Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[OH-:31].[K+].Cl>C(O)(C)(C)C.O>[OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:22]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH2:14])=[O:31])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: [OH-]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C#N)ccc32)cc1
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C(N)=O)ccc32)cc1

Procedure:
0.18 g (0.44 mmol) 1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbonitrile (Example 15A) is dissolved in 15 ml tert-butanol, mixed with 0.23 g (3.6 mmol) pulverized, 88% potassium hydroxide and heated under reflux for 11 h. Having cooled down, the mixture is hydrolyzed in water and acidified with 1N hydrochloric acid. Three extractions with diethyl ether, concentration to half the volume on the rotary evaporator, washing with water and with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellowish solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 1:1) and yields the product as a solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Sn](C)(C)C)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3]1.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH2:33][CH:32]([CH2:34][OH:35])[O:31][N:30]=2)=[N:27][CH:28]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:35][CH2:34][CH:32]1[O:31][N:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3][C:2]4=[O:1])=[CH:8][CH:9]=3)=[CH:28][N:27]=2)[CH2:33]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Reactant: OCC1CC(c2ccc(Br)cn2)=NO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO)C4)nc3)cc2)C(=O)O1
Temperature: 90 °C
Yield: 26.8 %

Procedure:
N-({(5S)-2-Oxo-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide (300 mg, 0.76 mM), [3-(5-bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (194 mg, 0.76 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (78 mg, 0.076 mM) and tri-2-furylphosphine (35 mg, 0.152 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 15 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (83 mg).
Reaction SMILES: [C:1]([C:9]([NH:11][CH:12]1[C:18](=[O:19])[N:17]2[CH:20]([C:24]([NH:26][CH:27]3[CH2:31][C:30](=[O:32])[O:29][CH:28]3[O:33]CC3C=CC=CC=3)=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:41])[CH2:14][CH2:13]1)=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CC#N.O>>[C:1]([C:9]([NH:11][CH:12]1[C:18](=[O:19])[N:17]2[CH:20]([C:24]([NH:26][CH:27]([CH:28]=[O:33])[CH2:31][C:30]([OH:32])=[O:29])=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:41])[CH2:14][CH2:13]1)=[O:10])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)C(=O)c4ccccc4)C(=O)N23)C(OCc2ccccc2)O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)C(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.1 %

Procedure:
Compound 2001 (58.6 mg, 0.10 mmol) was treated with 15 mg of TFA/MeCN/water (1:2:3) and stirred at room temperature for 6.5 h. The reaction was extracted with ether. The aqueous layer was concentrated with azeotropic removal of the water using MeCN. The product was suspended in CH2Cl2, concentrated in vacuo and precipitated with ether to give 46.8 mg (99%) of 2002 as a white solid: 1H NMR (CD3OD) δ9.05 (0.25H, d), 8.15 (1H, d), 7.68 (1H, t), 7.64 (0.25H, d), 7.55 (3H, t), 7.35 (0.5H, m), 5.22 (1H, t), 4.90 (1H, m), 4.58 (1H, dd), 4.50 (1H, m), 4.28 (1H, bm), 3.45 (1H, m), 3.10 (1H, bt), 2.68 (1H, ddd), 2.60-2.45 (2H, m), 2.30 (1H, dd), 2.15-2.05 (2H, m), 1.90 (2H, bm), 1.68 (1H, bm).
Reaction SMILES: [OH-].[NH4+:2].C[O:4][C:5](=O)[C:6]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:7]>O1CCCC1>[C:8]1([C:6](=[O:7])[C:5]([NH2:2])=[O:4])[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Reaction time: 3 h
Yield: 86 %

Procedure:
Add concentrated ammonium hydroxide (2 mL) to a solution of (5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester (0.50 g, 2.06 mmol) in 10 mL of tetrahydrofuran at 0° C. Remove the cooling bath and stir the mixture for 3 hours. Dilute the reaction with 20 mL of water and filter the suspension. Wash the filter cake with 10 mL of water followed by 10 mL of diethyl ether, and dry under reduced pressure to provide the desired compound as a light yellow solid (0.403 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.Cl[CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[N:18]1[CH2:17][CH2:16][N:15]([C:13]([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[CH2:30][CH2:31][CH2:32][S:33]3(=[O:35])=[O:34])=[CH:7][C:6]=2[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3NS(C)(=O)=O)CC2)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3NS(C)(=O)=O)CC2)c(C)c1

Procedure:
Using N-{5-amino-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}methanesulfonamide (588 mg) described in Preparation Example 153 and 3-chloropropane-1-sulfonyl chloride (0.23 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (94 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:38])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=3)[CH3:30])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:37][C:33]1[N:32]=[C:31]([CH:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:20][C:12]2[CH:11]=[C:10]3[C:15]([C:16]([CH3:19])([CH3:18])[CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)=[O:38])[CH3:30])[CH:36]=[CH:35][N:34]=1
Reactant: CC(Nc1ccccc1C(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2(C)C)c1ccnc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Nc1ccccc1C(=O)Nc1ccc2c(c1)CNCC2(C)C)c1ccnc(N)n1

Procedure:
To a solution of 7-{2-[1-(2-amino-pyrimidin-4-yl)-ethylamino]-benzoylamino}-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Example 125) (80 mg, 0.154 mmol) in CH2Cl2 (3 mL) was added TFA (2 mL). The resulting mixture was stirred at RT for 18 h and basified with 5 N NaOH and extracted with CH2Cl2 (2×15 mL). The combined organic layers were washed with saturated NaHCO3, water, brine, dried over MgSO4, and evaporated in vacuo to give the product. MS m/z: 417.5 (M+H). Calc'd. for C24H29N6O-417.51.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[C:11](N1C=CN=C1)([N:13]1C=CN=C1)=[S:12].C([O-])(=O)C.[NH4+]>C(#N)C>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:11]([NH2:13])=[S:12])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)c1cc(NC(N)=S)n[nH]1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.5 g (11.3 mmol) 3-amino-5-tert-butylpyrazole dissolved in acetonitrile, was added drop-wise and slowly to a solution of 2.0 g (11.3 mmol) thiocarbonyldiimidazole in 25 ml acetonitrile, at 0° C. The batch was stirred for 20 minutes at 0° C., ammonium acetate (1.6 g, 21.5 mmol) was then added, and the mixture was heated in the microwave for 30 minutes at 90° C. (radiation power 200 Watt/without cooling). The solid formed was suction-isolated, the solution was concentrated and the oily residue (4.3 g) was crudely purified on silica gel (0.9 g yellowish solid)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)C.[NH3:21]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH2:21])=[O:3])=[C:8]([CH2:14][C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1Cc1ncc[nH]1
Reactant: N
Product: NC(=O)COc1ccc(Cl)cc1Cc1ncc[nH]1

Procedure:
Treatment of 4-chloro-2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester with ammonia as described in Example 8 gave 4-chloro-2-(1-imidazolylmethyl)phenoxyacetamide, m.p. 162°-164° C. (from isopropanol/petrol). Found: C, 53.91, H, 4.51, N, 15.79. C12H12ClN3O2 requires: C, 54.23, H, 4.57, N, 15.81%.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH2:17][C@@H:18]([CH2:31][O:32][C:33](=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:25](=[O:29])[NH:24][C:23]([NH2:30])=[N:22][C:21]1=2)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.FC(F)(F)C(O)=O>O>[C:33]([O:32][CH2:31][C@H:18]([CH2:17][CH2:16][O:15][C:13](=[O:14])[C@H:9]([CH:10]([CH3:12])[CH3:11])[NH2:8])[CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:25](=[O:29])[NH:24][C:23]([NH2:30])=[N:22][C:21]1=2)(=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](N)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 0 °C

Procedure:
The product from step b) (138 mg, 0.192 mmol) was cooled in an ice bath and trifluoroacetic acid (5 ml) was added. The solution was kept in the ice bath for 45 minutes and was then evaporated to give an oil. Water (0.5 to 1 ml) was added and evaporated twice. The residue was once more dissolved in water (5 ml), filtered and freeze-dried to give 148 mg of the desired product as the bistrifluoracetate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([Cl:18])[C:3]=1[CH2:4][CH:5]([C:6]#[N:7])[C:8]#[N:9]
Reactant: N#CC(C#N)=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 96.3 %

Procedure:
Using 1.0 g of (2,6-dichloro-4-(trifluoromethyl)benzyliden)malononitrile, 20 ml of ethanol and 0.03 g of sodium borohydride, and according to the process described in the Reference Production Example 3, there was obtained 0.97 g of (2,6-dichloro-4-(trifluoromethyl)benzyl)malononitrile (the intermediate (32)).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[C:23](O)=[O:24])([O-:14])=[O:13]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:23](=[O:24])/[CH:22]=[CH:21]/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccccc1[N+](=O)[O-]
Agent: Cl
Product: O=C(/C=C/c1ccccc1[N+](=O)[O-])N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-nitrophenyl)propenoic acid; MS (ES+) 302 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:31]([O:33]C)=[O:32])[CH:20]=4)[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:31]([OH:33])=[O:32])[CH:20]=4)[N:15]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCC(c4ccc(Cl)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(N3CCC(c4ccc(Cl)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Temperature: 50 °C
Reaction time: 2.17 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 2-(4-(4-chlorophenyl)piperidin-1-yl)-3-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.42 mmol, 1.00 equiv) in methanol (30 mL), sodium hydroxide (84 mg, 2.10 mmol, 5.00 equiv). The resulting solution was stirred for 130 minutes at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 30 mL of water. The pH value of the solution was adjusted to 3 with 1N hydrochloric acid. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 110 mg (57%) of 2-(4-(4-chlorophenyl)piperidin-1-yl)-3-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [OH:1][C:2]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:1]([C:2]([C:8]([F:11])([F:10])[F:9])([C:12]([F:13])([F:14])[F:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C(O)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Oc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (12.0 g.) is added, dropwise at 0° C. under nitrogen, to a stirred mixture of toluene (200 ml.) and sodium hydride (2.0 g. of a 60% dispersion in oil from which the oil has been washed with toluene). The mixture is stirred at ambient temperature for 1.5 hours, and phenyl-2-thienyliodonium trifluoroacetate (20.0 g.) is added. The mixture is heated under reflux with continued stirring for 1 hour, then cooled, and filtered. The filtrate is evaporated in vacuo, and the residual red oil (22.2 g.) is fractionally distilled at 24 mm. pressure to give ethyl 2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionate, b.p. 103°-105° C. (9.4 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]2[C:14]([N:20]=1)=[N+:15]([O-])[CH:16]=[CH:17][CH:18]=2.Cl.[OH2:22]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:20]=[C:14]2[NH:15][C:16](=[O:22])[CH2:17][CH:18]=[C:13]2[N:12]=1
Reactant: COc1ccc(-c2nc3c(ccc[n+]3[O-])[nH]2)c(OC)c1
Reactant: O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C2=NC3=CCC(=O)NC3=N2)c(OC)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Four grams of 2-(2,4-dimethoxy-phenyl)-imidazo[4,5-b]pyridin-4-oxide is suspended in 40 ml of acetic anhydride and refluxed for 2.75 hours. After cooling the mixture is poured onto 150 ml of ice, 25 ml of 6N hydrochloric acid are added, and the mixture is stirred at 120° C. for 30 minutes. It is cooled to ambient temperature, 50 ml of water are added, and the precipitate is subjected to suction filtration. The product is purified by chromatography on silica gel [eluant: methylene chloride/methanol (100:0 to 100:10)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[F:27])=[C:15]3[C:10]([CH:11]=[C:12]([F:35])[C:13]([F:34])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]4[NH:38][N:37]=[N:36][N:24]=4)=[CH:21][C:20]=3[F:27])=[C:15]3[C:10]([CH:11]=[C:12]([F:35])[C:13]([F:34])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OC(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(C(Oc3ccc(-c4nnn[nH]4)cc3F)C3CCCCC3)c2cc1F

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxy}-3-fluoro-benzonitrile (example 35) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as yellow solid. MS: m/e=539.2 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>CS(C)=O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([O:13][CH3:14])=[CH:3][C:2]=1[N:30]1[CH2:31][CH2:32][CH:27]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:28][CH2:29]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCCCC2)CC1
Temperature: 80 °C
Yield: 37.3 %

Procedure:
4-Chloro-2,5-dimethoxynitrobenzene (5.0 g, 23 mmol) was dissolved in DMSO (50 mL). K2CO3 (4.8 g, 34 mmol) and 4-piperidinopiperidine (3.9 g, 23 mmol) were added and the reaction mixture was heated to 80° C. and allowed to stir over the weekend. The mixture was then poured into H2O and extracted with EtOAc (2×). The combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (3.0 g, 37%). MS (M+H, ES+) 350.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][CH2:11][C:12]([OH:14])=[O:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[OH:13][C:12](=[O:14])[CH2:11][N:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3](=[O:4])[O:5][C:6]([CH3:8])([CH3:9])[CH3:7]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a cold (−20°) suspension of 60% NaH (120 g, 3.00 mol) in THF (700 mL) was added (30 min) a solution of Boc-glycine (175 g, 1.00 mol) in THF (300 mL). Thereafter, benzyl bromide was added to the mixture. After 15 min, the cooling bath was removed. The reaction mixture was stirred at room temperature for 1 h and then heated at reflux for 16 h. The reaction mixture was cooled to 0°. H2O (˜50 mL) was added dropwise over a 30 min period. After another 30 min, H2O (600 mL) was added. The mixture was washed with hexane (3×500 mL). 1N Aqueous HCl (1.3 L) was added slowly to the aqueous layer, followed by the addition of 4N aqueous HCl (300 mL). The aqueous solution was extracted with EtOAc (1.5 L) and then CH2C12 (3×500 mL). The combined organic layers were serially washed with H2O and brine, dried (MgSO4, Na2SO4, charcoal), filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound (241 g, 91% yield) as a pale yellow solid: Mp 94-97°; 1H NMR (400 MHz, DMSO-d6) δ10.5 (broad s, 1H), 7.23-7.33 (m, 5H), 4.40 (s, 2H), 3.80, 3.72 (2s, 2H), 1.38, 1.35 (2s, 9H); MS (FAB) m/z 266 (MH)+; Anal. Calcd for C14H19NO4 (and accounting for water content, 0.58% w/w as determined by Karl Fisher analysis): C, 63.01; H, 7.26; N, 5.25. Found: C, 62.79; H, 7.14; N, 5.13.
Reaction SMILES: C(OC(=O)[C@@H:5]([CH2:29][CH2:30][S:31][CH3:32])[NH:6][C:7](=[O:28])[C@@H:8]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH3:27])[CH:19]=1)[NH:9][C:10](OC(C)(C)C)=[O:11])C.Cl>C(O)=O>[CH3:27][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][C@H:8]2[NH:9][C:10](=[O:11])[C@@H:5]([CH2:29][CH2:30][S:31][CH3:32])[NH:6][C:7]2=[O:28])=[CH:19]1
Reactant: CCOC(=O)[C@@H](CCSC)NC(=O)[C@@H](Cc1cn(C)c2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O=CO
Product: CSCC[C@H]1NC(=O)[C@@H](Cc2cn(C)c3ccccc23)NC1=O
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
A mixture of N-tert-butoxycarbonyl-1-methyl-D-tryptophyl-D-methionine ethyl ester (2.4 g), formic acid (25 ml), and saturated solution of hydrogen chloride in formic acid (10 ml) was stirred on an ice bath for 1.5 hours. After removal of the solvent, the crude residue was dissolved in ethanol (20 ml) and saturated ammonia in ethanol (10 ml) was added. The resulting mixture was stirred for 16 hours at room temperature and precipitated mass was collected, washed with ethanol, and dried. Recrystallization from ethanol gave (3R,6R)-3-(1-methylindol-3-ylmethyl)-6-(2-methylthioethyl)piperazine-2,5-dione (1.16 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=1[C:60]#[N:61])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[C:60]#[N:61])=[O:57])[CH2:49][CH2:48]1
Reactant: N#Cc1ccccc1N=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 57 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-isocyanatobenzonitrile as starting materials in 57% yield. LCMS for C32H31ClN9O2 (M+H)+: m/z=608.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:24][N:23]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=2[F:20])[S:3][C:2]=1[NH:1][C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:24][N:23]=1)=[O:8]
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CN(C)C(=O)c1ccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)nc1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.510 mmol) and 6-chloro-N,N-dimethylnicotinamide (94 mg, 0.510 mmol) as starting materials.