Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:22][C:23]#[N:24].[C:25](=O)([O:29]CC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C(O)C>[C:23]([CH:22]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:8]=1[O:7][CH3:6])[C:25]([O:26][CH2:27][CH3:28])=[O:29])#[N:24]
Reactant: CCOC(=O)OCC
Reactant: COc1c(CC#N)cccc1Oc1ccccc1F
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2F)c1OC
Yield: 109.4 %

Procedure:
A mixture of sodium ethoxide prepared from sodium metal (470 mg) and ethanol (20 ml), 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetonitrile (5 g) and diethyl carbonate (9.2 g) in toluene (50 ml) was treated in a similar manner to that of Example 10-(4) to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetate (7 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:42])([F:41])[C:25]1[C:29]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:28]=2[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:42][C:24]([F:23])([F:41])[C:25]1[C:29]2[CH2:30][NH:31][CH2:32][CH2:33][C:28]=2[N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:26]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(F)(F)F)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3nc(C(F)(F)F)c4c3CCNC4)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (23 mg, 0.086 mmol) was dissolved in DCM (5 mL) and thionyl chloride (51 mg, 0.43 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) to this was added tert-butyl 3-(trifluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (25 mg, 0.086 mmol) followed by potassium carbonate (24 mg, 0.172 mmol). The reaction mixture was heated to 65° C. for 3 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was treated with 1:1 TFA/DCM (2 mL) for 2 h before being concentrated to dryness. Purification by preparative basic HPLC gave (R)—N-(5-((3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.3 mg, 5.2 μmol, 6.1%). MS (ESI): m/z [M+H]+ 443.2
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](O)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,4-Dichloro-benzoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-nitrobenzyl alcohol (6 g, 39 mmoles) is put into solution in dichloromethane (100 ml) and carbon tetrabromide (14.9 g, 45 mmoles) is added. Triphenylphosphine (11.8 g, 45 mmoles) is added in portions to the medium at 0° C. Then the mixture is agitated for 2 hours at ambient temperature. The solvent is evaporated off and the product obtained is purified on silica gel in an ethyl acetate/heptane mixture (1/2). It is obtained in the form of white needle-shaped crystals (7.2 g; 85%). Melting point: 97-98° C.
Reaction SMILES: C1C2C(=CC3C(C=2C[O:16][C:17]2[C:18]4[O:37][N:36]=[C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:19]=4[C:20]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:21][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=CC=CC=3)C=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:28]([C:20]1[C:19]2[C:35]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:36][O:37][C:18]=2[C:17]([OH:16])=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1nc(Cc2ccccc2)c2c(-c3ccccc3)noc2c1OCc1c2ccccc2cc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc(Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.8 %

Procedure:
Ethyl 7-(anthracen-9-ylmethoxy)-4-benzyl-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (110 mg, 0.23 mmol) was dissolved in 2 mL of CH2Cl2 and cooled in an ice bath. Trifluoroacetic acid (0.18 mL, 2.30 mmol) was added and the mixture was stirred at 0° C. for 20 min. Solvent and excess TFA were evaporated off, and the residue was partitioned between 20 mL of EtOAc and 20 mL of saturated sodium bicarbonate solution. The pH of the mixture was adjusted to 3 by addition of 4M hydrochloric acid. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. Purification of the residue by flash chromatography (0-40% EtOAc/hexanes) gave 36 mg of the title compound. MS: (+) m/z 375.37 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13](B(O)O)[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>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>[C:30]1([CH:36]2[CH:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7]3[CH:8]=[CH:9][C:10]([C:11]4[CH:12]=[CH:13][C:14]5[C:6]6=[C:7]7[C:19](=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:18][C:17]7=[CH:16][CH:15]=5)[CH:17]=[CH:18][C:5]=46)=[CH:20][C:19]=3[C:19]3[C:7]2=[CH:8][CH:9]=[C:10]([C:11]2[CH:12]=[CH:11][C:10]4[C:20]5=[C:16]6[C:15](=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:18][C:17]6=[CH:8][CH:9]=4)[CH:14]=[CH:13][C:12]=25)[CH:20]=3)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1cc2ccc3ccc(B(O)O)c4ccc(c1)c2c34
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1cc2ccc3ccc(-c4ccc5c(c4)-c4cc(-c6ccc7ccc8cc(C(C)(C)C)cc9ccc6c7c89)ccc4C(c4ccccc4)C5c4ccccc4)c4ccc(c1)c2c34
Temperature: 60 °C
Yield: 75 %

Procedure:
As illustrated in Formula 7, the product 4a in Formula 6 (1.2 g, 2.46 mmol), 7-tert-butylpyren-1-ylboronic acid (2.23 g, 7.38 mmol), potassium carbonate solution (2.0 M, 10 mL), and dried toluene (30 mL) were charged in a two-necked bottle. The bottle was deoxygenated and purged with nitrogen, and the mixture in the bottle was stirred at 60° C. until it was totally dissolved. The nitrogen pressure of the bottle was increased, and Pd(PPh3)4 (289 mg, 0.25 mmol) was rapidly added into the bottle. The reaction was heated to 110° C., and stirred for 48 hours. The resulting was cooled to room temperature to precipitate a solid, and the solid was collected by filtering. The solid was sublimated at a temperature of 330° C. to obtain a white solid of 1.56 g (yield=75%).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([OH:38])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:41]([O:48][C:49](=[O:53])[C@H:50]([CH3:52])O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][C@@H:50]([C:49]([O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:53])[CH3:52])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester and 647 mg benzyl-L-lactate in 25 ml THF were added 1.4 g triphenylphosphine and 938 mg diethylazodicarboxylate. After stirring for 16 h at RT LCMS indicated complete conversion and water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.7 g.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH2:35])O1.C(=O)([O-])O.[Na+]>COCCOC.O.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>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)[nH]c2c1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (6.50 g, 19.3 mmol) obtained in the same manner as in the method described in WO03/010140 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (5.08 g, 23.2 mmol) in 1,2-dimethoxyethane (90 ml) and water (45 ml) were added sodium hydrogen carbonate (4.81 g, 57.9 mmol) and tetrakis(triphenylphosphine)palladium (1.12 mg, 0.965 mmol), and the mixture was heated under reflux for 9 hr. The mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1-3:1) to give methyl 2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.48 g, yield 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:30][CH2:31][C:32]([C:34]2[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=2)=[O:33])CCN2CCC3(C4C(=CC=CC=4)N(S(C)(=O)=O)C3)CC2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:42][C:43]1C=C([Mg]Br)C=C(C)[CH:48]=1.BrC1C=C(C)C=C(C)C=1.[Mg]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:48][CH:43]=[CH2:42])[CH2:30][CH2:31][C:32]([C:34]2[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(C)cc(C(=O)CC[C@@H](CCN2CCC3(CC2)CN(S(C)(=O)=O)c2ccccc23)c2ccc(Cl)c(Cl)c2)c1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Agent: Cc1cc(C)cc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC[C@H](CCC(=O)c1cc(C)cc(C)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
1.42 g (4.50 mmol) of (N-Methoxy-N-methyl)-(4-(S)-(3,4-dichlorophenyl)-6-heptenyl)-amide (prepared in Example 134) was dissolved in 20 mL of dry THF. To it added 10 mL THF solution of 3,5-dimethylphenylmagnesium bromide prepared from 1.8 g (9.6 mmol) of 5-bromo-m-xylene and 463 mg of magnesium turnings. After stirring for 2 hr at rt, the reaction was quenched with saturated aqueous ammonium chloride solution. THF was removed under reduced pressure. The residual material was diluted with ethyl acetate. The organic phase was separated, aqueous phase was extracted twice with ethyl acetate. Combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated, chromatographed on silica gel eluting with a gradient of hexane ethyl acetate=10:1 to 5:1 to give 1.57 g of 4-(S)-(3,4-dichlorophenyl)-1-(3,5-dimethylphenyl)-hept-6-ene-1-one (97%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)CC)(C)C.[NH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[C:38]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:30][C:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:8])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
A mixture of 11.7 g of 4-imidazolecarboxylic acid, 18.7 g of 1,1'-carbonyldiimidazole, 20 ml of diisopropylethylamine and 600 ml of DMF was heated at 35° C. for approximately 18 hours. Twenty milliters of aminodiphenylmethane were added and the solution stirred at 35° C. for approximately 21/2 days. The mixture was concentrated in vacuo and the residue added to 400 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Two crystallizations from hot ethyl acetate/hexane provided 11 grams of the desired titled intermediate, m.p. 201°-202° C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[CH3:24][O:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([CH:34]=O)=[CH:28][N:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:34][C:29]2[C:30]([O:32][CH3:33])=[N:31][C:26]([O:25][CH3:24])=[N:27][CH:28]=2)[CH2:12]1)=[O:9])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: COc1ncc(C=O)c(OC)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ncc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)c(OC)n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
(R)-3-[[N-(2-Amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (17.2 mg, 0.04 mmol) was dissolved in THF (1 mL), and 2,4-dimethoxy-5-pyrimidinecarboxaldehyde (6.7 mg, 0.04 mmol) was added to the resulting solution. Sodium triacetoxyborohydride (12.7 mg, 0.06 mmol) and glacial acetic acid (2.4 mg, 0.04 mmol) were subsequently added to the mixture. The resulting mixture was stirred at 50° C. for 24 hours and then concentrated. The residue was dissolved in dichloromethane (1 mL) and washed with a 1 M aqueous solution (1 mL) of NaOH. The organic layer was collected and concentrated, and a dichloromethane solution of 25% trifluoroacetic acid (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The obtained residue was purified by HPLC to thereby provide (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(2,4-dimethoxypyrimidin-5-ylmethyl)pyrrolidine (Compd. No. 2175) (18.6 mg, 78%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 483 (M++H, C21H25F3N6O4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH2:31]Br)[CH:25]=1>C(#N)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH:25]=1)[CH2:31][N:11]1[C:10](=[O:13])[N:9]([CH:14]2[CH2:16][CH2:15]2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:12]1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: Fc1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2cc(Br)ccc2F)nc(-c2ccc(Cl)cc2)n1C1CC1

Procedure:
300 mg (1.27 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A] and 622 mg (1.91 mmol) of cesium carbonate were suspended in 5 ml of acetonitrile, and 536 mg (1.40 mmol) of 4-bromo-2-(bromomethyl)-1-fluorobenzene were added. The mixture was stirred under reflux for 18 h. The precipitated solid was then filtered off and the filtrate was concentrated under reduced pressure to a volume of about 1.5 ml. After addition of 0.5 ml of 1 N hydrochloric acid, the mixture was directly purified chromatographically [Method 19]. This gave 427 mg (56% of theory) of the target compound in a purity of 71%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]1)=[N:7][C:6]=2[NH2:16].[C:17](Cl)(=O)[CH3:18].C(=O)(O)[O-].[Na+]>O.C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH:17]=[CH:18][N:16]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH:15]=1
Reactant: Nc1nc2ccccc2c2cc(F)ccc12
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Fc1ccc2c(c1)c1ccccc1n1ccnc21
Temperature: 25 °C
Yield: 52 %

Procedure:
9-Fluoro-6-Phenanthridinamine (0.8 g, 3.7 mmol), and a 50% solution of acetyl chloride (0.4 g, 5.66 mmol) in water containing sodium bicarbonate (0.6 g, 7.54 mmol) was dissolved in isopropyl alcohol (25 mL). The reaction mixture was refluxed for 17 hours under a nitrogen pad. The reaction mixture was cooled to room temperature and the precipitate vacuum filtered and washed with methylene chloride. The crude product was purified by column chromatography using a 1:1 ratio of ethyl acetate and hexanes as the eluants followed by distillation to give 10-fluoro-imidazo[1,2-f]phenanthridine) (0.46 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:18]2[C:22]([Br:23])=[CH:21][N:20]([CH3:24])[N:19]=2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:23][C:22]1[C:18]([C:14]2[CH:13]=[C:12]([NH:11][C:6]([C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:7])[CH:17]=[CH:16][CH:15]=2)=[N:19][N:20]([CH3:24])[CH:21]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3ccc(Cl)cc3)c2)n1
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To 4-chlorobenzoyl chloride (15 mg, 0.08 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)4-bromo-1-methylpyrazole (21 mg, 0.08 mmol) and triethylamine (12 μL, 0.08 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (23 mg, 72%), m.p. 184.4-184.8° C. (EtOAc/hexane).
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][C:21]([NH2:24])=[C:20]4[O:25][C:26](Cl)=[CH:27][C:19]=34)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:39]2[CH:47]=[C:46]3[C:42]([CH2:43][NH:44][C:45]3=[O:48])=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([C:16]2[CH:15]=[N:14][N:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:30])[CH3:29])[CH2:8][CH2:9]3)[CH:17]=2)=[C:19]2[CH:27]=[C:26]([C:39]3[CH:47]=[C:46]4[C:42]([CH2:43][NH:44][C:45]4=[O:48])=[CH:41][CH:40]=3)[O:25][C:20]=12
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)NC3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(-c5ccc6c(c5)C(=O)NC6)cc34)cn2)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-{1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-1H-pyrazol-4-yl}-2-chloro-furo[2,3-c]pyridin-7-ylamine (50.0 mg, 0.112 mmol) in DME (0.894 mL) was added 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (43.5 mg, 0.168 mmol), sodium carbonate (2.0 M in water, 0.089 mL, 0.18 mmol), and Pd(PPh3)4 (20 mg, 0.02 mmol) and the reaction mixture was heated at 120° C. for 15 min in a microwave reactor. The reaction mixture was then concentrated. Purification of the residue by ISCO chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) afforded 49 mg (80%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C1COCC1>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
A solution of 5-(bromomethyl)-2-fluoropyridine (26.000 g, 137 mmol) in THF (30 mL) was cooled to −30° C. and morpholine (17.88 mL, 205 mmol) was slowly added. After min, triethylamine (57.2 mL, 410 mmol) was slowly added. Following addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature. After 30 min, the mixture was filtered through a fine-fritted funnel and the filtrate was concentrated to give an orange oil. The crude material was purified by chromatography through a Thompson Instruments pre-packed silica gel (330 gram) column eluting with a gradient of 0% to 100% EtOAc in hexane over 50 min to give 4-((6-fluoropyridin-3-yl)methyl)morpholine (15.767 g, 80 mmol, 58.7% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H); 7.79 (td, J=8.07, 2.45 Hz, 1H); 6.90 (dd, J=8.31, 2.84 Hz, 1H); 3.67-3.72 (m, 4H); 3.49 (s, 2H); 2.39-2.48 (m, 4H). m/z (ESI, +ve ion) 197.1 (M+H)+.