Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:14])([F:13])[CH:11]=[O:12].Cl>CCOCC.C([Li])CCC>[F:9][C:10]([F:14])([F:13])[CH:11]([OH:12])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC(F)(F)F
Reactant: C#Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(C#Cc1ccccc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
In a solution of phenylacetylene (4.08 g, 40 mmol) in dry ether (30 ml), n-butyllithium (27 ml, 1.5 M in hexane) was slowly added at -78° C. Trifluoroacetaldehyde (3.7 g, 38 mmol) was introduced in the above mixture under bubbling and the mixture was then agitated 2 hours at -78° C. After the temperature of reaction mixture was elevated to room temperature, the whole solution was poured into aqueous 2% HCl solution. Extraction was made for the oily layer using diethyl ether. The extracts were dried on magnesium sulfate and solvent was removed. Distillation gave 1,1,1-trifluoro-4-phenyl-3-butyne-2-ol (b.p.: 82° C./1.8 mmHg) at a yield of 74%. The above product gave the following analytical data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][CH2:6]N1C2C=CC=CC=2N=N1.[BH4-].[Na+].Cl.[Na]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][CH3:6]
Reactant: Fc1cccc(NCn2nnc3ccccc32)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
1-((3-Fluoroanilino)methyl)-1H-benzotriazole (173.9 g) was slurried in dry tetrahydrofuran. Sodium borohydride (32.5 g) was added portionwise to the mixture at room temperature. After addition was complete, the mixture was heated at reflux for 4 hours. The solution was cooled and poured slowly into 400 mL of 5M hydrochloric acid with ice and stirred for 1 hour at room temperature. The solution pH was adjusted to 9-10 using 10M sodium hdyroxide solution. The product was extracted using diethyl ether. The ether extracts were washed successively with 1M sodium hydroxide solution, saturated sodium chloride solution, and water. The organic phase was dried over sodium sulfate and evaporated under reduced pressure to yield 87.5 g (97%) of 3-fluoro-N-methylaniline as a colorless oil. [NMR (200 MHz, DMSO-d6): 67 2.76 (s, 3H); 3.41 (br s, 1H); 6.59-6.92 (m, 3H); 7.27 (q, J=8.0 Hz, 1H)].
Reaction SMILES: [Na].[OH:2][CH:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O-:6])=[O:5].CC(C)CC(=O)C(O)=O.S(=O)(=O)(O)O>>[CH3:9][CH:8]([CH2:7][C@@H:3]([OH:2])[C:4]([OH:6])=[O:5])[CH3:10]
Reactant: CC(C)CC(O)C(=O)[O-]
Agent: CC(C)CC(=O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CC(C)C[C@@H](O)C(=O)O
Reaction time: 24 h

Procedure:
Ten 500 ml Erlenmeyer flasks provided with a baffle and containing in each case 100 ml of medium B were inoculated with Coryneform strain NRS-130KH20B (FERM-P No. 3657, NRRL B-11088) from a slant culture and incubated for 24 hours under the same conditions as described in Example 1. 8.19 g of sodium DL-2-hydroxy-4-methylvalerate were added to each flask as the substrate and the fermentation was continued for 120 hours under the same conditions. According to the method described earlier it was found that 120 hours after the addition of the substrate 35 mg/ml of 4-methyl-2-oxovaleric acid and 37mg/ml of pure D-hydroxy-acid were present. The fermentation was therefore discontinued and the fermentation broth were combined and centrifuged. The supernatant was acidified to pH 1.5 with 38 ml of 50% sulphuric acid and extracted three times with 1 liter of diethyl ether. The combined ether extracts were washed three times with 10 ml of saturated sodium chloride solution and evaporated under reduced pressure. 100 ml of toluene were added to the residue and the mixture was concentrated under reduced pressure in order to remove the water. The yellowish-brown oily residue was dissolved in 400 ml of petroleum ether and the solution was stored overnight in the refrigerator. The crystallisate was collected by filtration, washed with 50 ml of cold petroleum ether and dried in vacuo. There were obtained 28.1 g of D-2-hydroxy-4-methylvaleric acid in the form of colourless crystals of melting point 79.9° C.; [α]D20 =+26.67° (c=2 in 1-N sodium hydroxide).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH3:21])=[N:18][N:17](CC4C=CC(OC)=CC=4)[C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:31])[C:5]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH3:21])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:31])[C:5]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3c(c2)c(OC)nn3Cc2ccc(OC)cc2)c1F
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1F
Temperature: 25 °C
Yield: 82.5 %

Procedure:
6-Chloro-2-fluoro-N-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.027 g, 0.0480 mmol) was heated to reflux in TFA overnight. The reaction mixture was cooled to room temperature and was concentrated to an oil. DCM was added to the oil resulting in a precipitate, which was collected by filtration giving 6-chloro-2-fluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.0175 g, 82%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.60 (s, 1H), 11.07 (1H, s), 9.99 (br s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 7.52-7.57 (m, 1H), 7.44-7.46 (m, 1H), 4.02 (s, 3H), 3.15-3.19 (m, 2H), 1.73-1.79 (m, 2H), 0.97-1.01 (m, 3H); m/z (APCI-pos) M+1=442.1.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]1.O.[CH2:10](Cl)Cl>>[CH3:10][O:8][C:5]1[CH2:6][CH2:7][O:1][CH2:2][CH2:3][N:4]=1
Reactant: ClCCl
Reactant: O=C1CCOCCN1
Solvent: O
Product: COC1=NCCOCC1

Procedure:
A solution of 1,4-oxazepan-5-one (1 g, 8.7 mmol) and (CH3)3O+BF4− (1.9 g, 12.8 mmol) in DCM (30 mL) was stirred at room temperature for 20 h. The reaction mixture was then poured into water (60 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was used for the next step without further purification.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14]([C@H:16]([CH2:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1)[CH2:17][CH:18]=O)=[O:15])C1C=CC=CC=1.Cl.Cl.[CH3:30][O:31][C:32](=[O:47])[CH2:33][CH:34]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:35][CH2:36][CH2:37][NH2:38].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:30][O:31][C:32](=[O:47])[CH2:33][CH:34]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:35][CH2:36][CH2:37][N:38]1[CH2:18][CH2:17][C@@H:16]([CH2:20][CH2:21][C:22]2([CH3:27])[O:26][CH2:25][CH2:24][O:23]2)[C:14]1=[O:15]
Reactant: CC1(CC[C@H](CC=O)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)OCCO1
Reactant: COC(=O)CC(CCCN)c1ccc(OC)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(CCCN1CC[C@@H](CCC2(C)OCCO2)C1=O)c1ccc(OC)nc1
Reaction time: 16 h

Procedure:
To a stirred suspension of 1-11 (530 mg, 1.41 mmol), 1-6(460 mg, 1.41 mmol) and triethylamine (0.59 mL, 4.24 mmol) in 1,2-dichloroethane (15 mL) was added sodium triacetoxyborohydride (449 mg, 2.12 mmol) and the mixture was stirred for 16 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography (silica gel, 3:0.3:0.3 to 8:0.8:0.8% ethanol/ammonium hydroxide/water in ethyl acetate) to give 1-12 as an inseparable mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(CC2=C(O)CC(CCc3ccc(OC)c(Cl)c3)(C3CCCC3)OC2=O)cc1

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-Methoxy-benzaldehyde using the AlCl3/reduction procedure described for Example B(13). 1H NMR (CDCl3): δ 1.45-1.85 (brm, 8H), 1.98 (m, 2H), 2.29 (t, J=7.6 Hz, 1H) 2.44-3.02 (m, 7H), 3.88 (s, 3H), 3.94 (s, 3H), 6.73-7.85 (m, 7H). ESIMS (MH+): 471.7
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])=[O:8].[CH2:18]([O:25][C:26]([NH:28][C@@H:29]([CH3:33])[C:30](O)=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[NH:9][C:7]([C:3]1[N:2]([NH:1][C:30](=[O:31])[C@@H:29]([NH:28][C:26](=[O:27])[O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:33])[CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: Cc1cccc(C)c1NC(=O)c1cccn1N
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: Cc1cccc(C)c1NC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Yield: 74.8 %

Procedure:
The title compound was prepared from 1-amino-N-(2,6-dimethylphenyl)-1H-pyrrole-2-carboxamide (324 mg, 1.41 mmol) and (S)-2-(benzyloxycarbonylamino)propanoic acid (347 g, 1.55 mmol) following the experimental procedure described in Preparation 73a. 458 mg (75% yield) of the desired compound were obtained.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[C:4]([F:11])[C:3]=1[O:12][CH3:13].N([O-])=O.[Na+].[PH2](O)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>Cl.O>[F:11][C:4]1[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=[CH:2][C:3]=1[O:12][CH3:13]
Reactant: COc1c(N)cc(F)c(OC)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: COc1ccc(F)c(OC)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A 0.3M solution of Compound 2 (0.566 g, 2.99 mmol) in 4M HCl is chilled in an ice bath, and treated with a cold solution of sodium nitrite (1.05 equivalents) in water. The resulting diazonium salt solution is stirred for 15 minutes, and then hypophosphorous acid (50% aqueous solution, Aldrich, 20 equivalents) is added over 5 minutes. The resulting mixture is stirred at room temperature for two hours, then diluted with water. The resulting mixture is neutralized with aqueous sodium carbonate or sodium hydroxide, and extracted twice with ether. The organic extract is washed once with water, once with brine, and dried over anhydrous sodium sulfate. The solution is concentrated in vacuo and the resulting residue is purified by flash chromatography to give 0.38 g (73%) of Compound 3 as a clear, colorless liquid: 1H NMR (CDCl3) 6.80 (td, 1H), 6.58 (m, 1H), 4.00 (s, 3H), 3.87 (s, 3H); 19F NMR (CDCl3) 138.8 (d, 1F), 150.1 (d, 1F). Anal. calc. for C8H8O2F2 : C, 55.19; H, 4.63. Found: C, 54.76; H, 4.63.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17](O)=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:20]([F:23])([F:22])[F:21])([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.[CH3:57][NH:58][CH2:59][CH:60]1[CH2:65][CH2:64][N:63]([C:66]2[CH:71]=[CH:70][C:69]([C:72]([F:75])([F:74])[F:73])=[CH:68][CH:67]=2)[CH2:62][CH2:61]1>ClCCl.CS(C)=O.C(#N)C>[CH3:57][N:58]([CH2:59][CH:60]1[CH2:65][CH2:64][N:63]([C:66]2[CH:67]=[CH:68][C:69]([C:72]([F:75])([F:73])[F:74])=[CH:70][CH:71]=2)[CH2:62][CH2:61]1)[C:17]([C@H:14]1[CH2:15][CH2:16][C@H:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:20]([F:21])([F:22])[F:23])[CH:6]=2)[CH2:12][CH2:13]1)=[O:18]
Reactant: CNCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(CC1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.33 h

Procedure:
A suspension of trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxylic acid (7.88 g; 23.7 mmol, prepared in accordance with Example 42), diisopropylethyl amine (8.56 mL; 47.4 mmol), and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (8.74 g; 22.6 mmol) in a mixture of dichloromethane (300 mL) and dimethylsulfoxide (5 mL) was stirred for 20 min. Afterward, methyl-[1-(4-trifluoromethyl-phenyl)-piperidin-4-ylmethyl]-amine (6.15 g; 22.6 mmol, prepared in accordance with Example 56) was added. The resulting suspension was stirred for 15.5 hr at room temperature. This resulted in a clear solution, which was extracted with water (1 L). The organic phase was dried over sodium sulfate. After concentrating under reduced pressure, the resulting residue obtained was dissolved in a small volume of acetonitrile and filtered over a silica gel pad. The solvent was removed under reduced pressure, and the resulting solid was dried at 40° C. under a pressure of 3 mbar to afford the desired product (12.9; 22.0 mmol).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[C:10]([CH3:18])=[C:11]([C:15](=O)[CH3:16])[CH:12]=[CH:13][CH:14]=1>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[Br:8][C:9]1[C:10]([CH3:18])=[C:11](/[C:15](=[N:7]/[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])/[CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(Br)c1C
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cccc(Br)c1C
Temperature: 75 °C

Procedure:
To a stirring solution of (R)-2-methylpropane-2-sulfinamide (326 mg, 2.69 mmol) and Intermediate 12A (600 mg, 2.82 mmol) in THF (2 mL) at rt was added tetraethoxytitanium (1.06 mL, 5.12 mmol). The reaction mixture was heated at 75° C. for 16 h. The reaction mixture was cooled and used directly in the next step. LCMS=2.12 min [M+1]=318.0 (Method B).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:21]=[CH:20][C:12]3[N:13]([CH2:16][CH:17]4[CH2:19][CH2:18]4)[N:14]=[N:15][C:11]=3[C:10]=2[Cl:22])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30].O>O1CCCC1>[Cl:22][C:10]1[C:11]2[N:15]=[N:14][N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:12]=2[CH:20]=[CH:21][C:9]=1[O:8][C:3]1[C:2]([C:29]([OH:30])([CH3:31])[CH3:28])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Clc1c(Oc2ncccc2Br)ccc2c1nnn2CC1CC1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Cl
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
5-[(3-Bromopyridin-2-yl)oxy]-4-chloro-1-(cyclopropylmethyl)-1H-benzotriazole (395, 33 mg, 0.09 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (2 mL), cooled to −70° C. and treated dropwise with n-butyllithium (2.5 M in tetrahydrofuran, 0.038 mL, 0.10 mmol, 1.1 equiv.). After 5 minutes, the mixture was treated with acetone (7.57 mg, 0.13 mmol, 1.5 equiv.). After an additional ten minutes at −70° C., the mixture was treated with water. The mixture was poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC (80:20 to 5:95; water containing 0.05% trifluoroacetic acid:acetonitrile containing 0.05% trifluoroacetic acid). The appropriate fractions were poured into sodium bicarbonate (saturated aqueous, 20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford the titled compound 396 as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.10 (dd, 1H, J=7.6, 1.9 Hz), 7.97 (d, 1H, J=8.9 Hz), 7.88 (dd, 1H, J=4.8, 1.8 Hz), 7.44 (d, 1H, J=9.2 Hz), 7.14 (dd, 1H, J=7.4, 4.6 Hz), 4.66 (d, 2H, J=7.5 Hz), 1.68 (s, 6H), 1.45-1.38 (m, 1H), 0.60-0.57 (m, 2H), 0.52-0.49 (m, 2H) ppm. High resolution mass spectrometry (ES+) m/z 359.1277 [(M+H)+; calculated for C18H20ClN4O2: 359.1269].
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]([OH:18])[C:9]#[C:10][CH:11](OCC)OCC)=[CH:6][N:5]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:4]=1)#[N:2].[BrH:31].O.CCOCC>O1CCOCC1>[Br:31][C:9]1[CH:10]=[CH:11][O:18][C:8]=1[C:7]1[C:3]([C:1]#[N:2])=[N:4][N:5]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:27])([F:28])[F:29])=[CH:21][C:20]=2[Cl:30])[CH:6]=1
Reactant: CCOC(C#CC(O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N)OCC
Reactant: Br
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1occc1Br

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(4,4-diethoxy-1-hydroxybut-2-ynyl)pyrazole (0.04 g) in dioxane (1 ml) was added dropwise at room temperature hydrobromic acid (0.04 g). After 30 minutes the reaction mixture was poured into water (10 ml) and ether (10 ml). The organic layer was separated, dried (MgSO4) and evaporated. Recrystallisation from ether/hexane gave the title compound as a pale brown solid, m.p. 99-101° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:37])=O.N1C=CC=CC=1.C(=O)(O)[O-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][Cl:37])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CO)cc2)nn1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CCl)cc2)nn1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of [5-({[1-(4-Hydroxymethyl-benzyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (690 mg, 1.331 mmol) in 10 mL of DCM was added dropwise a solution of thionyl chloride (0.107 mL, 1.464 mmol) and pyridine (1.615 μL, 0.02 mmol) in 10 mL of DCM. The reaction mixture was stirred for 3 h at 40° C. and saturated aqueous bicarbonate solution was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic solution was dried over MgSO4, filtered and concentrated under vacuum to yield the crude product which was used in the next step without further purification. LCMS (Method A) RtA=1.681; [M+H]+=485.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.OO.C([O-])([O-])=[O:32].[K+].[K+]>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:32])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: Cn1c(-c2ccccc2)nc(-c2ccc(C(N)=O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}benzonitrile (Example 2, 25 mg, 0.062 mmol) in 2 mL DMSO at 0° C. was added lint of 30% H2O2 (aq). A catalytic amount of K2CO3 was added and the reaction was stirred at 50° C. for 60 min. The reaction mixture was diluted with MeOH and the product was purified by reverse phase HPLC. The fractions containing the product were collected and diluted with EtOAc, washed with aq NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.23 (d, 2H), 7.84 (d, 2H), 7.78 (m, 2H), 7.58 (m, 3H), 7.28 (d, 2H), 7.08 (d, 2H), 6.23 (broad s, 1H), 5.82 (broad s, 1H), 3.72 (s, 3H). LCMS: m/z 420 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[C:23]([O:40][CH3:41])[CH:22]=2)=[N:6][C:7]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)=[C:8]([CH2:10][CH3:11])[N:9]=1)(=[O:3])[NH2:2].Cl>C(OCC)(=O)C>[CH2:10]([C:8]1[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[C:23]([O:40][CH3:41])[CH:22]=2)=[N:6][C:7]=1[NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([OH:19])[CH2:17][CH2:18]1)[CH3:11]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(OC)c2)nc1N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(C3CCNCC3)c(OC)c2)nc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 4-[4-({3-carbamoyl-5-ethyl-6-[(trans-4-hydroxycyclohexyl)amino]pyrazin-2-yl}amino)-2-methoxyphenyl]piperidine-1-carboxylate (Example 382) (270 mg) and ethyl acetate (10 mL), 4M hydrogen chloride in ethyl acetate (4 mL) was added under ice cooling and stirred at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate and chloroform were added to the residue. The precipitated solid was collected by filtration and dried to give 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(3-methoxy-4-piperidin-4-ylphenyl)amino]pyrazine-2-carboxamide (85 mg) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([O:42]CC4C=CC=CC=4)=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.C(Cl)Cl.CO>[OH:42][C:39]1[CH:38]=[CH:37][C:36]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]4[N:32]=[CH:33][CH:34]=[CH:35][C:23]=4[N:22]3[C:18]=2[C:15]2[CH:16]=[CH:17][C:12]([C:8]3([NH:7][C:6](=[O:50])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:9][CH2:10][CH2:11]3)=[CH:13][CH:14]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(OCc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 97.4 %

Procedure:
Atmosphere of tert-butyl[1-(4-{2-[4-(benzyloxy)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (430 mg, 0.650 mmol) and 10% Pd—C(dry) (43 mg) in THF (7 mL) and MeOH (7 mL) was exchanged to H2 and stirred at 50° C. for 24 hours. The mixture was diluted with CH2Cl2+MeOH and filtrated through Celite pad. The filtrate was concentrated and the reaction was repeated again. Atmosphere of the residue and 10% Pd—C(dry) (43 mg) in THF (21 mL) and MeOH (21 mL) was exchanged to H2 and stirred at 50° C. for 25 hours. The mixture was diluted with CH2Cl2 and filtrated through Celite pad. The filtrate was concentrated and the residue was purified by column chromatography (CH2Cl2/MeOH=5:1) to afford the desired product (362 mg, 97%) as a pale brown solid. 1HNMR (DMSO-d6) 400 MHz δ: 9.42 (s, 1H), 8.51 (s, 1H), 8.04 (d, J=3.4 Hz, 1H), 7.93 (dd, J=7.4, 1.4 Hz, 1H), 7.36-7.26 (m, 5H), 7.14-7.08 (m, 3H), 6.88-6.81 (m, 2H), 6.64 (d, J=8.6 Hz, 2H), 2.42-2.33 (m, 4H), 2.02-1.97 (m, 1H), 1.81-1.74 (m, 1H), 1.34 (br s, 5H), 1.17 (br s, 4H). LCMS: 572 [M+H].