Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14]Br)[C:9]([CH2:12]Br)=[CH:10][CH:11]=1.[C-:16]#[N:17].O>CS(C)=O>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:1]#[N:2])=[C:8]([CH2:14][C:16]#[N:17])[CH:7]=1
Reactant: COc1ccc(CBr)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC#N)c(CC#N)c1
Reaction time: 0.25 h

Procedure:
Finely ground sodium cyanide (73 gm., 1.48 m) was suspended in dimethylsulfoxide (500 ml.) by means of a "Vibro-Mixer". A solution of 4-Methoxy-α,α'-dibromo-o-xylene (113 gm., 0.384 m) in dimethylsulfoxide (200 ml.) was added dropwise to the cyanide suspension. The internal temperature was kept at 35°-38° C. by means of an ice bath. The addition took 15 minutes. Agitation of the reaction was continued for a further 11/2 hours. The reaction mixture was poured into water (4 l.). The aqueous mixture was extracted with ether (2×1 l., 3×500 ml.) and the combined ether extracts were washed with dilute hydrochloric acid (6 N) (2×500 ml.), saturated sodium carbonate solution (1×500 ml.), water (3×500 ml.) and saturated sodium chloride solution (2×500 ml.). The ether layer was dried over magnesium sulfate. The dried ethereal solution was evaporated to an oil which was distilled and the fraction with boiling range 160°- 165° (0.1 mm) was collected. wt.=53 gm. The oil obtained was crystallized from ether (650 ml.) to give 45 gm. (m.p. 51°-53°). A second drop of 5.8 gm.(m.p. 49°-51°) was obtained.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[Br:16]Br>C(Cl)Cl>[Br:16][C:14]1[CH:13]=[N:12][N:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:15]=1
Reactant: BrBr
Reactant: CC(C)(C)n1cccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a suspension of Na2CO3 (3.6 g, 33.9 mmol) in CH2Cl2 (30 mL) was added 1-tert-butyl-1H-pyrazole (2.1 g, 17 mmol) and Br2 (0.9 mL). The mixture was stirred at room temperature overnight. The formed solid was removed by filtration and the filter cake was washed with CH2Cl2 (30 mL). The filtrates were washed with water (20 mL) and brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to afford crude 4-bromo-1-tert-butyl-1H-pyrazole (2.9 g, 85%), which was used in next step without further purification. MS (ESI) m/z: 203 [M+H]+.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:16]=1>CC(O)=O>[Cl:8][C:20]1[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[N:16][C:17]([N:21]2[CH2:22][CH2:23][CH:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:25][CH2:26]2)=[N:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CS(=O)(=O)NC1CCN(c2nccc(-c3ccccn3)n2)CC1
Solvent: CC(=O)O
Product: CS(=O)(=O)NC1CCN(c2ncc(Cl)c(-c3ccccn3)n2)CC1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
NCS (370 mg, 2.83 mmol) was added to a solution of N-(1-(4-(pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanesulfonamide (180 mg, 2.36 mmol) in AcOH (10 mL) at 60° C. and the reaction solution was stirred for 2 h. LC-MS indicated the reaction was almost complete. The reaction solution was concentrated and purified by chromatography, eluted with CH2Cl2:MeOH (6:1) to give crude product, which was further purified by Prep-HPLC to give title compound (251 mg, 29%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.68-8.70 (d, 1H), 8.29 (s, 1H), 7.75-7.79 (m, 1H), 7.70-7.72 (d, 1H), 7.31-7.34 (t, 1H), 4.60-4.63 (d, 2H), 4.18-4.20 (d, 1H), 3.53-3.57 (t, 1H), 2.94 (s, 3H), 1.99-2.02 (d, 1H), 1.39-1.49 (m, 1H); m/z for C15H18ClN5O2S 390.1 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]([CH:25]=1)=[N:22][O:23][N:24]=2>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[C:21]([CH:25]=2)=[N:22][O:23][N:24]=3)[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: BrCc1ccc2nonc2c1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: N#Cc1ccc(N(Cc2ccc3nonc3c2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 5-bromomethylbenzofurazan
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:9]=12)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 381 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:16])[C:18]([F:20])([F:19])[F:17])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C=O)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(C(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
To a solution of tert-butyl 2-chloro-6-formylisonicotinate (1.5 g, 6.2 mmol) in THF (40 mL) were added (trifluoromethyl)trimethylsilane (1.49 mL, 4.31 mmol) and ground 4 A° molecular sieves. The mixture was cooled to 0° C. and TBAP (1.0 M in THF; 1.86 mL, 1.86 mmol) was added dropwise. The mixture was warmed to ambient temperature. After 30 min, additional (trifluoromethyl)trimethylsilane (0.5 mL, 1.44 mmol), TBAP (1.0 M in THF; 0.62 mL, 0.62 mmol) and ground 4 A° molecular sieves were added. After 30 min, the mixture was filtered with Celite. Aqueous 1 N HCl was added to the filtrate and the filtrate was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→95% hexanes/ethyl acetate) gave the title compound (1.4 g). MS 312.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[N:16]([CH3:41])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH2:39][CH3:40])[N:18]=3)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:39]([C:31]1[N:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([C:11]4([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:16]3[CH3:41])=[C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:20]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1)[CH3:40]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCNCC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.3 g, 2.31 mmol) in DCM (10 mL) was added TFA (2 mL) and the resulting mixture allowed to stir at r.t. for 3 h. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ol (1.1 g, quant.). LCMS (method H): RT 1.79 min, [M+H]+ 463.3
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[C:3]=1[O:11][C:12](=[O:23])[CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:44]>ClCCl>[Br:44][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:11][C:12](=[O:23])[CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:4]([CH3:10])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(CO)cc(C)c1OC(=O)CNCC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)cc(C)c1OC(=O)CNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of 2.88 g of 4-(tert-butoxycarbonylmethylamino)acetoxy-3,5-dimethylbenzaldehyde and 0.34 g of sodium borohydride in 25 ml of tetrahydrofuran was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and was washed with 0.25N HCl. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain (tert-butoxycarbonylmethylamino)acetic acid 2,6-dimethyl-4-hydroxymethylphenyl ester (2.9 g) as a colourless syrup. To a solution of 2.8 g of (tert-butoxycarbonylmethylamino)acetic acid 2,6-dimethyl-4-hydroxymethylphenyl ester and 2.73 g of triphenylphosphine in 30 ml of dichloromethane, 3.44 g of carbon tetrabromide was added and the mixture was stirred for 1 h at room temperature. The mixture was concentrated and the residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2)to obtain (tert-butoxycarbonylmethylamino)acetic acid 4-bromomethyl-2,6-dimethylphenyl ester (2.97 g, 89% ) as a colourless oil.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:33]3[CH2:35][CH2:34]3)[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:36])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:33]1([C:13]2[C:14]([NH:18][C:19](=[O:32])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[C:23]([F:31])[CH:22]=3)=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:36])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16]3)[CH2:35][CH2:34]1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C3CC3)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@H](CO)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C3CC3)ccc2c1=O
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with (R)-2-(6-cyclopropyl-5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (23 mg, 0.000046 mol), potassium carbonate (9.4 mg, 0.000068 mol) and methanol (2 mL, 0.05 mol) and 2 drops of water and the reaction was stirred for 30 minutes. The reaction mixture was then filtered over celite and the solvent removed under reduced pressure. The residue was then purified by preparative HPLC (reverse phase) to get the product as a sticky mass. MS m/z=463.5 (M+H). 1H NMR (400 MHz; Acetone-d) δ 9.02 (s, 1H), 8.03 (d, J=8.15 Hz, 1H), 7.61 (t, J=7.52 Hz, 1H), 7.42 (d, J=5.01 Hz, 1H), 7.39 (s, 1H), 7.24 (d, J=7.52 Hz, 1H), 6.91 (d, J=8.15 Hz, 1H), 6.36 (d, J=8.15 Hz, 1H), 4.99-4.97 (m, 1H), 3.93 (s, 2H), 3.68-3.64 (m, 2H), 2.04-1.94 (m, 1H), 1.24 (d, J=7.32 Hz, 3H), 0.81-0.77 (m, 2H), 0.60-0.56 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([F:32])=[CH:16][C:17]3[N:21]=[C:20]([CH2:22][C:23](OCC)=[O:24])[N:19]([CH:28]4[CH2:30][CH2:29]4)[C:18]=3[CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[NH:34][NH2:35]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([F:32])=[CH:16][C:17]3[N:21]=[C:20]([CH2:22][C:23]([NH:35][NH:34][C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:24])[N:19]([CH:28]4[CH2:29][CH2:30]4)[C:18]=3[CH:31]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)Cc1nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2n1C1CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NNC(=O)Cc1nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2n1C1CC1
Reaction time: 65 h

Procedure:
Ethyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]1-cyclopropyl-5-fluoro-2-benzimidazoleacetate (1.8 g, 4 mmol; from Example 2d) and tert.butyl carbazate (21 g, 16 mmol) are dissolved in pyridine (40 ml) and stirred at 115° under argon for 65 hours. The reaction solution is concentrated and triturated with 50 ml of ether. The separated product is filtered off under suction and dried. There is obtained tert-butyl 3-[[6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benzimidazolyl]acetyl]carbazate. Yield: 0.49 g (23%); m.p. 202°-203°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.C(N(C(C)C)CC)(C)C>C(O)C.[Pd]>[F:16][C:13]([F:14])([F:15])[C:4]1[N:3]=[CH:2][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1
Reaction time: 6 h
Yield: 97.7 %

Procedure:
To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (30.2 g, 119.0 mmol) in ethanol (594 mL) under nitrogen were added palladium (10% on carbon, 50% water wet; 2.58 g, 1.21 mmol) and diisopropylethylamine (50.0 mL, 286.0 mmol). The mixture stirred under hydrogen (1 atm). After 6 h, the mixture was filtered with Celite. The filtrate was concentrated and ethyl acetate was added. The mixture was washed with sat. NaHCO3 (2×), brine, dried over Na2SO4, filtered and concentrated to give the title compound (25.6 g). MS 221.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[NH:23][N:22]=2)=[N:4][C:5]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl>CO.[Pd]>[NH2:8][CH2:7][C:6]1[C:5]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH3:12])=[N:4][C:3]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:28])[CH3:29])[NH:23][N:22]=2)=[C:2]([F:1])[CH:9]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Reaction time: 6 h
Yield: 77 %

Procedure:
The mixture of (S)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Example 16; 0.90 g, 2.26 mmol), conc. HCl (0.3 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.55 g) in MeOH (20 ml) was flushed with N2, evacuated, and then placed under H2 (40 psi) for 6 hrs. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated. The resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml) and treated with a saturated aqueous Na2CO3 solution (100 ml). The mixture was shaken vigorously for 30 min and allowed to separate. The aqueous layer was extracted with DCM (3×100 ml). The combined organic layers were dried, filtered and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.7 g, 77%). 1H NMR (400 MHz, CD3OD) δ 7.45-7.41 (m, 2H), 7.35 (d, J=10.9 Hz, 1H), 7.03-6.99 (m, 2H), 5.35 (s, 1H), 5.09-5.04 (m, 1H), 4.55-4.49 (m, 1H), 4.18 (d, J=14.2 Hz, 1H), 4.08 (d, J=14.2 Hz, 1H), 1.59 (d, J=6.8 Hz, 3H), 1.31 (d, J=8.3 Hz, 6H). MS: Calcd.: 402. Found: [M+H]+ 403.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[CH2:7]=[C:8]1O[C:10](=[O:11])[CH2:9]1>>[C:4]([CH:3]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:7])[N:1]=[C:2]1[CH3:6])#[N:5]
Reactant: C=C1CC(=O)O1
Reactant: C/C(N)=C/C#N
Product: CC1=CC(=O)C(C#N)C(C)=N1

Procedure:
3-Cyano-2,6-dimethylpyrid-4-one was prepared from 3-aminocrotononitrile and diketene following the procedure of Kato et al (Yakugaku Zasshi 91, 740, 1971).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:4]=1[Br:11].[Al+3].[Cl-].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Br:11]
Reactant: COc1cccc(Br)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1cccc(Br)c1O
Yield: 7.2 %

Procedure:
To 2,3-dimethoxy-bromobenzene (8.2 g, 0.45 moles) in 50 mL of toluene was added AlCl3 (22.1 g, 0.178 moles). The reaction mixture was refluxed for 3 hours, cooled, poured into 800 mL of water, and extracted with 800 mL of ether. The ether extracts were dried over magnesium sulfate, filter and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluted with methylene chloride and the fraction were combined and evaporated under reduced pressure to yield 2,3-dihydroxy-bromobenzene (6.1 g, 73% yield).
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][C:17]2[C:20]([CH2:25]O)=[C:21]([Cl:24])[CH:22]=[CH:23][C:16]=2[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][C:17]2[C:20]([CH2:25][Cl:5])=[C:21]([Cl:24])[CH:22]=[CH:23][C:16]=2[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CO)c2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add methanesulfonyl chloride (1.1 g, 9.63 mmol; alternatively 2.36 g, 20.7 mmol) to 3-tert-butoxycarbonyl-7-chloro-6-hydroxymethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.5 g, 8.03 mmol; alternatively 3.2 g, 10.3 mmol) and triethylamine (2.2 mL, 16.06 mmol; alternatively 4.3 mL, 30.8 mmol) in DCM (50 mL; alternatively 60 mL) at 0° C. Warm the mixture to room temperature and stir for 1 h., alternatively for 16 h. Dilute the reaction with DCM and wash the organic phase with water. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to afford the title compound as a clear oil that was used immediately without any further purification. MS (ES+) m/z: 274 [M-(t-Bu)+H]+.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=1)(=O)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>COCCOC.C(Cl)Cl>[O:19]1[CH2:20][CH2:21][N:16]([C:5]2[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: COCCOC
Product: CCOC(=O)c1cnc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 108 %

Procedure:
A solution of sulfone 121 (0.184 g, 0.80 mmol) in ethyleneglycol dimethylether (5 mL) was treated with neat morpholine (0.3 mL, 3.4 mmol) and the mixture was stirred at room temperature for 48 h. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 in brine, dried over MgSO4, filtered, concentrated and stored under vacuum to give intermediate 122 (0.205 g, >99% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7](O)=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].[OH-].[K+]>O>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]=[C:7]1[CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: Nc1ccccc1N
Reactant: O=C(O)C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 190 °C
Yield: 99.4 %

Procedure:
A mixture of 4-piperidine carboxylic acid (5.30 g, 40 mmol), 1,2-diaminobenzene (4.32 g, 40 mmol) and polyphosphoric acid (40 g) were heated to 190° C. for 14 hours. Cooled, diluted with water (150 ml) and basified with 50% KOH to pH 8. Solution cooled in an ice/salt bath to give a precipitate which was collected by filtration and washed with water. Solid dried in vacuo to afford the title compound (8.0 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=1)(=[O:11])=[O:10]>CO.C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:11])=[O:10]
Reactant: Nc1ccc(OS(=O)(=O)c2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(OS(=O)(=O)c2c(Cl)cccc2Cl)cc1N
Yield: 49 %

Procedure:
To a solution of 2 g of 4-amino-3-nitrophenyl 2,6-dichlorobenzenesulfonate in 85 cm3 of methanol and 33 cm3 of pure acetic acid are added 2.25 g of iron powder. The reaction medium is refluxed for three hours. The insoluble material is filtered off and washed with three times 10 cm3 of preheated methanol. The filtrate is evaporated to dryness under reduced pressure (2 kPa) at a bath temperature of 50° C. The residue is taken up in 50 cm3 of water and then brought to pH 8-9 with sodium hydrogen carbonate and extracted with five times 80 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (98/2 by volume)], 900 mg of 3,4-diaminophenyl 2,6-dichlorobenzenesulfonate are obtained in the form of orange crystals, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCC1CC(c2ccc(Br)cc2)=NO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
[3-(4-Bromophenyl)-4,5-dihydroisoxazol-5-yl]methanol (4.44 g, 17 mmol) was dissolved in a mixture of triethylamine (2.9 ml, 19 mmol) and dichloromethane (100 ml). The resulting solution was cooled to 0° C., then a 1 M solution of tert-butyldimethylsilylchloride (19 ml) in dichloromethane was added dropwise over 5 minutes. 4-Dimethylamino pyridine (0.423 g, 3.4 mmol) was added and the reaction mixture left to stir overnight at room temperature. A second portion of tert-butyldimethylsilylchloride (19 ml) in dichloromethane and triethylamine (2.9 ml, 19 mmol) were added and the reaction mixture left to stir overnight at room temperature. The reaction mixture was concentrated in vacuo then redissolved in dichloromethane (200 ml) and washed with water (200 ml). The dichloromethane layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo onto silica gel (5 ml). This was then subjected to column chromatography (50 g silica gel bond elut: 0% to 50% ethyl acetate/hexanes) to yield 5.405 g (84%) of the desired compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24]OS(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:24][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Product: COC(=O)CCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxy carbonylbutyl)propanamide (152.5 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-methoxycarbonylbutyl)propanamide (32.4 mg) together with a less polar by-product. The by-product was not investigated further.