Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:24])[C:21]([CH3:23])=[CH2:22].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C=C(C)C(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reaction time: 8 h
Yield: 23.4 %

Procedure:
To a stirred solution of 7-amino-4-[(3-bromophenyl)amino]quinazoline (J Med Chem, 1995;38:3482) (150 mg, 0.48 mmol) in dry DMF (20 mL) was added methacrylic acid (200 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) (2.5 mol, 228 mg), the reaction mixture was stirred overnight then further amounts of EDCI.HCl (230 mg) and methacrylic acid (200 mg) were added. After a further 2 days stirring the solvent was removed under vacuum and the residue diluted with saturated NaHCO3, extracted with ethyl acetate (EtOAc) and then the combined organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure and chromatographed on silica gel eluting with MeOH/CH2Cl2/EtOAc (5:45:50) to MeOH/CH2Cl2/EtOAc (10:40:50) to give N-[4-[(3-bromophenyl)amino]quinazolin-7-yl]-2-methyl-acrylamide (43 mg, 24%) as a pale brown solid, np (CH2Cl2/hexane) 255-259° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH:5][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1cc(F)cc(Br)c1
Reactant: ClCCN1CCCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc(NCCN2CCCC2)c1
Yield: 50.5 %

Procedure:
A solution of 3-bromo-5-fluoroaniline (CAS 134168-97-1) (380 mg, 2.0 mmol) and 1-(2-chloroethyl)pyrrolidine (CAS 505041-9) (380 mg, 2.2 mmol) in NMP (20 mL) was heated to 120° C. overnight. The solution was diluted with EtOAc (100 mL) and washed with saturated Na2CO3 aqueous solution (3×40 mL). The combined organic layer were dried over Na2SO4, concentrated and purified by prep-TLC (DCM:MeOH=10:1) to give the titled product (290 mg, 50%). LCMS (0-60 AB), RT=1.076 min, M+H, 289.0
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([CH3:13])=O>C(O)C>[Br:1][C:2]1[N:7]2[CH:10]=[C:11]([CH3:13])[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2c(Br)cccc2n1
Yield: 82.3 %

Procedure:
6-Bromopyridin-2-amine (25.0 g, 144 mmol) and 1-chloroacetone (20.0 mL, 251 mmol) were dissolved in ethanol (300 mL) and the mixture was heated under reflux for 3 days. The precipitated solid was collected by filtration and dissolved in dichloromethane. The solution was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (25.0 g, yield 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19]([OH:21])=O)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.[N:29]1([O:38][C:39](N(C)C)=[N+](C)C)[C:33]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19]([N:29]([O:38][CH3:39])[CH3:33])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)c2ccccc12
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1nc(C)c2ccccc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
A mixture of 4-(3-fluorophenyl)-1-methylisoquinoline-3-carboxylic acid (400 mg, 1 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (700 mg, 1.8 mmol) and triethylamine (0.99 mL, 7.1 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (180 mg, 1.8 mmol) was added and the resulting suspension was stirred at room temperature for 2 hours. The mixture was quenched with water and then extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, concentrated and the residue purified on silica gel (eluting with 0-80% ethyl acetate in hexane) to give the desired product (0.257 g, 60%). LCMS calculated for C19H18FN2O2 (M+H)+: m/z=325.1; Found: 325.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:39][Cl:40]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:39][Cl:40])=[O:14])=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2)cc1
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(C(=O)OCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-methoxybenzyloxy) benzoic acid (5.16 g, 20 mmole) in 100 ml 1,4-dioxane was added a 40% solution of tetrabutylammonium hydroxide (14.27 g, 22 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 60 ml dichloromethane and iodochloromethane (35.3 g 200 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. About 100 ml ethyl actate was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 4.48 g=73%
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:8]=2)[NH:3]1.[O:15]=[C:16]1[C:21]2=[CH:22][NH:23][C:24]([CH:25]=O)=[C:20]2[CH2:19][CH2:18][O:17]1>>[O:1]=[C:2]1[C:10](=[CH:25][C:24]2[NH:23][CH:22]=[C:21]3[C:16](=[O:15])[O:17][CH2:18][CH2:19][C:20]=23)[C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2=Cc1[nH]cc2c1CCOC2=O

Procedure:
N-(2-Oxo-2,3-dihydro-1H-indol-6-yl)-acetamide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH:1]1([PH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH3:12].C([Li])CCC.CC1C=CC(S(O[CH:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)(=O)=O)=CC=1>>[CH:7]1([P:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:38]2[CH2:37][CH2:36][CH:35]([C:32]3[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=3)[CH2:40][CH2:39]2)[CH2:8][CH2:9][CH2:10][CH2:11]1.[BH3:12]
Reactant: C1CCC(PC2CCCC2)C1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccccc3)CC2)cc1
Agent: B
Agent: [Li]CCCC
Product: c1ccc(C2CCC(P(C3CCCC3)C3CCCC3)CC2)cc1

Procedure:
The product is made similarly to its analog in Example 1 from dicyclopentyl-phosphine-borane (10.6 g; 57.5 mmol.), n-butyl lithium (39.5 mL of 1.6 M solution; 63.3 mmol.) and 4-phenylcyclohexyl 4-methylbenzenesulfonate (22.8 g; 68.9 mmol.). Yield 14.5 g (74%). 31P{1H} NMR (δ, C6D6, ppm): 33.22 and 33.83 (broad); 1H NMR (δ, C6D6, ppm): 0.944 (m, 3H, BH3), 1.2-2.2 (m, 27H, cyclopentyl+cyclohexyl), 2.82 (m, 1H, PhCH), 7.0-7.25 (m, 5H, Ph).
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:13]O>>[NH2:1][CH2:2][C:3]([F:8])([F:7])[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: NCC(F)(F)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(F)(F)CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask, 3-amino-2,2-difluoropropanoic acid (500 mg, 4 mmol) was solubilized in MeOH (10 mL). At 0° C., SOCl2(1 mL) was added dropwise. The reaction mixture was then stirred at room temperature overnight. Evaporation of the reaction mixture gave methyl 3-amino-2,2-difluoropropanoate, as its HCL salt, as a white solid (570 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.63 (t, J=16 Hz, 2 H) 3.87 (s, 3 H) 9.07 (br. s., 2 H).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 40.6 mg (0.15 mmol) of 2-morpholin-4-yl-5-nitro-benzoyl chloride, 29 mg (0.18 mmol) 4-phenyl-1,2,3,6-tetrahydro-pyridine (commercial) and 62.5 ul (0.45 mmol) NEt3 in 1 ml DCM was stirred at room temperature for 16 h. After evaporation of the volatiles the residue was taken up in 1 ml CH3CN/DMF/HCOOH 3/5/2 and subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water gradient to yield after evaporation the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]23[O:20][CH2:19][CH2:18][O:17]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCCO
Reactant: O=C1Nc2ccc(C3CCCCC3)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2ccc(C3CCCCC3)cc2C12OCCO2

Procedure:
5-Cyclohexyl-1H-indole-2,3-dione (1 equivalent), ethane-1,2-diol (5 equivalents) and p-toluenesulphonic acid (0.02 equivalents) in dry toluene were heated under reflux overnight with azeotropic removal of water. The reaction mixture was cooled, washed with saturated sodium bicarbonate solution, and then worked up in the usual manner to afford the title compound.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:33])(=O)C.[S:34]1(=[O:40])(=[O:39])[CH2:38][CH2:37][CH2:36][NH:35]1>>[O:39]=[S:34]1(=[O:40])[CH2:38][CH2:37][CH2:36][N:35]1[C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:22][CH2:23]2)=[O:17])=[C:9]([N:6]2[CH2:7][CH2:8][NH:4][C:5]2=[O:33])[CH:14]=1
Reactant: O=S1(=O)CCCN1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)C1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCNC3=O)CC2)nc1C
Yield: 52.6 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (190 mg) described in Preparation Example 258 and isothiazolidine 1,1-dioxide (73 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (109 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1)(=[O:14])=[O:13])#[N:2]>CO.[NH4+].[OH-].[Ni]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([S:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]3[CH2:23][O:22][B:21]([OH:24])[C:20]=3[CH:25]=2)(=[O:13])=[O:14])=[C:3]([CH2:1][NH2:2])[CH:8]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzenesulfonamide (1.077 g, 3 mmol) in MeOH/NH4OH (100 ml/10 ml) was added Raney Ni (2 g) under nitrogen, then the solution was stirred under hydrogen atmosphere at room temperature for overnight. The mixture was filtered and the filtrate was concentrated to give title compound 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (1.0 g, 100%) as a green solid. 1H NMR: DMSO 400 MHz. δ7.41 (d, J=14.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.63 (s, 1H), 6.33 (d, J=8.4 Hz, 1H), 5.82 (brs, 2H), 4.84 (s, 2H), 3.95 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:34][Si](C)(C)C.CCOCC>CC(CC)=O>[ClH:34].[CH3:33][N:2]([CH3:1])[C:3]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCCCCc2c[nH]c3ccccc23)CC1
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexyl)-N-[5-(1H-indol-3-yl)pentyl]-acetamide (112 mg, 0.25 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.048 ml, 0.38 mmol) was added. After 1 h ether (15 ml) was added to the reaction mixture. The product was obtained as a pink-coloured solid in a yield of 90% (108 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.Br[C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:26]2[CH:27]=[CH:28][CH:29]=[CH:11][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)=[O:14])=[CH:3][CH:2]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1Br
Reactant: NCCc1ccncc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCCc1ccncc1
Temperature: 160 °C

Procedure:
4-Pyridineethanamine (Maybridge Chemical Co, Cornwall, England; 0.31 g , 2.5 mmol) is added to a stirred mixture of 2-bromo-N-[3-(trifluoromethyl)phenyl]benzamide (intermediate 1x; 1.72 g, 5 mmol), powdered potassium carbonate (0.35 g, 2.5 mmol) and copper(1)iodide (Fluka, Buchs, Switzerland; 0.48 g, 2.5 mmol) in dimethylformamide (10 mL). The resulting mixture is then purged with argon and subsequently heated at 160° C. under an argon atmosphere for 15 hours. The mixture is cooled, treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washesdwith an aqueous solution of ammonia (2-10%), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 50% ethyl acetate in hexane and recrystallised from ethyl acetate-hexane to give the title compound as a colourless crystalline solid, m.p. 151-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])=[C:4]([N:13]=O)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1>[NH2:13][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N:8]([CH3:12])[CH2:9][CH2:10][OH:11]
Reactant: CN(CCO)c1ccc(Br)cc1N=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCO)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
2-((4-bromo-2-nitrosophenyl)(methyl)amino)ethanol (6.5 g, 0.025 mol) was dissolved in THF (100 ml), Sodium hydrosulfite (26.2 g, 0.15 mol in water 150 mL) was added. The reaction was stirred at rt for 1 h. The mixture was extracted with EtOAc (2×100 ml). The combined organic layers was concentrated and purified by flash chromatography eluted with EtOAc to give 3.1 g, (50.3%) of 2-((2-amino-4-bromophenyl)(methyl)amino)ethanol LCMS-ESI+ (m/z): [M+H]+ calcd for C9H13BrN2O4:244.03; found 244.96, 246.91.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:19]3[N:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:22][CH:21]=4)[CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([O:35]C)[CH:15]=4)[C:10]=3[CH:9]=[CH:8][C:7]=2[CH:37]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:19]3[N:18]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]5)=[CH:24][CH:25]=4)[CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([OH:35])[CH:15]=4)[C:10]=3[CH:9]=[CH:8][C:7]=2[CH:37]=1
Reactant: COc1ccc2c(c1)CN(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(OC)ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: Oc1ccc2c(c1)CN(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
A solution of the product of Example 13 (195 mg, 0.39 mmol) in methylene chloride (25 mL) was treated with ethanethiol (200 mg, 220 mL, 3.2 mmol) and aluminum chloride (320 mg, 2.4 mmol). After stirring for 4 h at ambient temperature, the mixture was quenched carefully with THF (25 mL) and saturated sodium bicarbonate (25 mL). The layers were separated, the aqueous layer was extracted with THF (25 mL), and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by radial chromatography (silica gel, 1:1 hexane:ethyl acetate, 10-20% methanol, under an ammonia atmosphere) to provide 110 mg (60%) of the title compound as a tan foam. An analytical sample was crystallized from methanol as a light red solid: 1H NMR (300 MHz, dimethylformamide-d7) d 9.92 (br s, 1H), 9.74 (br s, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.98 (dd, J=9.0, 2.1 Hz, 1H), 6.84 (dd, J=8.4, 2.1 Hz, 1H), 6.73 (m, 5H), 3.92 (t, J=5.9 Hz, 2H), 2.57 (t, J=5.9 Hz, 2H), 2.38 (m, 4H), 1.4-1.5 (m, 4H), 1.3-1.4 (m, 2H); IR (KBr) 3560, 3490 cm-1 ; MS (FD+) m/e 466 (M+); Anal. calc'd. for C30H30N2O3.0.5H2O: C, 75.75; H, 6.58; N, 5.89. Found: C, 75.32; H, 6.76; N, 5.95.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+:19]([C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([N+]([O-])=O)[C:23]=1[C:24]#[N:25])([O-:21])=[O:20]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:26]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[C:23]=2[C:24]#[N:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2cccc([N+](=O)[O-])c2C#N)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a suspension of tert-butyl-4-(2-hydroxyethyl)piperidine-1-carboxylate (769 μL, 3.50 mmol) and NaH (118 mg, 3.50 mmol, 60% dispersion in mineral oil) in dry DMF (5 mL) at 0° C., was added a solution of 2,6-dinitrobenzonitrile (614 mg, 3.18 mmol) in dry DMF (4 mL). The reaction was stirred under N2, warming to rt. Upon completion, the reaction was quenched with H2O (50 mL), and the precipitate was collected by vacuum filtration to provide tert-butyl-4-(2-(2-cyano-3-nitrophenoxy)ethyl)piperidine-1-carboxylate (955 mg, 80%) as a tan solid 1H NMR (400 MHz, CDCl3) δ 1.09 (m, 2H), 1.40 (s, 9H), 1.73 (m, 5H), 2.70 (m, 2H), 3.94 (m, 2H), 4.32 (t, J=6.8 Hz, 2H), 7.75 (m, 1H), 7.92 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[C:14]([CH:20]=O)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:12][C:13]1[C:14]([CH2:20][NH:11][C@H:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: N[C@@H]1CCCc2cccnc21
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN[C@@H]2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of (R)-5,6,7,8-tetrahydro-quinolin-8-ylamine in CH2Cl2 (4 ml) with 3,5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave (R)-(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine as a brown oil. 1H NMR (CDCl3) δ 1.78 (m, 1H), 2.03 (m, 1H), 2.10 (m, 1H), 2.26 (s+m, 4H), 2.33 (s, 3H), 2.81 (m, 2H), 3.96 (t, 1H, J=6.0 Hz), 4.02 (d, 1H, J=12.0 Hz), 4.17 (d, 1H, J=12.0 Hz), 5.41 (br s, 2H), 7.06 (dd, 1H, J=7.5, 3.0 Hz), 7.25 (s, 1H), 7.37 (d, 1H, J=9.0 Hz), 8.24 (s, 1H), 8.40 (d, 1H, J=3.0 Hz).
Reaction SMILES: [NH2:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[S:7][C:8]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)=[O:4].[CH3:26][C:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([C:8]2[S:7][C:6]([NH:5][C:3]([C:2]([NH:1][C:30]([C:27]3([CH3:26])[CH2:29][CH2:28]3)=[O:31])([CH3:25])[CH3:24])=[O:4])=[N:10][C:9]=2[C:11]([F:13])([F:14])[F:12])=[O:23])=[CH:17][CH:18]=1
Reactant: CC1(C(=O)O)CC1
Reactant: CC(C)(N)C(=O)Nc1nc(C(F)(F)F)c(C(=O)c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC1(C(=O)NC(C)(C)C(=O)Nc2nc(C(F)(F)F)c(C(=O)c3ccc(F)cc3)s2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-Amino-N-[5-(4-fluoro-benzoyl)-4-trifluoromethyl-thiazol-2-yl]-2-methyl-propionamide (150 mg, 0.400 mmol), 1-methylcyclopropyl carboxylic acid (80 mg, 0.80 mmol), triethylamine (140 uL, 1.00 mmol) and HBTU (300 mg, 0.809 mmol) was stirred at RT for 18 h, partitioned between ethyl acetate and, sequentially, 3 M HCl and aqueous KOH. The organic extract was dried over MgSO4, concentrated and purified by HPLC to give the title compound. m/z 458.3 (MH+). 1H NMR (CDCl3) δ 7.91 (dd, J=8, 4 Hz, 2H), 7.16 (t, J=8 Hz, 2H), 6.04 (br s, 1H), 1.63 (s, 6H), 1.38 (s, 3H), 1.30-1.25 (m, 2H), 0.70-0.65 (m, 2H), retention time 1.42 min (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:5]=[N:6][CH:7]=1.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.C(OCC)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:18]([O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[N:17][C:9]=1[O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cccnc1Oc1cncc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)c1cccnc1Oc1cncc(Cl)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A 15 ml flask was charged with 2-(5-chloro-pyridin-3-yloxy)-nicotinic acid (0.056 grams, 0.22 mmole), benzyl alcohol (0.052 grams, 0.44 mmole), 4-DMAP (˜3 mg), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.048 grams, 0.25 mmole), diethyl ether (4 ml) and pyridine (1 ml) and stirred at room temperature. After 1 hour the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 9/1 ethyl acetate/hexane to give 0.060 g of the title compound as a colorless oil. Anal. calcd. for C18H13ClN2O3: M.S. m/z [M+] 341; 1H NMR (CD3OD) d 4.58 (s, 2H), 7.45(m, 7H), 7.71 (s, 1H), 8.28 (m, 2H), 8.38 (m, 2H).