise. After stirred at room temperature for 6 hours, the reaction mixture is poured into water, extracted with methylene chloride, is washed water and brine, dried over sodium sulfate. Concentration gave the crude title compound, which is used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[NH4+:20]>>[CH2:15]([N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:20])[C:11]=2[N:12]=[CH:13]1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
A mixture of 4.0 g (0.0154 mole) of 4-chloro-1-isobutyl-1H-imidazo [4,5-c]quinoline (from Example 77) and 25 cc of concentrated ammonium hydroxide was placed in a metal bomb and heated at 150° C. for about 16 hours. After cooling the solid was separated by filtration, washed with water and recrystallized from ethanol to provide white crystals of 1-isobutyl-1H-imidazo [4,5-c]quinolin-4-amine, m.p. 288°-291° C. Recrystallization from N,N-dimethylformamide is preferred. Analysis: Calculated for C14H16N4 : % C, 70.0; H, 6.7; % H, 23.3; Found: % C, 69.3; % H, 6.6; % N, 23.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 72.4 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-n-propyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[Na+].CN([CH:21]=[O:22])C>O>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:21]=[O:22])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cc(Cl)ccc12
Temperature: 37 °C
Reaction time: 0.75 h
Yield: 88 %

Procedure:
This Vilsmeyer reaction was performed according to H. G. O. Becker, Organikum, pp. 364-365, Johann Ambrosius Barth Verlag, Heidelberg-Leipzig (1996). To 5 mL DMF in a three-necked flask equipped with a thermometer, 1.8 mL POCl3 was added dropwise in a temperature range between 15° C. and 20° C. Then, a solution of 1 g (6.6 mMol) of 6-chloro-1H-indole in 2 mL DMF was added dropwise in a temperature range between 20° C. and 30° C. The reaction mixture was stirred for 45 minutes at 37° C. Afterwards, the reaction mixture was poured in a mixture of 15 g ice in 10 mL water under stirring. 3.4 g NaOH in 18 mL were added between in a temperature range between 20 and 30° C. The resulting mixture was then refluxed for 5 minutes. After cooling to room temperature, the precipitate was filtered off and washed with 10 mL cold water. Crystallization from ethanol yielded 6-chloro-1H-indole-3-carbaldehyde as a white solid (1.04 g, 88%).
Reaction SMILES: [CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[NH:9][C:10]=31)[CH2:4][CH2:3]2.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:13])([F:14])[F:15])[N:9]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]=31)[CH2:4][CH2:3]2
Reactant: BrCCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(CC(F)(F)F)n1CCc1ccccc1
Temperature: 100 °C
Yield: 11.5 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 47; 150 mg, 0.55 mmol), tetrabutylammonium iodide (220 mg, 0.60 mmol) and (2-bromoethyl)benzene (660 μL, 4.8 mmol) in dimethylformamide (2 mL) was heated in a pressure tube in an oil-bath at 100° C. for 24 h. Dichloromethane (75 mL) was added and the solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with methanol, and dried under high vacuum at 90° C. for 3 h to give (4S,7R)-7,8,8-trimethyl-1-phenethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (24 mg, 12%) as a yellow gum. ES(+)-MS (M+H) 379.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[NH:12][N:11]=1.[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35]([NH:16][CH2:15][C:13]4[NH:12][N:11]=[C:10]([CH3:9])[CH:14]=4)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1
Reactant: Cc1cc(CN)[nH]n1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3C[C@@H](C)N(Cc4ccc(F)cc4)C3=O)nc2C)[nH]n1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (3-methyl-1H-pyrazol-5-yl)-methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid the title compound was obtained as a white solid: mp 215-216° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.31 (br, 1H), 7.40-7.35 (m, 2H), 7.22-7.16 (m, 2H), 5.89 (s, 1H), 4.59 (d, J=15.5 Hz, 1H), 4.33-4.16 (m, 4H), 3.78-3.71 (m, 1H), 3.55 (dd, J=10.1, 6.8 Hz, 1H), 2.46 (s, 3H), 2.17 (s, 3H), 1.22 (d, J=6.1 Hz, 3H); MS (ES+) m/z 442.9 (M+1).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:13])([F:12])[C:5]1[N:6]=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:10]1[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=1[C:4]([F:3])([F:12])[F:13]
Reactant: O=c1cc(C(F)(F)F)nc[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cnc(C(F)(F)F)c1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Bromine (4.62 g) was added in one portion to a stirred solution of 4-trifluoromethylpyrimidin-6-one (4.3 g) and sodium acetate (10.53 g) in acetic acid (43 ml). After stirring for 2 hours, the reaction mixture was left to stand for a period of 3 days, after which time it was heated to 80° C. for 1 hour. After cooling to the ambient temperature (ca 22° C.), the solvent was evaporated under reduced pressure. The resultant orange solid was dissolved in ethyl acetate, and washed several times with water. The combined agueous washings were extracted with ethylacetate, and the combined organic layers were washed with agueous sodium thiosulphate solution, followed by agueous sodium bicarbonate solution and brine. After drying over magnesium sulphate, evaporation of the solvent under reduced pressure gave 5-bromo-4-trifluoromethylpyrimidin-6-one as a white solid (4.8 g, mpt 226°-227° C.);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 10.2 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (500 mg, 1.60 mmol) was reacted with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (516 mg, 2.41 mmol) to afford the desired product (80 mg, >99%) as an orange foam: ESI MS m/z 489 [C24H30BrN3O3+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]>CS(C)=O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[CH3:1])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(CCl)ccc1Cl
Reactant: Cc1nc2ccccc2[nH]1
Solvent: CS(C)=O
Product: Cc1nc2ccccc2n1Cc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
Prepared analogously to Example 9a from 2-methyl-benzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethylsulphoxide.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([OH:16])=O>C1C=CC=CC=1>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([Cl:3])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2o1
Solvent: c1ccccc1
Product: O=C(Cl)c1cc2ccccc2o1
Temperature: 25 °C

Procedure:
Thionyl chloride (12.5 ml) was added to a suspension of benzofuran-2-carboxylic acid (20 g) in anhydrous benzene (250 ml). The mixture was refluxed for 3 hours, then allowed to cool down to room temperature. Removal of the volatiles left the desired acid chloride (21.8 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH:17]([C:18]([OH:20])=[O:19])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=3)=[CH:26][CH:27]=1)[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Br)ccc2nc1Cl
Reactant: NC(Cc1ccc(Oc2ccc(Br)cn2)cc1)C(=O)O
Product: O=C(O)c1cc2cc(Br)ccc2nc1NC(Cc1ccc(Oc2ccc(Br)cn2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 6-bromo-2-chloroquinoline-3-carboxylic acid is reacted with 2-amino-3-[4-(5-bromo-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[F:20][C:21]1[CH:22]=[C:23]([N:35]2[CH2:39][C@H:38]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])[O:37][C:36]2=[O:45])[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30]1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[C:42]([NH:41][CH2:40][C@@H:38]1[O:37][C:36](=[O:45])[N:35]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3([OH:34])[CH2:33][CH2:32][N:31]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]5[CH:12]5[CH2:14][CH2:13]5)=[CH:4][C:3]=4[F:19])[CH2:30]3)=[C:21]([F:20])[CH:22]=2)[CH2:39]1)(=[O:44])[CH3:43]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1, step 7 with 39 mg 7-chloro-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.24 mmol), 99 mg N-{(5S)-3-[3-fluoro-4-(3-hydroxy-pyrrolidin-3-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide. (MW: 367.38, 0.24 mmol) 101 mg triethylamine (MW: 101.19, 1.0 mmol) and 80 mg trimethylchlorsilan (MW: 108.64, 0.75 mmol) in 2 ml N-methyl-pyrrolidin-2-one. Yield: 70 mg, 46%. MS: 614.7 (M+H)+, 612.7 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:8]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:9]([CH3:14])[CH2:10][N:11]=[N+]=[N-])(=O)=O.N#N.CCN(C(C)C)C(C)C>CO.[Pd]>[Si:16]([O:15][C@@H:8]1[C@@H:9]([CH3:14])[CH2:10][NH:11][CH2:6][C@H:7]1[NH:23][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:17])[CH3:18]
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of (2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentyl methanesulfonate (0.59 g, 1.3 mmol) in MeOH (10 mL) was deoxygenated with N2 for 20 min. DIPEA (0.55 mL, 3.2 mmol) was added, followed by 10 wt % Pd on carbon (0.1 g, 0.1 mmol). The mixture was hydrogenated at 1 atm. for 2 h, and then filtered. The filtrate was concentrated to afford the sub-title compound (0.43 g, 98%). LCMS calc. for C17H37N2O3Si (M+H)+: m/z=345.3. found 345.2. 1H NMR (500 MHz, CDCl3) δ 4.35 (bs, 1H), 3.32 (dt, J=13.1, 6.3 Hz, 1H), 3.25 (d, J=12.3 Hz, 1H), 3.04 (t, J=8.8 Hz, 1H), 2.94 (ddd, J=13.1, 4.1, 1.5 Hz, 1H), 2.33 (dd, J=12.6, 10.5 Hz, 1H), 2.24 (dd, J=13.1, 10.9 Hz, 1H), 1.76 (bs, 1H), 1.55 (tdd, J=8.9, 6.7, 4.2 Hz, 1H), 1.41 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (s, 9H), 0.07 (d, J=10.3 Hz, 6H) ppm.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH3:15].[OH-].[Na+].O>O1CCOCC1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:13][CH2:14][CH3:15])=[C:4]([CH:9]=1)[C:3]([OH:16])=[O:2])(=[O:12])[CH3:11]
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(C(C)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
A mixture of 5-acetyl-2-ethoxybenzoic acid methyl ester (9.6 g, 0.043 mol), 5M aqueous sodium hydroxide solution (44 ml, 0.217 mol), water (80 ml) and 1,4-dioxan (80 ml) was stirred at room temperature for 18 hours. The solvent was removed by evaporation under vacuum, the residue dissolved in water (100 ml) and the resulting solution acidified to pH 1with concentrated hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (4×100 ml) and the combined extracts dried (Na2SO4) and evaporated under vacuum. The resulting solid was crystallised form ethyl acetate to give the title compound as a colourless solid (5.4 g, 60%), m.p. 122°-125° C. Found: C,63.20; H,5.81. C11H12O4 requires C,63.45; H,5.81%.
Reaction SMILES: C(OC(N[C@:7]([CH2:35]CC)([C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C@H:18]1[C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])=O)CC1C=CC=CC=1)=O)C.[ClH:38].[CH2:39]([O:41][C:42]([NH:44][C@:45](CCC)([C:53](N1CCC[C@H]1C(OCC1C=CC=CC=1)=O)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])[CH3:40]>>[ClH:38].[CH2:39]([O:41][C:42]([NH:44][C@H:45]([C:53]([C@@:18]1([C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])[CH2:32][CH2:33][CH2:34][N:17]1[CH2:15][CH2:7][CH3:35])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])[CH3:40]
Reactant: CCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)N[C@H](C=O)CCCNC(=N)N
Agent: Cl
Product: CCCN1CCC[C@]1(C(=O)N[C@H](C=O)CCCNC(=N)N)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC

Procedure:
By methods substantially equivalent to those described in Example 37, 0.34 g of EtOCO-Phe(αn-Pr)-Pro-Arg-H.HCl was prepared from EtOCO-Phe(αn-Pr)-Pro-OBzl (TLC Rf =0.67, 50% ethyl acetate:hexanes). EtOCO-Phe(αn-Pr)-Pro-Arg-H.HCl was purified by RPHPLC (98/2 (A/B), 60 min; to 80/20 (A/B), 300 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cn1
Yield: 18.3 %

Procedure:
Following general procedure D, (6-bromo-4-(6-(2-(dimethylamino)ethoxy)pyridin-3-ylamino)quinolin-3-yl)(cyclopropyl)methanone (100 mg, 0.22 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (90 mg, 0.33 mmol) to afford the desired product (21 mg, 18%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.25 (s, 1H), 8.08 (d, J=2.7 Hz, 1H), 7.94 (m, 2H), 7.82 (s, 1H), 7.56 (dd, J=8.8, 2.7 Hz, 1H), 7.06-6.96 (m, 2H), 6.92 (d, J=8.8 Hz, 1H), 4.53 (t, J=5.5 Hz, 2H), 3.00 (t, J=5.5 Hz, 2H), 2.95-2.86 (m, 1H), 2.51 (s, 6H), 1.23-1.14 (m, 2H), 1.17-1.07 (m, 2H); ESI MS m/z 521 [C28H26ClFN4O3+H]+; HPLC>99% (AUC), tR=11.15 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[CH:9].[F:10][C:11]([F:32])([F:31])[C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:15][N:16]1[C:20]([Cl:21])=[C:19]([CH:22]=[O:23])[N:18]=[N:17]1.O.Cl>C1COCC1.C[Mg]Br>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:14]([CH:13]=[C:12]([C:11]([F:10])([F:32])[F:31])[CH:26]=1)[CH2:15][N:16]1[C:20]([Cl:21])=[C:19]([CH:22]([OH:23])[C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:18]=[N:17]1
Reactant: O=Cc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Reactant: C#Cc1ccccc1Cl
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OC(C#Cc1ccccc1Cl)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Reaction time: 0.67 h

Procedure:
Dissolve 1-chloro-2-ethynyl-benzene (22.1 g, 162 mmol) in THF (300 mL) and slowly add methyl magnesium bromide (50 mL, 3.0 M in ether). Stir solution at RT for 40 min, then add a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbaldehyde (29.6 g, 82.8 mmol) in THF (160 ml). Stir resulting solution at RT for 2 h then pour into cold water (500 mL) and 1N HCl (150 mL) and extract with EtOAc (3×200 mL). Combine the organic phases and wash with saturated NaHCO3 (200 mL) and brine (200 mL) then dry, filter, and concentrate. Purify the crude material by triturating with 30% ether/hexanes to give the title compound. MS (IS) 494.0 (M+1), MS (ES−) 492.0 (M−1); 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.79 (s, 2H), 7.47 (dd, 1H, J=1.9, 7.3), 7.37 (dd, 1H, J=1.4, 7.9), 7.25 (dt, 1H, J=2.0, 7.3), 7.19 (dt, 1H, J=1.5, 7.3), 5.92 (d, 1H, J=6.7), 5.62 (s, 2H), 2.79 (d, 1H, J=6.4).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CN(C=O)C.CC#N>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(-c2ccncc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: C1=C(c2ccccn2)CCN(Cc2ccccc2)C1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A Solution of 2 g (12.8 mmol) of 4-(2-pyridyl)pyridine (Aldrich) and 2.18 g (12.8 mmol) of benzylbromide in 15 mL of DMF and 15 mL of CH3CN was stirred at 95° C. for 4 h. The reaction mixture was then concentrated and redissolved in 20 mL of methanol. To the reaction mixture at 0° C. was added 0.95 g, (25.6 mmol) of NaBH4 and the reaction mixture was stirred for 1 h. The reaction was quenched with 6N HCl, and was partitioned between CH2Cl2 and 1N NaOH. The aqueous layer was extracted 3 times with CH2Cl2, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified chomatography [silica, CH2Cl2:ethyl acetate:(2M NH3 in MeOH), 100:100:2] to give 3.2 g of the title compound.