Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:15][C@@H:14]3[C@@H:10]([N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]3)[CH2:9]2)=[CH:4][C:3]=1[CH2:23]OS(C)(=O)=O.[C-:29]#[N:30].[K+]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:15][C@@H:14]3[C@@H:10]([N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]3)[CH2:9]2)=[CH:4][C:3]=1[CH2:23][C:29]#[N:30]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(c3cnc(Br)c(COS(C)(=O)=O)c3)C[C@@H]21
Reactant: [C-]#N
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(c3cnc(Br)c(CC#N)c3)C[C@@H]21
Temperature: 60 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
The product of Example 66A (0.300 g, 0.630 mmol) in N,N-dimethylfomamide (5 mL) was treated with KCN (61 mg, 0.945 mmol). The mixture was warmed to 60° C. and allowed to stir for 20 hours. The mixture was then concentrated under reduced pressure and the residue purified via chromatography (SiO2, 50% ethyl acetate/hexanes) to provide the title compound (0.100 g, 0.246 mmol, 39% yield). MS (DCI/NH3) m/z 409 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:5][CH2:6]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: N#Cc1nnc(NC2CCNCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nnc(NC2CCN(Cc3cccc(C(F)(F)F)c3)CC2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
A mixture of 5-(piperidin-4-ylamino)-[1,3,4]thiadiazole-2-carbonitrile (D6) (0.16 g, 0.76 mmol), 3-(trifluoromethyl)benzaldehyde (0.152 ml, 1.14 mmol) and sodium triacetoxyborohydride (0.24 g, 0.95 mmol) in N,N-dimethylformamide (3 ml) was stirred at room temperature for 16 h. After this period, the reaction mixture was diluted with ethyl acetate and extracted with a saturated solution of sodium carbonate (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 1-4% ammonia in methanol (7M)/dichloromethane) to yield E17 (0.025 g, 9%) as a white solid. C16H16F3N5S requires 367. Found 368 (MH+).
Reaction SMILES: [N:1]([CH:4]([C:9]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O.C1COCC1>[CH3:10][C:9]([CH3:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[NH2:1]
Reactant: COC(=O)C(N=[N+]=[N-])C(C)(C)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H](N)C(C)(C)c1ccccc1
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A solution of methyl 2-azido-3-methyl-3-phenylbutanoate (2.6 g, 11.2 mmol) and PPh3 (4.4 g, 16.7 mmol) in H2O (400 uL) and THF (100 mL) was stirred at 25° C. over 2d then at 50° C. for 12 h. The solution was concentrated and purified via column chromatography (silica, 5% MeOH in DCM (1% NH4OH)) yielding the title compound (1.4 g, quant.): LCMS (ES) m/e 208 (M+H)+.
Reaction SMILES: [CH:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8]CC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O>>[CH:11]1([PH:7](=[O:8])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOP(c1ccccc1)C1CCCCC1
Solvent: O
Product: O=[PH](c1ccccc1)C1CCCCC1
Reaction time: 3 h
Yield: 95.7 %

Procedure:
36 g (0.153 mol) of ethyl cyclohexylphenylphosphinite are heated to 90° C. under a nitrogen atmosphere and 2.9 g (0.161 mol) of water are added dropwise with constant stirring in the course of 3 hours. The batch is further stirred at 85° to 90° C. for 3 hours. An ethanol/water mixture is then distilled off in vacuo up to an internal temperature of 95° C. 30.5 g of cyclohexylphenylphosphine oxide are obtained as residue. This corresponds to a yield of 96% of theory.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[OH:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[OH:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:6]4[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=4)[CH2:12][CH2:13]3)=[O:18])=[CH:27][CH:26]=2)[CH2:33][CH2:32]1
Reactant: OCCN1CCNCC1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(CCO)CC3)cc2)CC1
Yield: 82 %

Procedure:
By the same procedure as described in the example 19, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 1-(2-hydroxyethyl)piperazine. Then, the product was recrystallized using isopropanol and ether to give the desired compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:14]#[N:15])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.CC[O:18]C(C)=O>[Pd]>[NH2:1][C:4]1[C:5]([C:14]([NH2:15])=[O:18])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: NC(=O)c1ncc(C(F)(F)F)cc1N

Procedure:
To a solution of 3-nitro-5-trifluoromethyl-pyridine-2-carbonitrile (1194 g, 5500 mmol) in EtOAc (12 l) was added 450 g Pd/C (10%) and hydrogenated (1.1 bar) at ambient temperature for 7 days. The reaction mixture was filtered and concentrated. The crude product was recrystallized from heptane/DCM to give 880 g of the desired product as a yellowish solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].Cl.C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]2[NH:35][N:34]=[N:33][N:18]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(Cc1cc(Br)ccc1OCC1CC1)c1ccc(C#N)nn1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(Br)ccc1OCC1CC1)c1ccc(-c2nnn[nH]2)nn1
Temperature: 102.5 °C
Yield: 74 %

Procedure:
6-[N-(5-Bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]-3-cyanopyridazine (reference example 14) (1.63 g) was dissolved in dimethylacetamide (DMA) (17 mls) under argon. Triethylamine hydrochloride (0.87 g, 6.3 mmol) and sodium azide (0.82 g, 12.6 mmol) were added and the mixture heated at 95-110° C. for 3 hours. It was then cooled and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with 10% 2N HCl saturated aqueous ammonium chloride (×2) and brine (×2), dried over Na2SO4, filtered and evaporated. The residue was recrystallised from acetonitrile to give the title product (1.34 g, 74.0%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.N1CCCCC1.N1C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])C=O>O>[F:20][C:21]1[CH:22]=[C:23]([CH2:3][CH2:2][C:1]([OH:7])=[O:6])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1F
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(CCC(=O)O)cc1F
Temperature: 120 °C
Yield: 65.8 %

Procedure:
Malonic acid (7.5 g, 72.1 mmols) and piperidine (0.84 g, 9.83 mmols) were added to a pyridine (20 ml) solution of 3-fluoro-4-methoxybenzaldehyde (10.1 g, 65.5 mmols), and the mixture was stirred under heat at 120° C. for 7 hours. The reaction mixture was poured into water containing ice, and the powder that precipitated was taken out through filtration. The powder was dried and dissolved in acetic acid (300 ml) without being further purified. To this was added 5% palladium-carbon (3 g, containing 50% water), and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 8.54 g (yield: 66%) of the target compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][S:11][CH:12]=1.O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]1[N:27]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([C:9]3[C:8]([CH3:7])=[CH:12][S:11][CH:10]=3)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[O:19][N:29]=1
Reactant: COc1ccccc1C(N)=NO
Reactant: Cc1cscc1-c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3cscc3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (106 μL; 1.26 mmol; 3 eq.), Intermediate 32 (120 mg; 0.42 mmol; 1 eq.), Intermediate 1 (70 mg; 0.42 mmol, 1 eq.) and DIEA (217 μL; 1.26 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) followed by crystallization from n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@@H:6]1[CH:18]=[CH2:19].O.B(O[O-])=[O:34].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[OH:34][CH2:19][CH2:18][C@@H:6]1[C@H:5]([CH2:4][CH2:3][CH:2]([OH:1])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1
Reactant: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: O=BO[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CCO)c2c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
33.4 cm3 of triethylamineborane complex were added with stirring, at a temperature in the region of 20° C., to a solution of 52.6 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)-3-vinylpiperidine in 500 cm3 of toluene and then the mixture was heated for 18 hours at a temperature in the region of 110° C. After having concentrated the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 45° C., the residue obtained was taken up in 500 cm3 of tetrahydrofuran. The solution which resulted therefrom had approximately 63 cm3 of water added over 20 minutes and then 47.5 g of sodium perborate were added portionwise over approximately 1 hour. The mixture was stirred for 4 hours at a temperature in the region of 20° C. and then 300 cm3 of a saturated ammonium chloride solution were added. The organic solution was separated by settling, dried over magnesium sulfate, and concentrated under the same conditions as above. The residue obtained was purified by chromatography on a column of silica gel (particle size 20-45 μm; diameter 9 cm; silica volume 2500 cm3), elution was carried out first with a dichloromethane/methanol (97.5/2.5 by volume) mixture, and 1-liter fractions were collected. Fractions 1 to 17 were separated and then elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, 1-liter fractions were collected. Fractions 30 to 35 were combined and, finally, elution was carried out with a dichloromethane/methanol (90/10 by volume) mixture, 1-liter fractions were collected. Fractions 36 to 41 were combined, while the combination of fractions 30 to 41 was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 20 g of (3R,4R)-3-(2-hydroxyethyl)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine were obtained in the form of an oil.
Reaction SMILES: [H-].[Na+].[OH:3][C@:4]1([C:22]2[CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=[CH2:35])[CH:29]=3)[CH:25]=[CH:26][CH:27]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1.[CH3:36]I>CN(C=O)C>[CH3:36][O:3][C@:4]1([C:22]2[CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=[CH2:35])[CH:29]=3)[CH:25]=[CH:26][CH:27]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1
Reactant: C=Cc1cccc(-c2cccc([C@]3(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C3)c2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1cccc(-c2cccc([C@]3(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C3)c2)c1
Reaction time: 3 h
Yield: 77.1 %

Procedure:
NaH (60% in oil) (0.446 g, 11.16 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-1,2-dicarboxylate (2.9 g, 6.20 mmol) and methyl iodide (0.698 mL, 11.16 mmol) at 0° C. in DMF and stirred at this temperature for 3 hrs. The reaction was then quenched with saturated NH4Cl solution and ether. The ether layer was washed with brine, dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (5-45% EtOAc in hexanes) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-1,2-dicarboxylate (2.3 g, 4.78 mmol, 77% yield) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.04-0.11 (m, 9H) 0.89-1.12 (m, 2H) 2.56 (dd, J=13.18, 8.91 Hz, 1H) 2.86 (t, J=12.67 Hz, 1H) 2.99 (d, J=3.01 Hz, 3H) 3.66-3.92 (m, 1H) 3.79 (d, J=7.03 Hz, 3H) 3.99-4.12 (m, 1H) 4.18-4.29 (m, 2H) 4.44-4.70 (m, 1H) 5.33 (d, J=10.79 Hz, 1H) 5.84 (d, J=16.82 Hz, 1H) 6.80 (dd, J=17.57, 11.04 Hz, 1H) 7.34 (d, J=7.53 Hz, 1H) 7.39-7.52 (m, 4H) 7.53-7.59 (m, 3H). LCMS: rt=2.49 min. [M+H]+=482; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)[CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:28]([N:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:38]=1)[CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCCCCCN(C)Cc1ccc(N)cc1
Product: CCCCCCN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(n-hexyl)-N-methyl-aminomethyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=10:1) C31H35N3O3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:19](=[O:20])[CH:14]2[CH2:15][S:16][CH2:17][CH2:18][N:13]2[C:12]1=[O:21]>CO>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[C:19](=[O:20])[CH:14]3[CH2:15][S:16][CH2:17][CH2:18][N:13]3[C:12]2=[O:21])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1C2CSCCN2C(=O)N1c1ccc([N+](=O)[O-])cc1Cl
Solvent: CO
Product: Nc1ccc(N2C(=O)C3CSCCN3C2=O)c(Cl)c1
Reaction time: 18 h
Yield: 59.2 %

Procedure:
The 2-(2-chloro-4-nitrophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]thiazine-1,3(2H)-dione (124 mg, 0.38 mmol) and 5% Pt sulfided on carbon (148 mg, 0.04 mmol) were added to a flask under argon. Methanol (8 mL) was added. The flask was purged with vacuum and H2 gas, then H2 gas was applied by balloon (1 atm) with stirring for about 18 hours. The mixture was diluted with MeOH and poured through Celite, washing with MeOH. The filtrate was concentrated under vacuum to give about 125 mg of crude product. The compound was purified by chromatography on silica gel (12 g) eluting with a 0-to-50% A-to-B gradient (A is DCM: B is 10% MeOH/DCM with 1% ammonium hydroxide) to give 67 mg of 2-(4-amino-2-chlorophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]thiazine-1,3(2H)-dione, 1.2.40.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=2)[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si](C)(C)C)=[CH:26][N:25]=2)=[CH:11]1)([CH3:9])[CH3:8]>CO>[CH:7]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=2)[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][N:25]=2)=[CH:11]1)([CH3:9])[CH3:8]
Reactant: CC(C)n1cc(-c2ccc(C#C[Si](C)(C)C)cn2)c2ccc(NS(C)(=O)=O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2cn(C(C)C)c3cc(NS(C)(=O)=O)ccc23)nc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
Add potassium carbonate (208 mg, 1.5 mmol) to N-[1-isopropyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-1H-indol-6-yl]-methanesulfonamide (63 mg, 0.15 mmol) in MeOH (5 mL) and stir at room temperature for an hour. Evaporate the solvent. Purification of the crude residue using silica gel chromatography gave 14 mg (27% yield) of the desired product.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1.Cl>ClCCl>[F:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([C:4]2[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)Cc1cccc(F)c1
Reactant: CSc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2cccc(F)c2)cc1

Procedure:
To a stirred solution of 68 ml thioanisole in 600 ml dichloromethane at 0° C., were added slowly in a series aluminum chloride (77.3 g) and (3-fluorophenyl)acetyl chloride (100 g). The reaction mixture was stirred for an hour, after which 1 L of aqueous HCl was added slowly to the reaction mixture. The quenched mixture was stirred for another hour, which was followed by extraction with methylene chloride. The organic layer was washed with brine and then was dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resulting residue was purified by recrystallization from hexane/dichloromethane to yield 142.9 g of 2-(3-fluorophenyl)-1-{4-(methylthio)-phenyl}-ethanone. mp: 94.5-95.5° C. NMR: δ2.52 (s, 3H), 4.23 (s, 2H), 6.95-7.05 (m, 3H),7.25-7.30 (m, 3H), 7.92 (d, J=8.7 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(O)C>[Br:10][C:11]1[CH:12]=[N:13][C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Nc1ccc(CO)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: OCc1ccc(Nc2ncc(Br)cn2)cc1
Temperature: 200 °C

Procedure:
To a solution of 4-aminobenzyl alcohol 14 (8.12 mmol) and 5-bromo-2-chloro-pyrimidine 4 (9.74 mmol) in 2-propanol (20 mL) is added sodium iodide (8.12 mmol) and diisopropylethylamine (16.2 mmol). The reaction mixture is heated in the microwave oven at 200° C. for 15 min. Purification by silica gel chromatography with hexane:EtOAc=7:3 affords [4-(5-bromo-pyrimidin-2-ylamino)-phenyl]-methanol 15. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H) 7.07 (bs, 1H), 4.60 (s, 2H). MS (m/z) (M+1)+: 280.3, 282.3.
Reaction SMILES: [CH3:1][CH:2]([N:6]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7]1)[C:3]([OH:5])=O.[CH3:18][NH:19][CH3:20].N>>[CH3:18][N:19]([CH3:20])[C:3](=[O:5])[CH:2]([C:1]1[CH:13]=[CH:12][CH:8]=[CH:9][CH:10]=1)[N:6]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7]1
Reactant: CNC
Reactant: Cc1cn(C(C)C(=O)O)nc1-c1ccccc1
Agent: N
Product: Cc1cn(C(C(=O)N(C)C)c2ccccc2)nc1-c1ccccc1

Procedure:
Following the procedure of Example 68, but substituting 4-methyl-α,3-diphenylpyrazole-1-acetic acid for α,4-dimethyl-3-phenylpyrazole-1-acetic acid and dimethylamine for aqueous ammonia, there was obtained N,N,4-trimethyl-α,3-diphenylpyrazole-1-acetamide having a melting point of 135.5°-138° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]([C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[C:15]([CH3:25])=[CH:14][C:13]([CH2:11][CH3:12])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cn1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Yield: 42.8 %

Procedure:
Using 5-bromo-2-picolinic acid (206 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (220 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (170 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:26](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:26])[CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC1CCC(NCCNC(=O)OC(C)(C)C)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(N(C)CCNC(=O)OC(C)(C)C)CC1
Reaction time: 19 h

Procedure:
To a solution of ethyl 2-[4-[2-(tert-butoxycarbonylamino)ethylamino]cyclohexyl]acetate (326 mg, 1 mmol) in dichloromethane (4 mL) was added formalin (97 μL, 1.2 mmol) followed by acetic acid (60 μL, 1 mmol) and sodium triacetoxyborohydride (255 mg, 1.2 mmol). The resulting cloudy solution was stirred for 19 hours. To the mixture was added sodium carbonate (2 mL, saturated aqueous solution). The mixture was diluted with ethyl acetate and separated. The organic extract was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (10 g silica; eluted with 2-20% methanol in dichloromethane) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=3[CH:12]=2)[C:6]([N+:22]([O-])=O)=[CH:5][CH:4]=1>C(O)(=O)C.CCOC(C)=O.[Zn]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=3[CH:12]=2)[C:6]([NH2:22])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCc2ccc3nc(SC)sc3c2)n1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(N)c(NCc2ccc3nc(SC)sc3c2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a mixture of 6-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine (431 mg, 1.19 mmol) from Step 5 of this Example in acetic acid (6 mL) was added zinc powder (235 mg, 3.57 mmol) slowly at 0° C. The reaction mixture was stirred at 0° C. for 20 min and then stirred at rt for 4 h. The resulting reaction mixture was diluted with 30 mL of EtOAc and filtered through a Celite pad. The filtrate was neutralized with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of EtOAc-CH2Cl2 (1:3, v/v) as eluent to give 6-methoxy-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine as a brown oil (389 mg, 98%). LCMS (ESI) m/z 333 (M+H)+.