Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[N:11](C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=3)[N:4]2[N:3]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:9]1[N:4]2[N:3]=[C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc2nc(N)nn12
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1nc2cccc(-c3ccc[nH]3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure and work up described for example 9, but starting from tert-butyl 2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate ((A6), 50 mg; 0.17 mmol; 1.0 eq.) and benzoyl chloride (47 mg; 0.33 mmol; 2.0 eq.) as a white solid (22.7 mg, 45%). HPLC, Rt: 3.23 min. (purity 91.6%). LC/MS, M+(ESI): 304.3, M−(ESI): 302.3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][OH:12])[C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[C:4]=2[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc2c1CCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc2c1CCO2

Procedure:
A solution of 2-(2,3-dihydrobenzofuran-4-yl)-ethanol (1.13 g) in dichloromethane (11 ml) was treated with triethylamine (1.25 ml), followed by methanesulfonyl chloride (0.64 ml). After 5 min the reaction mixture was poured into 2M hydrochloric acid (10 ml) and extracted with dichloromethane (2×10 ml). The combined extracts were washed with water (10 ml), dried (Na2SO4) and the solvent evaporated to give the title compound (1.76 g) as a yellow oil.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([O:6][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21])=[O:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72634728 %

Procedure:
A mixture of N-Boc-β-Ala-OH (1 g, 5.29 nmol), N-hydroxysuccinimide (0.9 g, 7.82 mmol) in DMF (10 mL) were added HOBt (0.7 g, 5.25 mmol) and EDCI.HCl (1 g, 5.23 mmol) at 5° C. The reaction mixture was warmed to RT and stirred for 16 h. The progress of the reaction was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (3×100 mL), brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was triturated with ether (2×25 mL) to afford N-Boc-β-Ala-OSu (1.1 g, crude) as white solid. 1H NMR (500 MHz, CDCl3): δ 5.10 (bs, 1H), 3.52 (q, J=6.0 Hz, 2H), 2.85-2.82 (m, 6H), 1.31 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].FC(F)(F)C[O:24][C:25](=O)[NH:26][C:27]1[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:32]([C:30]1[CH:31]=[C:27]([NH:26][C:25]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[O:24])[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1noc2cc(Oc3ccc(F)cc3CN)ccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(C)noc3c2)cc1
Temperature: 75 °C
Yield: 77.5 %

Procedure:
5-Fluoro-2-(3-methyl-benzo[d]isoxazol-6-yloxy)-benzylamine (9v) (60 mg, 0.22 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trifluoro-ethyl ester (12v) (89 mg, 0.22 mmol) and diisopropylethylamine (0.058 mL, 0.33 mmol) were combined in DMF (2 mL) and heated at 75° C. for 3 hours. The reaction was cooled and concentrated in vacuo and purified by column chromatography (silica, 30 to 40% EtOAc/hexanes) to provide compound (10v) (90 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 7.02-6.88 (m, 5H), 6.15 (s, 1H), 5.99 (s, 1H), 5.28 (t, J=7.6 Hz, 1H), 4.36 (d, J=5.5 Hz, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 1.31 (s, 9H); MS (ESI+) m/z 528 (M+H) detected; HPLC (5 to 95%) 3.49 min.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1([C:25]([OH:27])=O)[CH2:24][CH2:23]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[NH2:28][NH2:29].O>C1COCC1>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][C:22]1([C:25]([NH:28][NH2:29])=[O:27])[CH2:24][CH2:23]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(C(=O)NN)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
CDI (12.5 g, 0.077 mol) was added to a 0° C. solution of 1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acid (15.0 g, 0.07 mol) in THF (250 mL). The mixture was allowed to warm to rt, and stirred at rt. for 2 hrs, and then NH2NH2.H2O (10.5 g, 0.21 mol) was added rapidly. The mixture was stirred for another 1 hr. The reaction mixture was concentrated, and then CH2Cl2 (500 mL) was added. The combined organic layer was washed with H2O (100 mL), dried over Na2SO4, and concentrated to afford tert-butyl(1-(hydrazinecarbonyl)cyclopropyl)methylcarbamate (13.5 g, 84%). ESI-MS (EI+, m/z): 230.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CCNC1CCCC1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A solution of 2.2 g (0.011 mole) of (rac)-3-(2-methyl-cyclopentylamino)-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-92:8) gave 3.3 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-57).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5](C(O)C(O)=O)=[CH:4][CH:3]=1.CN(C(C1C=CC=CC=1)C#N)C.[OH:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30](O)[C:31]#[N:32])=[CH:28][CH:27]=1.C1(O)C=CC=CC=1.S(=O)(=O)(O)O>>[OH:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]([C:5]2[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=2)[C:31]#[N:32])=[CH:28][CH:27]=1
Reactant: N#CC(O)c1ccc(O)cc1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Agent: CN(C)C(C#N)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: Oc1ccccc1
Product: N#CC(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
The afore-mentioned process can not advantageously be employed to prepare cyanobisphenols wherein R1 is hydrogen. When R1 and all R2 are hydrogen, the following procedure is effective to prepare the cyanobisphenol. 4-Hydroxybenzaldehyde is reacted with sodium cyanide in the presence of sodium bisulfite to yield 4-hydroxymandelonitrile, a cyanohydrin which has the following formula. ##STR13## The reaction and conditions are described in Landenberg et al., "Synthesis of 3-Hydroxy-2(3)-Benzofuranone and of 4-Hydroxymandelic Acid", 58 J. Amer Chem Soc. 1292 (1936) and in Taylor, et al, "a-N,N-Dimethylaminophenylacetonitrile", 5 Organic Synthesis 437 (1962). 4-Hydroxymandelonitrile is then reacted with excess phenol in the presence of sulfuric acid at a temperature of about 55° C. to 60° C. to yield bis-(4-hydroxyphenyl)acetonitrile: ##STR14## A description of the reaction and its conditions is found in Schraufstatter, "Darstellung und Reaktionen von 4,4'-Dihydroxydiphenylacetonitril", 295 Arch. Pharm. 269 (1962).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][N:9]([CH2:11][CH2:12][CH2:13][C:14]1([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[O:22][CH2:21][C:20]2[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=[CH:16][C:15]1=2)C.CC(Cl)OC(Cl)=O.C(N(C(C)C)CC)(C)C>CO>[CH3:8][NH:9][CH2:11][CH2:12][CH2:13][C@:14]1([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[O:22][CH2:21][C:20]2[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=[CH:16][C:15]1=2
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNCCC[C@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 12.5 °C
Reaction time: 0.5 h

Procedure:
The toluene solution containing citalopram base was mixed with 1,2-dichloromethane (400 lit) and cooled to 10-15° C. A solution of 1-chloro ethyl chloroformate (110.8 Kg, 0.77 kmoles) was added to the reaction mass below 20° C. The reaction mass was further stirred for 30 minutes at 15-20° C. Diisopropylethyl amine (30.24 Kg, 0.23 kmoles) was added to the reaction mixture below 20° C. and further stirred for 30 minutes. The temperature of the reaction mass was raised to 60-65° C. and maintained for 2-3 hrs. The reaction mass was diluted with methanol (320 lit) at 60-65° C., heated further for 2-4 hrs at 60-65° C. and evaporated. The reaction mass was cooled to 25-30° C., diluted with water (480 lit) and stirred for 30 minutes. The phases were separated, aqueous layer was extracted with toluene (2×200 lit) and pH of the aqueous layer was adjusted to 9-10 with ammonia solution (320 lit). Toluene (400 lit) was added and the reaction mass stirred for 30 minutes. The organic layer was separated. Aqueous layer was extracted with toluene (2×200 lit). The combined toluene layer was washed with water, followed by brine. The toluene layer was dried on sodium sulphate, filtered and stirred with charcoal (15 Kg). The reaction mass was filtered and evaporated under reduced pressure to afford the title compound. Yield—140 Kg, 91.5%
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([CH:16]=[N:17][OH:18])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][C:25]#[CH:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][C:25]1[O:18][N:17]=[C:16]([CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:19])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:26]=1
Reactant: CC(C)CC(C=NO)NC(=O)OCc1ccccc1
Reactant: C#CCCC(=O)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCc1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Yield: 29.4 %

Procedure:
To a stirred solution of [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid benzyl ester (6.0 g, 22.7 mmol) and pent-4-ynoic acid methyl ester (3.8 g, 34 mmol) in CH2Cl2 (80 ml) was added triethylamine (0.2 ml) followed by Clorox bleach (80 ml). After 4 h at room temperature the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (25 ml×3). The combined organics were dried over MgSO4; filtered and concentrated under reduced pressure to give a yellow oil. Purification by Flash 40 chromatography using a silica gel column and eluting with 10-20% EtOAc/hexane gave 2.5 g of the title compound as a waxy pale yellow solid. MS [M+1]+375.3; 1H nmr (400 MHz, CDCl3) δ0.91 (m, 6H), 1.51-1.76 (m, 3H), 2.67 (t, J=7.5 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 3.67 (s, 3H), 4.89 (m,1H), 5.08 (m, 3H), 5.92 (s, 1H), 7.31 (m, 5H).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=2)[CH2:9][CH2:8]1>O1CCCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:18]2[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=[C:14]2[NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][N:4]=[C:1]=[S:3])[CH2:8][CH2:9]2)=[CH:21][CH:22]=1
Reactant: S=C=S
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (below 10° C.) mixture of 5.04 parts of carbon disulfide, 2.06 parts of N,N'-methanetetraylbis[cyclohexamine] and 45 parts of tetrahydrofuran is added dropwise a solution of 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine in tetrahydrofuran. Upon completion, stirring is continued overnight while the mixture is allowed to reach room temperature. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4 parts (100%) of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12](=[O:15])[CH2:13]Br)[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: O=C(CBr)Nc1cc(Cl)ccc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNc1ccccc1)Nc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
A solution of 4-chloro-2-(bromoacetamido)benzoic acid from Example 40 (6.5 g, 0.02 mol), aniline (5.2 mL, 250 mol %) and anhydrous DMF (50 mL) was heated to 100-105° C. for 4 h, and stirred at rt for 20 h. The reaction mixture was poured into ice-water (400 mL) and the precipitated product was solubilized by adding aqueous 5% KOH (60 mL). The resulting milky homogenous solution was extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were set aside and the aqueous layer was acidified with aqueous 5% HBr to pH=3. The resulting oil was extracted into EtOAc (3×100 mL) and the combined extract was washed with brine, dried, filtered and concentrated. Trituration of the resulting solid with diethyl ether afforded 4.5 g (66%) of the crude title compound as light-beige crystals, mp 177.8-180° C. The crude compound (4.5 g) was stirred with EtOAc (~100 mL) and the resulting insoluble portion was filtered off. The filtrate was concentrated to a light-beige solid which was refluxed with benzene (80 mL) for 40 min. The bnenzene mixture was filtered while hot and the filtered solid was dried for 4 h under high vacuum, yielding 2.75 g (40%) of the title compound as light crystals, mp 229-230° C. (became "wet" at 227° C.); 1H NMR (DMSO-d6) δ 13.6 (bs, 1H), 12.11 (s, 1H), 8.82 (d, J=1.6, 1H), 7.93 (d, J=8.8, 1H), 720 (dd, J=6.0, J=2.6, 1H), 7.10 (t, J=7.6, 2H) 6.63-6.58 (m, 4H), 3.85 (s, 2H); 13C NMR (DMSO-d6) δ 171.48, 168.31, 148.01, 141.53, 138.58, 132.86, 128.97, 128.30, 122.61, 118.72, 118.67, 117.16, 114.68, 112.45, 48.89.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[C:28]([O:41][CH3:42])=[C:29]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30](N)=[CH:31][CH:32]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[C:28]([O:41][CH3:42])=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: COc1c(F)ccc(N)c1Nc1ccccc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (779 mg, 4.1 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (671 mg, 3.5 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (5 mL). 4-Fluoro-3-methoxy-N2-phenylbenzene-1,2-diamine (283 mg, 1.2 mmol) was added and the reaction heated at 70° C. for 1.5 hours. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (349 mg, 74%). LCMS (Method C): RT=3.52 min, [M+H]+=386.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc(COCCCCCBr)cc1OC
Agent: Cl
Product: COc1ccc(COCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(3,4-dimethoxybenzyloxy)-pentyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(3,4-dimethoxybenzyloxy)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>CN1C(=O)CCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:2]3=[N:9][CH:8]=[CH:7][C:6]([I:10])=[C:3]3[CH:4]=[N:19]2)=[CH:14][CH:13]=1
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1ccc(F)cc1
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(I)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a dry 16×100 mm CHEMGLASS® reaction tube under N2 was added 2-fluoro-4-iodonicotinaldehyde (600 mg, 2.390 mmol), (4-fluorophenyl)hydrazine (332 mg, 2.63 mmol), and anhydrous NMP (3.2 mL). The reaction mixture was flushed with argon, securely capped, stirred for 20 min at room temperature, and then placed in a 185° C. oil bath for 2 h. The reaction mixture was then allowed to stir at room temperature for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and the organic layer was extracted with water (5×50 mL), brine (1×50 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by BIOTAGE® Silica gel chromatography on a 90 g Thompson Single Step silica cartridge using a linear gradient from 100% hexanes to 100% dichloromethane over 12 column volumes to give 480 mg (59.2%) of the title compound, Intermediate 1A, as an off white solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.22-8.28 (3 H, m), 8.15 (1 H, s), 7.78 (1 H, d, J=4.88 Hz), 7.25-7.37 (2 H, m). LC/MS (Condition A): 100% purity; ret. T=2.9 min, (M+H)+ 339.97.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:36].CO>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: CO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 90 °C

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (196 mg, 0.364 mmol) and ammonia in methanol 7M (8 ml, 56.0 mmol) and heating to 90° C. for 24 h, the title compound, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide was obtained (94 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 7.93 (d, J=5.2 Hz, 1H), 7.55-7.70 (m, 1H), 7.35-7.43 (m, 1H), 7.31 (t, J=6.3 Hz, 1H), 7.14-7.27 (m, 3H), 6.70 (s, 2H), 5.79 (d, J=5.13 Hz, 1H), 1.35 (s, 9H). MS (ESI): 519.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].O>C(OCC)C>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[N:3]=1
Reactant: CCNCC
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CCOCC
Solvent: O
Product: CCN(CC)c1nc(Cl)c(C#N)c(Cl)n1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A stirred solution of 6.3 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 150 ml of diethyl ether was cooled to -10°, and a solution of 4.4 grams of diethylamine in 75 ml of diethyl ether was added dropwise. Upon complete addition, the reaction mixture was stirred at -10° for 1 hour. Water was added to the reaction mixture. The diethyl ether layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure to a residue. The residue was recrystallized from methylcyclohexane to give 3.8 grams of 4,6-dichloro-2-diethylamino-5-pyrimidinecarbonitrile; mp, 125°-126°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH2:18][OH:19].C(O)(=O)C.[BH3-]C#N.[Na+]>C1(C)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=2[CH2:18][OH:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1CO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2CO)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1-(tert-butyloxycarbonyl)-4-piperidinone (20 g, 0.10 mol), 2-amino-5-chlorobenzyl alcohol (17.34 g, 0.11 mol) and acetic acid (14 mL, 0.22 mol) in dry toluene (500 mL) was heated at reflux temperature, with water elimination by means of azeotrope distillation with a Dean-Stark device, for 6 hours. The mixture was then cooled and vacuum concentrated up to half volume. NaBH3CN (20 g, 0.32 mol) and dry THF (300 mL) were added to the resulting solution. Acetic acid (10 mL, 0.17 mol) was then dripped for one hour. The reaction was stirred at room temperature for 24 hours. The mixture was vacuum concentrated and the residue was dissolved in ethyl acetate (750 mL), washed with a NaHCO3-saturated solution (4×250 mL) and a NaCl-saturated solution (250 mL), dried and evaporated to dryness. The residue was purified by means of flash chromatography eluting with a mixture of ethyl acetate:petroleum ether (1:3). The desired product was thus obtained as an oil (32.7 g, 96%).