Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]1[CH2:18][CH2:17][CH2:16][C:15]=1[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=[C:9]([C:23]([OH:25])=[O:24])[CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:28]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:23]([OH:25])=[O:24])[CH:8]=2)[C:13]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]([O:21][CH3:22])=[O:20])=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1[nH]c2cc(C(=O)O)ccc2c1C1=C(C(=O)OC)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1c(C2=C(C(=O)OC)CCC2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-butyl-3-(2-methoxycarbonyl-cyclopent-1-enyl)-1H-indole-6-carboxylic acid on Wang resin (100 mg; compound 7-1, prepared according to the procedure outlined in Example 7) in dimethylformamide (1.5 mL) was added sodium hydride (60% in mineral oil; 20 mg) and the mixture was stirred at room temperature for 30 min. Benzyl bromide (0.1 mL) was added and the mixture was stirred for 3 h. The mixture was filtered, washed with water (1×1.5 mL), tetrahydrofuran (2×1.5 mL), dichloromethane (2×1.5 mL), and dried. The product was cleaved from the resin by treatment with 1:1 trifluoroacetic acid/dichloromethane for 1 h; 1H NMR (DMSO-d6) δ 0.76 (t, 3 H), 1.20 (m, 2 H), 1.98 (m, 2 H), 2.00 (m, 2 H), 2.68 (t, 2 H), 2.82 (m, 4 H), 3.43 (s, 3 H), 5.56 (s, 2 H), 6.96 (d, 2 H), 7.30 (m, 4 H), 7.60 (d, 1 H), 7.90 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[CH:45]1([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13]([N:54]3[CH2:55][CH2:56][N:51]([CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:52][CH2:53]3)=[O:14])=[O:18])[CH2:20][CH2:21]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCN(C3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and 1-cyclohexylpiperazine (35.5 mg, 2.0 equiv) in dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) at 0° C. was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0° C. for 4 h. The reaction was concentrated and purified by column chromatography (95:5:1 to 90:10:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 62.3 mg (92%) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ 0.75-2.10 (m, 20H), 2.29 (m, 1H), 2.47 (m, 1H), 2.56 (s, 3H), 2.77-3.41 (m, 9H), 3.73 (m, 1H), 4.04-4.49 (m, 2H), 5.52 (dd, J=8.2, 7.3, 1H), 7.11 (s, 1H), 7.22 (dd, J=7.0, 7.0, 1H), 7.33 (d, J=7.9, 1H), 7.42-7.53 (m, 2H), 7.53-7.76 (m, 2H), 8.01 (s, 1H). Mass spec.: 625.33 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1.Cl[C:14]([O:16][CH3:17])=[O:15]>>[CH3:17][O:16][C:14]([NH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1)=[O:15]
Reactant: NCC1CNc2ccccc2C1
Reactant: COC(=O)Cl
Product: COC(=O)NCC1CNc2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound is prepared from 3.1 g of 3(R,S)-aminomethyl-1,2,3,4-tetrahydroquinoline and 2.2 ml methyl chloroformate in an analogous manner to that described in Example 54) (stirring for 2 h at 0° C.) and is purified by chromatography over silica gel with a 1:2 mixture of hexane and ethyl acetate as the mobile phase: Rf (A)=0.25; FAB-MS: (M+H)+ =221.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]2[CH:4]([CH2:5]2)[N:3]1C(OCC1C=CC=CC=1)=O.Cl>>[F:17][C:14]([F:15])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[C:2](=[O:1])[NH:3][CH:4]3[CH:6]2[CH2:5]3)[CH:13]=[CH:12][N:11]=1
Reactant: O=C(OCc1ccccc1)N1C(=O)N(c2ccnc(C(F)(F)F)c2)C2CC21
Agent: Cl
Product: O=C1NC2CC2N1c1ccnc(C(F)(F)F)c1
Yield: 112.8 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 30 for the preparation of I-30c, benzyl 3-oxo-4-(2-(trifluoromethyl)pyridin-4-yl)-2,4-diazabicyclo[3.1.0]hexane-2-carboxylate (I-32a: 55 mg, 0.1458 mmol) was treated with 4.0 mL of 6N HCl to yield the 40 mg of the product (85% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH2:2][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:10]=1)[C:6]#[N:7])([O-:13])=[O:12]
Reactant: C1CCNC1
Reactant: N#Cc1cc(CBr)cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(CN2CCCC2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of 3-(bromomethyl)-5-nitrobenzonitrile (1.50 g, 6.22 mmol) and pyrrolidine (0.53 g, 7.46 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.88 g, 18.68 mmol) dropwise at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-nitro-5-(pyrrolidin-1-ylmethyl)benzonitrile (1.30 g, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.45 (br s, 1H), 8.39 (br t, 1H, J=1.6 Hz), 8.02 (br s, 1H), 3.78 (s, 2H), 2.56 (br s, 4H), 1.84 (br s, 4H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:8]2)=[CH:4][CH:3]=1.[C:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:27]([N:34]1[CH2:35][CH2:36][N:37]([C:2]2[S:6][C:5]([CH:7]3[N:11]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[F:19])[N:10]=[C:9]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:8]3)=[CH:4][CH:3]=2)[CH2:38][CH2:39]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(Br)s2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (500.0 mg, 1.08 mmol) prepared in Step 8 of Preparation 13, 1-BOC-piperazine (303.0 mg, 1.63 mmol), Pd2(dba)3 (50.2 mg, cat.), BINAP (67.3 mg, cat.) and sodium t-butoxide (187.6 mg, 1.95 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 483.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Cl:19][C:17]1[CH:16]=[CH:15][C:12]2[C:13]3[C:7](=[CH:6][N:5]([CH2:4][CH2:3][OH:2])[CH:14]=3)[CH2:8][N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:11]=2[CH:18]=1
Reactant: COC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 2 h

Procedure:
A solution of 2.3 g (6.0 mmol) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl ester in 25 ml of tetrahydrofuran was added dropwise to a solution of 0.5 g (13 mmol) of lithium aluminum hydride in 30 ml of tetrahydrofuran which was cooled to -78°. The reaction was allowed to warm to 0° and was stirred for 2 hr. The excess lithium aluminum hydride was discharged by the addition of 0.6 ml of water, 0.6 ml of 10% sodium hydroxide and 2.0 ml of water. The resulting precipitate was removed by filtration and the filtrate was concentrated at reduced pressure to dryness. The residue crystallized from ether to give a white solid. Recrystallization from a mixture of ether and petroleum ether gave colorless prisms, mp 145°-147°.
Reaction SMILES: N[C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].S(=O)(=O)(O)N.[C:31]([OH:35])(=[O:34])[CH2:32][SH:33]>C(O)(=O)C.O.C(=O)([O-])[O-].[Cu+2].C(OCC)(=O)C>[CH3:16][O:15][C:3]1[C:2]([S:33][CH2:32][C:31]([OH:35])=[O:34])=[CH:14][C:6]2[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1N)oc1ccccc12
Reactant: O=C(O)CS
Agent: [Cu+2]
Agent: NS(=O)(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(cc1SCC(=O)O)oc1ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 19.2 %

Procedure:
3-Amino-2-methoxydibenzofuran (10 g, 46.9 mmol) was stirred in a mixture of acetic acid (100 ml), water (120 ml) and concentrated sulphuric acid (23.5 ml) at 80° C. for 15 minutes. The mixture was cooled to 0° C. and a solution of sodium nitrite (3.9 g, 57 mmol) in water (15 ml) was added at such a rate that the temperature did not exceed 4° C. The mixture was cooled -5° C. After 15 minutes, the excess sodium nitrite was decomposed by addition of an excess of sulphamic acid (0.9 g). The solution of the diazonium salt was added in a steady stream to a stirred mixture of basic copper carbonate (2.9 g) in water (50 ml) at 0° C. to which had been added thioglycolic acid (4.1 ml, 59 mmol). The mixture was allowed to attain ambient temperature during 30 minutes and then stirred thus for 4.5 hours until gas evolution (nitrogen) had ceased. Ethyl acetate (100 ml) was then added and solid material removed by filtration through diatomaceous earth, washing the filter pad with ethyl acetate. The organic layer was separated from the filtrate and washings extracted with 2 M aqueous sodium hydroxide solution (7×100 ml). Those extracts containing product [as indicated by thin layer chromatography (tlc) of a neutralised aliquot on silica, using ethyl acetate as eluant] were combined, washed with ether (100 ml), then neutralised with 2 M hydrochloric acid in the presence of ether (100 ml). This ether layer was separated, washed with brine and the solvent evaporated. Toluene was added to the residue and then removed by evaporation to remove remaining acetic acid. The residual yellow-brown solid was recrystallised from toluene to give 2-(2-methoxydibenzofuran-3-yl-thio)acetic acid (D) as a tan solid (2.60 g), m.p. 180°-182° C., which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-])=O.[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([S:11]([C:16]2([Cl:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:17]2[NH2:18])(=[O:13])=[O:12])=[CH:5][C:4]=1[NH2:1]
Reactant: Nc1ccccc1Cl
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1cc(S(=O)(=O)C2(Cl)C=CC=CC2N)ccc1Cl
Yield: 14.7 %

Procedure:
A solution of 3-nitro-4-chlorobenzenesulphonyl chloride (768 mg, 3.0 mmol), 2-chloroaniline (383 mg, 3.0 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and pyridine (0.30 ml, 3.6 mmol) in DCM (35 ml) was stirred at ambient temperature overnight. The solution was evaporated to dryness, the residue dissolved in EtOAc and washed with 1.0 M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in EtOAc (30 ml) and hydrogenated over 10% Pd/C for 4 h at ambient temperature. The catalyst was removed by filtration and the EtOAc evaporated to dryness. The residue was purified by column chromatography on basic alumina using 5% methanol in EtOAc to give, as a solid, the title compound (140 mg, 0.44 mmol). MS: 315.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:9]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:11][CH2:12][CH3:13])=[O:10]>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:9](=[O:10])/[CH:14]=[CH:7]/[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccncc1
Yield: 43.1 %

Procedure:
A solution of 4-pyridinecarboxaldehyde (333 mg, 3.11 mmol) and (carboethoxy-methylene)triphenylphosphorane (1.19 g, 3.42 mmol) in toluene (8.0 ml) was stirred at 90° C. under nitrogen for 3 hours. Once cooled, the solvent was removed under reduced pressure, the crude product was acidified with 1M HCl (25 ml) and the solution was washed with Et2O (25 ml×2). The aqueous solution was made basic with 1M NaOH and extracted with CH2Cl2 (25 ml×2). The combined organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure, giving (E)-3-pyridin-4-yl-acrylic acid ethyl ester as a white solid (238 mg, 1.34 mmol, 43%). 1H NMR (CDCl3) δ 1.35 (t, 3H, J=7.2 Hz), 4.29 (q, 2H, J=7.2 Hz), 6.59 (d, 1H, J=16.2 Hz), 7.37 (d, 2H, J=6.1 Hz), 7.60 (d, 1H, J=16.2 Hz), 8.66 (d, 2H, J=6.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)O)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:33])=O>C(Cl)(Cl)Cl>[Cl:33][CH:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc(C(O)c2cccc3nc(Nc4ccc(C(F)(F)F)cc4)nn23)ccn1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(C(Cl)c2cccc3nc(Nc4ccc(C(F)(F)F)cc4)nn23)ccn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The reaction was performed in two batches of starting material (0.250 g and 0.324 g) according to the following procedure. The crude reaction mixtures were recombined and used in the subsequent step without additional purification or characterization. To a suspension of (2-methoxypyridin-4-yl)(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methanol (0.324 g, 0.780 mmol) in chloroform (3.90 mL) at 0° C. was added dropwise thionyl chloride (0.153 mL, 2.090 mmol). The reaction was stirred at 0° C. for 45 min then at room temperature overnight. Additional thionyl chloride (0.05 mL) and reaction time (5 h) were necessary to drive the reaction to completion. The reaction was quenched with water and neutralized with sodium carbonate. 5-(Chloro(2-methoxypyridin-4-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine was obtained as a yellow oil not further purified or characterized. MS (ESI): m/z 434.2 [M+1]+.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CN1CCOCC1.[Cl:34][C:35]1[CH:36]=[C:37]([NH:42][C:43]([N:45]2[CH2:50][CH2:49][C:48]3[O:51][N:52]=[C:53]([C:54](O)=[O:55])[C:47]=3[CH2:46]2)=[O:44])[CH:38]=[CH:39][C:40]=1[Cl:41].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.C(OCC)C>CN(C=O)C>[Cl:34][C:35]1[CH:36]=[C:37]([NH:42][C:43]([N:45]2[CH2:50][CH2:49][C:48]3[O:51][N:52]=[C:53]([C:54]([N:17]4[CH2:18][CH2:19][C:12]5([CH2:13][CH2:14][N:9]([C:6]6[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=6)[CH2:10][CH2:11]5)[CH2:15][CH2:16]4)=[O:55])[C:47]=3[CH2:46]2)=[O:44])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: O=C(O)c1noc2c1CN(C(=O)Nc1ccc(Cl)c(Cl)c1)CC2
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCc2onc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)c2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecane dihydrochloride (0.17 g, 0.562 mmol) was dissolved in DMF (8.6 ml) and triethylamine (0.15 ml, 1.123 mmol), and 4-methylmorpholine (0.17 g, 1.685 mmol) was added, followed by 5-(3,4-dichlorophenylcarbamoyl)-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylic acid (0.2 g, 0.562 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.32 g, 1.3 mmol). The reaction mixture was stirred for 15 h at RT, and then the solvent was removed in vacuo. The residue was taken up in ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and then the combined organic phases were washed with sat. sodium chloride solution and sat. sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol 20:1+1% ammonia solution (25% aq.)). The purified product was dissolved in methyl ethyl ketone (2 ml); 2 M hydrogen chloride in diethyl ether (4 equiv.) was added at 0° C., and stirring was carried out for 1 h in an ice bath. The solid was filtered out with suction, washed with diethyl ether and dried in vacuo. Yield: 0.16 g (47%). MS, Rt=3.4 min; m/z=569.3 [MH]+
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:1][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=2)[CH:9]=1
Reactant: Cc1cc(C)nc(Cl)c1
Reactant: N#Cc1ccc(N[C@@H]2CCCC[C@@H]2N)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)ccc2C#N)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of rel-2-amino-4-{[(1R,2S)-2-aminocyclohexyl]amino}benzonitrile (100 mg, 0.430 mmol), 2-chloro-4,6-dimethylpyridine (65 mg, 0.46 mmol), palladium(II) acetate (12 mg, 0.053 mmol), cesium carbonate (284 mg, 0.860 mmol) and Xantphos (58 mg, 0.10 mmol) was purged with nitrogen. To this mixture was added 1,4-dioxane (10 mL), and the reaction mixture was heated to 90° C. under a nitrogen atmosphere. After 3 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give rel-4-{[(1R,2S)-2-aminocyclohexyl]amino}-2-[(4,6-dimethylpyridin-2-yl)amino]benzonitrile. MS ESI calc'd. for C20H26N5 [M+H]+ 336. Found 336.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([OH:18])(=O)[C@H:14]([CH3:16])[OH:15].ON1C2C=CC=CC=2N=N1.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34][NH2:35]>CN(C)C=O.ClCCl>[F:29][C:30]([F:43])([F:44])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=1)[CH2:34][NH:35][C:13](=[O:18])[C@H:14]([CH3:16])[OH:15]
Reactant: C[C@H](O)C(=O)O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](O)C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.5 g) was added to a solution of L-(+)-lactic acid (1.17 g) and 1-hydroxybenzotriazole (1.99 g) in dimethyl formamide (15 ml) at 0° C. under a nitrogen atmosphere. After stirring for 30 mins, 3,5-bistrifluoromethylbenzylamine was added and the solution was stirred at room temperature for 16h. The solution was diluted with dichloromethane (150 ml) and washed with sodium bicarbonate solution, water and brine. After drying (Na2SO4) the solvent was evaporated in vacuo to leave a viscous yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:10]1(Cl)[CH2:12][C:11]1(Br)Br)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Li]>C(OCC)C>[CH3:9][C:2]([C:10]1[CH2:11][CH:12]=1)([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(c1ccccc1)C1(Cl)CC1(Br)Br
Agent: [Li]C
Solvent: CCOCC
Product: CC(C)(C1=CC1)c1ccccc1
Reaction time: 0.17 h
Yield: 121.2 %

Procedure:
Into a 50 ml flask equipped with a stirbar and septum and under an atmosphere of dry nitrogen was added 1.73 g (4.9 mmol) of 1-(α,α-dimethylbenzyl)-1-chloro-2,2-dibromocyclopropane and 12 ml of diethyl ether. After cooling in an ice bath for 10 minutes, 9.0 ml (12.6 mmol) of 1.4 M methyllithium in diethyl ether was added via syringe. A precipitate formed immediately. After stirring for 10 minutes the reaction was quenched with 3 ml of water. The aqueous layer was removed and the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo with the bath temperature at +25° C. yielding 0.94 g of 1-(α,α-dimethylbenzyl)-cyclopropene.