Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:11]O>CC(O)=O.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccn1
Reactant: OO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)c1cccc[n+]1[O-]
Yield: 71.5 %

Procedure:
Preparation C3, Step 1: 2-tert-butylpyridine (2.00 g, 14.8 mmol, 1 eq.) was dissolved in HOAc (10 mL) and 30% hydrogen peroxide (1.68 mL, 14.8 mmol, 1 eq.) at room temperature then the reaction was refluxed for 20 hours. The reaction was stripped to obtain an amber oil which was dissolved in methylene chloride (10 mL) then dried over sodium sulfate and stripped to obtain 2-tert-butylpyridine-N-oxide (1.60 g) as an amber oil. Yield=71.5%. LCMS detects (M+H)+=152.09.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]=[C:23]([NH2:33])[N:22]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C[O-].[Ti+4].C[O-].C[O-].C[O-]>[CH:2]([NH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]=[C:23]([NH2:33])[N:22]=3)=[CH:18][CH:19]=2)[CH:10]=[CH:9][N:8]=1)([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[O-]
Solvent: ClCCl
Product: CC(C)NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.2 %

Procedure:
Acetone (11.51 mg, 0.20 mmol), N4-(4-{[2-(aminomethyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine (80 mg, 0.21 mmol, Example 39) and titanium (IV) methoxide (68.2 mg, 0.40 mmol) were suspended in CH2Cl2 (5 mL) and stirred at rt for 24 h. Sodium triacetoxyborohydride (105 mg, 0.50 mmol) was added into the reaction mixture and the mixture was stirred at rt for another 24 h. The mixture was filtered through a Celite® pad and washed with CH2Cl2. A small amount of Celite® was added to the filtrate and 5 mL of water was added to quench the reaction. After it was stirred for 20 min, the CH2Cl2 was removed in vacuo. The residue was taken up in ethyl acetate and washed with 1N NaOH (2×) and water (3×). The organic layer was concentrated and purified by Prep-TLC (MeOH) to give 36 mg (42.2%) of the title product as a white solid. 1H NMR (CD3OD) δ 8.35 (d, 1H), 7.82 (d, 2H), 7.00 (d, 2H), 7.44 (m, 3H), 7.08 (m, 2H), 7.01 (s, 1H), 6.82 (m, 1H), 6.46 (s, 1H), 3.81 (s, 2H), 2.80 (m, 1H), 1.10 (d, 6H); MS ES 427 (M+H)+, calcd 427, RT=2.59 min; TLC (MeOH)Rf=0.38.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 88.7 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (5.56 g, 25 mmol), piperidin-4-ylmethanol (3.17 g, 27.50 mmol) and DIPEA (5.66 mL, 32.50 mmol) in DMF (50 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between DCM and 1M aqueous K2CO3. The organic phase was washed with brine, dried over MgSO4, evaporated and triturated with ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to afford [1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methanol (6.68 g, 89%) as a cream crystalline solid.
Reaction SMILES: C([O:4][C:5]1([C@:9]2([C:29]([N:31]3[CH2:36][C@@H:35]4[CH2:37][C@H:32]3[CH2:33][N:34]4[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30])[CH2:13][CH2:12][C@@H:11]([N:14]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[C@@H:15]3[C@H:20]([O:21][CH3:22])[CH2:19][O:18][CH2:17][CH2:16]3)[CH2:10]2)[CH2:8][CH2:7][CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:41]([O:40][C:38]([N:34]1[CH2:33][C@@H:32]2[CH2:37][C@H:35]1[CH2:36][N:31]2[C:29]([C@@:9]1([C:5]2([OH:4])[CH2:6][CH2:7][CH2:8]2)[CH2:13][CH2:12][C@@H:11]([N:14]([C:23](=[O:28])[C:24]([F:26])([F:27])[F:25])[C@@H:15]2[C@H:20]([O:21][CH3:22])[CH2:19][O:18][CH2:17][CH2:16]2)[CH2:10]1)=[O:30])=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)(C2(OC(C)=O)CCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)(C2(O)CCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A mixture of 1.43 g (2.26 mmol) of 3-{[(1R,3S)-3-[1-(acetyloxy)cyclobutyl]-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}cyclopentyl](trifluoroacetyl)amino}-1,5-anhydro-2,3-dideoxy-4-O-methyl-D-erythro-pentitol and 1.60 g (11.6 mmol) of powdered potassium carbonate in 8 mL of methanol was stirred at ambient temperature for 18 h, then partitioned between dichloromethane and brine, with sufficient water to dissolve solids. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using acetate to provide 1.33 g (100%) of the title compound as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34-1.62 (m, 10H) 1.66-2.93 (m, 15H) 3.20-3.63 (m, 8H) 3.66-4.03 (m, 3H) 4.06-4.24 (m, 3H) 4.25-4.65 (m, 2H) 4.68-5.29 (m, 1H). TLC Rf 0.33 (EtOAc). LC-MS ES+ 590.3.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ccc(OCCO)cc1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(OCCO)ccc1N
Reaction time: 1 h
Yield: 81.5 %

Procedure:
2-Amino-5-(2-hydroxyethoxy)benzoic acid hydrochloride (0.209 g, 895 μmol; CAS 78299-60-2) was suspended in dichloromethane (10 ml) at r.t under an argon atmosphere. The reaction mixture was diluted with MeOH (3 ml). Then trimethylsilyldiazomethane solution (1.45 ml, 2.9 mmol; 2M in hexane) was added dropwise. The reaction mixture was stirred at r.t for 1 hr. The solvents were evaporated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient to give the title compound (154 mg, 82%) as light yellow, waxy solid.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCCl)cc1

Procedure:
The title compound, m.p. 126° C. and MS: m/e=313 (M+), was prepared from 4-(tert-Butyl-dimethyl-silanyloxy)-phenylamine and 3-chloropropionyl chloride.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([C:29]([OH:31])=O)[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.C[CH2:34][N:35](C(C)C)[CH:36](C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.CNC>C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([C:29]([N:35]([CH3:36])[CH3:34])=[O:31])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 10 (100 mg) was mixed with DIPEA (1.5 eq), EDC (1.25 eq), HOBt (1 eq) and dimethylamine hydrochloride (3 eq) in DCM (20 ml). The reaction was stirred at RT overnight and washed with NaHCO3 solution, dried. The solution was evaporated and purified with silica gel column to give the titled product (80 mg). Mass: (M+1), 464
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]([C:12](O)=[O:13])=[C:10]([CH2:15][N:16]3[CH2:21][CH2:20][C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[N:9]=[CH:8]2)=[CH:4][CH:3]=1.C1N=C[N:38](C(N2C=NC=C2)=O)C=1.N.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([C:12]([NH2:38])=[O:13])=[C:10]([CH2:15][N:16]3[CH2:21][CH2:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:18][CH2:17]3)[N:9]=[CH:8]2)=[CH:34][CH:35]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1c(CN2CCC(c3ccccc3)(c3ccccc3)CC2)ncn1Cc1ccc(Cl)cc1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1c(CN2CCC(c3ccccc3)(c3ccccc3)CC2)ncn1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
The product of Example 19 (0.03 g) was dissolved in N,N-dimethylformamide (2 ml), N,N-carbonyldiimidazole (0.020 g) was added and the solution heated at 60° C. for 2 hours and cooled. Aqueous ammonia solution (1 ml) was added and the mixture stirred at room temperature for 16 hours. Brine and ethyl acetate were added, the organic phase was separated, dried and the solvent removed by evaporation to give a solid. Trituration under ether gave the product as a solid (0.014 g), m.p. 227-228° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18]Cl)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(C1C=CC(C2CCNCC2)=CC=1)CCC.ClCC(Cl)=O.[N+:42]([C:45]1[CH:50]=[CH:49][C:48]([NH:51][C@H:52]2[CH2:57][CH2:56][C@H:55]([OH:58])[CH2:54][CH2:53]2)=[CH:47][C:46]=1[C:59]([F:62])([F:61])[F:60])([O-:44])=[O:43]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][O:58][C@H:55]3[CH2:56][CH2:57][C@H:52]([NH:51][C:48]4[CH:49]=[CH:50][C:45]([N+:42]([O-:44])=[O:43])=[C:46]([C:59]([F:60])([F:61])[F:62])[CH:47]=4)[CH2:53][CH2:54]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Reactant: CCCCc1ccc(C2CCN(C(=O)CCl)CC2)cc1
Agent: CCCCc1ccc(C2CCNCC2)cc1
Agent: O=C(Cl)CCl
Product: CCCCc1ccc(C2CCN(C(=O)CO[C@H]3CC[C@H](Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1

Procedure:
1-[4-(4-Butyl-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-butyl-phenyl)-piperidine (also known as 1-[4-(4-butyl-phenyl)-piperidin-1-yl]-2-chloroethanone) was prepared with a 72% yield from 4-(4-butyl-phenyl)-piperidine (prepared in accordance with Example 9) and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-butyl-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(4-butyl-phenyl)-piperidine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (36% yield). The structure was confirmed using Protocol II-A. Calculated mass=548; observed mass=548; HPLC retention time=4.92 min.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][Si](C)(C)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[CH3:1])#[CH:10]
Reactant: Cc1nc(N)ccc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N)nc1C

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 4.3 g (21.0 mmol) 6-methyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 1.5 g (10.5 mmol) K2CO3 in 30 mL MeOH. The product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 3.6 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]>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]>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:14]([C:12]#[N:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCOC(=O)CC#N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)C(C#N)c1ccc(C(F)(F)F)cc1
Yield: 82 %

Procedure:
Method A of the above general procedure was followed using 4-bromobenzotrifluoride (226 mg, 1.01 mmol), ethyl cyanoacetate (123 mg, 1.09 mmol), pentaphenylferrocenyl ligand (14 mg, 0.020 mmol) and Pd(dba)2 (6.0 mg, 0.010 mmol). The reaction mixture was purified by column chromatography on silica gel (1:3 dichloromethane/hexanes) to give the desired product (213 mg, 82%) as a colorless oil: 1H NMR (CDCl3) δ 7.71-7.69 (m, 2H), 7.63-7.60 (m, 2H), 4.80 (s, 1H), 4.27 (dq, 7.2, 1.2 Hz, 2H), 1.30 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 164.28, 133.81, 131.66 (q, 33.0 Hz), 128.55, 126.38 (q, 3.7 Hz), 123.68 (q, 272.3 Hz), 115.00, 63.78, 43.52, 13.89.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[CH:15]([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH:14]1C(O)=O.S(Cl)(Cl)=O.SC1C=CC=C[N+]=1[O-]>ClCCl.N1C=CC=CC=1>[OH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[CH:15]([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH2:14]1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)O)C2c1ccc2c(c1)OCO2
Agent: [O-][n+]1ccccc1S
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)CC2c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of (1RS, 2SR, 3RS)-3-[2-(methoxymethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (0.2 g, 0.39 mmol) in dichloromethane (4 ml) and pyridine (28 pl, 1.6 mmnol) was cooled to 0° C. under argon. To this solution was added thionyl chloride (60 μl, 0.8 mmol). The mixture was allowed to warm to ambient temperature over 20 min. and the volatiles removed in vacuo. The residue was redissolved in toluene and evaporated in vacuo (twice). The residue was dissolved in dichloromethane (4 ml) and triethylarmine (250 μl) added. To this solution at room temperature under argon was added 2-mercaptopyridine-N-oxide (120 mg, 0.8 mmol) dissolved in dichloromethane (1 ml). After stirring for 20 min at room terrnperature t-butylthiol (450 μl, 4 mmol) was added and the mixture irradiated for 20 min (150 watt spotlight). The volatiles were removed in vacuo and the product partitioned between ethyl acetate and 3M-aq. HCl. The organic extract was washed with water, sat. aq. NaHCO3 solution and finally brine. After drying (MgSO4 anhydrous), the product was filtered and evaporated. Purification by column chromatography gave the title compound (0.075 g, 41%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]3[NH:19][N:20]=[CH:21][C:13]=23)[CH:7]=1)([CH3:5])[C:3]#[N:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].CC#N>C1COCC1>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]3[NH:19][N:20]=[CH:21][C:13]=23)[CH:7]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: Cc1cnc2[nH]ncc2c1-c1cccc(C(C)(C)C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cnc2[nH]ncc2c1-c1cccc(C(C)(C)CN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a cooled solution of 2-methyl-2-(3-(5-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)propanenitrile (108 mg, 0.3908 mmol) at 0° C. in THF (20 ml) was added slowly a solution of lithium aluminium hydride (781.5 μL of 2 M, 1.563 mmol). The reaction mixture was allowed to stir at 0° C. for 2 hours and then allowed to warm to RT and stirred for 16 hours. The mixture was then cooled to 0° C. and quenched with water. EtOAc was added and the mixture passed through a celite pad. The organics were separated, washed with saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure to give a semi solid which was lyophilized from MeCN/H20 (34 mg, Yield=31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:8]([CH3:22])([CH3:21])[CH2:9][C:10]([O:17][CH2:18][O:19][CH3:20])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])[CH:7]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[CH2:29][Mg]Br>C1COCC1>[CH3:25][C:26]1[CH:34]=[C:33]([CH2:35][CH:11]([OH:12])[C:10]([O:17][CH2:18][O:19][CH3:20])([C:13]([F:16])([F:15])[F:14])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:23][CH3:24])([CH3:21])[CH3:22])[CH:32]=[C:28]([CH3:29])[CH:27]=1
Reactant: Cc1cc(C)cc(C[Mg]Br)c1
Reactant: COCOC(C=O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Solvent: C1CCOC1
Product: COCOC(CC(C)(C)c1cc(F)ccc1OC)(C(O)Cc1cc(C)cc(C)c1)C(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of 398 mg (1.1 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-2-methoxymethoxy-4-methyl-2-trifluoromethylpentanal in 4 mL of anhydrous THF, 10 mL (2.5 mmol) of a 0.25 M solution of 3,5-dimethylbenzylmagnesium bromide in THF was added. The mixture stirred for 4 hours and was then quenched with 10 mL of saturated ammonium chloride and extracted with three 10 mL portions of EtOAc. The combined organic layers were washed with three 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The mixture of diastereomers was purified by chromatography on silica gel eluting with dichloromethane-hexanes (0:100, then 10:90, then 15:85, then 20:80, then 25:75, then 3:7, then 4:6) to afford first 121 mg (22%) of a single diastereomer of 1-(3,5-dimethylphenyl)-5-(5-fluoro-2-methoxyphenyl)-3-methoxymethoxy-5-methyl-3-trifluoromethylhexan-2-ol, and then 137 mg (25%) of the second diastereomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([C:23]2[S:27][N:26]=[CH:25][N:24]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][C:19](=O)[CH2:18][O:17][C:16]=3[CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:23]2[S:27][N:26]=[CH:25][N:24]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:22]=2)(=[O:11])=[O:10])=[CH:28][CH:29]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)OCC(=O)N3)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of borane tetrahydrofuran complex, 1.0 M in tetrahydrofuran (4.76 mL, 4.76 mmol) was added dropwise to a mixture of N-(4-methoxybenzyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE K, 1.372 g, 3.17 mmol) in THF (15.86 mL) to form a heterogeneous mixture at 0° C. Gas evolution was observed upon addition, as well as gradual solubilization. After the addition, the reaction was warmed to RT for 5 h. The reaction was then quenched with MeOH (16.0 mL) and stirred overnight at room temperature. The reaction was then concentrated under a vacuum, and re-diluted with MeOH, and concentrated (×2). The resulting material was diluted once more in methanol and the solids were triturated and filtered, washing with methanol to yield 1.122 g of INTERMEDIATE L, N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (1.122 g, 2.68 mmol, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.34-3.38 (m, 2 H) 3.72 (s, 3 H) 4.10 (t, J=4.40 Hz, 2 H) 5.03 (s, 2 H) 6.62-6.66 (m, 1 H) 6.82-6.89 (m, 2 H) 7.04 (d, J=2.35 Hz, 1 H) 7.16-7.21 (m, 1 H) 7.25-7.31 (m, 2 H) 8.35 (s, 1 H). m/z (ESI) 418.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[CH:15]=[CH:14][C:13](=[CH:16][C:17]#[N:18])[CH2:12][C:7]32[CH2:11][S:10][CH2:9][C:8]=13.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>CN(C)C=O>[C:17]([CH:16]=[C:13]1[CH2:12][C:7]23[CH2:11][S:10][CH2:9][C:8]2=[C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:3]=[CH:4][N:5]=[C:6]3[CH:15]=[CH:14]1)#[N:18]
Reactant: N#CC=C1C=CC2=NC=CC(Cl)=C3CSCC23C1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C2=C3CSCC34CC(=CC#N)C=CC4=NC=C2)CC1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 79.7 %

Procedure:
11.6 g (43 millimoles) of 4-chloro-10-cyanomethylenethieno[4,3-e]benzoazepine were dissolved in 70 ml of dimethylformamide, and 10 ml (90 millimoles) of N-methylpiperazine and 10 ml (75 millimoles) of triethylamine were added, a highly exothermic reaction taking place. The mixture was stirred for from 2 to 3 hours at 100° C. under nitrogen, the dark homogeneous reaction mixture was then cooled and poured onto ice water, the yellowish crude product 10-cyanomethylene-4-(4-methylpiperazin-1-yl)-thieno[4,3-e]benzoazepine, was filtered off under suction. The crude product was dried in a drying oven under reduced pressure and then recrystallized from ethanol with the addition of active carbon or purified by column chromatography (silica gel, mobile phase 95:5 methylene chloride/methanol). 11.6 g (81%) of yellowish 10-cyanomethylene4-(4-methylpiperazin-1-yl)-thieno[4,3-e]benzoazepine were obtained in the form of a cis/trans isomer mixture of melting point 90°-92° C.
Reaction SMILES: [CH2:1]([C@:3]1([OH:19])[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[C@H:4]1[CH3:18])[CH3:2]>[Pd].O>[CH2:1]([C@:3]1([OH:19])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:18])[CH3:2]
Reactant: CC[C@]1(O)CCN(C(=O)OCc2ccccc2)[C@H]1C
Agent: [Pd]
Solvent: O
Product: CC[C@]1(O)CCN[C@H]1C

Procedure:
By an operation in the same manner as in Reference Example 4 and using benzyl (2S,3S)-3-ethyl-3-hydroxy-2-methylpyrrolidine-1-carboxylate (1.95 g) and 50% water containing-10% Pd/C (0.05 g), the title compound was obtained as a colorless solid (yield: 1.20 g, yield: 93%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[SH:7].CC(C)([O-])C.[K+].Cl[C:15]1[N:20]=[C:19]([C:21]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH3:29])[N:25]=2)=[O:22])[C:18]([S:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[CH:17][CH:16]=1.Cl>O.C(Cl)(Cl)Cl.CC(N(C)C)=O>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([S:30][C:18]2[C:19]([C:21]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH3:29])[N:25]=3)=[O:22])=[N:20][C:15]([S:7][C:3]3[N:2]([CH3:1])[CH:6]=[N:5][N:4]=3)=[CH:16][CH:17]=2)=[CH:32][CH:33]=1
Reactant: Cn1cnnc1S
Reactant: Cc1nsc(NC(=O)c2nc(Cl)ccc2Sc2ccc(O)cc2)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(O)cc2)n1
Temperature: 160 °C
Yield: 63.7 %

Procedure:
20 g of 4-methyl-4H-1,2,4-triazole-3-thiol and 19 g of potassium t-butoxide were added to a dimethylacetamide (130 ml) solution of 13 g of 6-chloro-3-[(4-hydroxyphenyl)thio]-N-(3-methyl-1,2,4-thiadiazol-5-yl)pyridine-2-carboxamide, and stirred under heat at 160° C. for 8 hours. At room temperature, chloroform and water were added to it, and its pH was controlled to 3 with aqueous 1 N hydrochloric acid solution added thereto. This was extracted with chloroform, and the organic layer was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol) to obtain 10.0 g of the entitled compound as a yellow solid.