Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:15])[CH2:10][CH2:11][CH2:12][NH:13][CH3:14].O1CCCC1.[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[N:26][C:27]=1[Cl:28]>O>[Cl:21][C:22]1[CH:23]=[C:24]([S:29]([N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH3:15])[CH3:8])[CH3:14])(=[O:31])=[O:30])[CH:25]=[N:26][C:27]=1[Cl:28]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Cl)c1
Reactant: CNCCCN(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)CCCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
With cooling with ice, triethylamine (0.57 ml, 4.06 mmol) and N,N,N′-trimethylpropane-1,3-diamine (0.34 ml, 2.23 mmol) were added to a tetrahydrofuran solution (5 ml) of 5,6-dichloropyridin-3-sulfonyl chloride (500 mg, 2.03 mmol), and stirred for 5 minutes. Saturated saline water was added to the reaction solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=6:1 to 4:1) to obtain 5,6-dichloro-N-[3-(dimethylamino)propyl]-N-methylpyridine-3-sulfonamide (454 mg, yield: 69%) as a red solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C@@H:17]([NH2:24])[C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:29][C:28]=1[C:43](O)=[O:44]>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C@@H:17]([NH:24][C:43]([C:28]3[CH:29]=[C:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:35][CH:34]=4)[CH:31]=[CH:32][C:27]=3[O:26][CH3:25])=[O:44])[C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Reactant: Cc1noc([C@H](N)Cc2cccc(-c3ccc(F)c(Cl)c3)c2)n1
Agent: Cl
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1cccc(-c2ccc(F)c(Cl)c2)c1)c1nc(C)no1
Yield: 63 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.073 g) was prepared from 2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride salt [0.07 g, 0.19 mmol, prepared from [2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butylester following general procedure N] and 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.056 g, 0.19 mmol) following general procedure A.
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11](=[O:30])[NH:12][C:13]1([C:16](=[O:29])[NH:17][C:18]2([C:21]3[CH:26]=[C:25]([CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=3)[CH2:20][CH2:19]2)[CH2:15][CH2:14]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35]Br.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.CC#N.O>[CH2:3]([O:10][C:11](=[O:30])[NH:12][C:13]1([C:16](=[O:29])[NH:17][C:18]2([C:21]3[CH:26]=[C:25]([CH2:27][N:28]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:20]2)[CH2:14][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCc1ccnc(C2(NC(=O)C3(NC(=O)OCc4ccccc4)CC3)CC2)c1
Reactant: BrCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: O=C(NC1(C(=O)NC2(c3cc(CN4CCCC4)ccn3)CC2)CC1)OCc1ccccc1
Temperature: 80 °C
Yield: 35 %

Procedure:
{1-[1-(4-Aminomethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid benzyl ester dihydrochloride (200 mg, 0.441 mmol) was dissolved in dry DMA (5 mL). 1,4-Dibromobutane (0.264 mL, 2.206 mmol) was added followed by Na2CO3 (0.234 g, 2.206 mmol). The reaction mixture was heated at 80° C. in a microwave reactor for 20 min. The reaction mixture was diluted with MeCN (4 mL) and water (1 mL) and filtered. The resultant crude product was purified by mass triggered LCMS using 5-35% MeCN/water as the gradient to afford 67 mg of {1-[1-(4-Pyrrolidin-1-ylmethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid benzyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Br)c2)CC1
Temperature: 65 °C
Yield: 85 %

Procedure:
The mixture of 3-bromophenol (2.0 g, 11.56 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.87 g, 13.872 mmol) and caesium carbonate (11.27 g, 34.68 mmol) in DMF (25 ml) was heated at 65° C. for 14 hours. Cooled to RT and diluted with ether. Ether layer was washed with water and brine, dried over sodium sulphate and distilled off the solvent to afford 3.5 g (85.3% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 5% ethyl acetate in hexane as eluent. MS: m/z=356.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][CH2:11]2)[C:6]1=[O:17].C(N(CC)CC)C.FC(F)(F)S(O[Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])(=O)=O>ClCCl>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([O:16][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:14][CH2:15]2)[C:6]1=[O:17]
Reactant: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Dissolve 3-(2,4-dichloro-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (0.5 g, 1.46 mmol) in dichloromethane (15 mL), cool to 0° C., and add triethylamine (0.26 mL, 1.90 mmol) and t-butyldimethylsilyl trifluoromethanesulfonate (0.40 mL, 1.75 mmol). After 16 h, wash the mixture with 1 N HCl, saturated aqueous NaHCO3 and brine, dry over Na2SO4 and evaporate the solvent. Purify the residue by column chromatography on silica gel (eluting 0% to 40% ethyl acetate in hexanes) to give the desired intermediate (0.54 g, 81%).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][CH2:4]2.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](O)=[O:22])=[N:13]1>>[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([NH:1][CH2:2][C:3]23[CH2:10][CH2:9][CH2:8][N:7]2[CH2:6][CH2:5][CH2:4]3)=[O:22])=[N:13]1
Reactant: NCC12CCCN1CCC2
Reactant: Cn1nc(C(=O)O)c2ccccc21
Product: Cn1nc(C(=O)NCC23CCCN2CCC3)c2ccccc21

Procedure:
Following the procedure of example 1, 7a-Aminomethylhexahydro-1H-pyrrolizine is reacted with N-methylindazole-3-carboxylic acid [J. Medicinal Chemistry (1987) 30: 1535] to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:26][NH:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][N:27]([CH3:26])[C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:24]
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CNCCO
Product: CN(CCO)C(=O)c1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-methylamino-ethanol.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].[C:13]([O:17][C:18](=[O:23])[NH:19][CH2:20][CH2:21]Br)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18](=[O:23])[NH:19][CH2:20][CH2:21][N:3]1[C:2]([Br:1])=[C:6]([N+:7]([O-:9])=[O:8])[C:5]([Br:10])=[N:4]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 14.7 %

Procedure:
A solution of 3,5-dibromo-4-nitropyrazole (2) (16.0 g, 59 mmol) in DMF (130 ml) was added dropwise over 20 min to a stirred solution of NaH (2.6 g, 65 mmol; 60% dispersion in oil washed beforehand with hexane under an inert atmosphere) in DMF (80 ml). After stirring for 10 min, a solution of (2-bromoethyl)carbamic acid tert-butyl ester (19.85 g, 88.5 mmol; obtained by reaction of 2-bromoethylamine with di(tert-butyl)dicarabonate) in DMF (35 ml) was added dropwise over 10 min. The reaction mixture was heated at 80° C. for 3 h and then the DMF was evaporated under reduced pressure. A mixture of DCM/water (200 ml, 1/1) was added to the residue and the organic phase was washed with water (100 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The [2-(3,5-dibromo-4-nitropyrazol-1-yl)ethyl]carbamic acid tert-butyl ester (3.6 g, 15%) was obtained in the form of a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=1>C(O)C.[C].[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(N)cc1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
Ethyl(2E)-3-(4-amino-2-fluorophenyl)acrylate (12.4 g, 59.3 mmol) was dissolved in ethanol (120 mL), and 10% palladium-carbon (50% water-containing product, 4.0 g) was added. The mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-50% ethyl acetate/hexane) to give the title compound (9.89 g, yield 79%) as a pale-brown oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C(N[CH2:15][CH3:16])C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C1COCC1>[CH3:17][Si:18]([C:21]#[C:22][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:16]#[C:15][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: Brc1ccc(Br)c2nsnc12
Reactant: C#C[Si](C)(C)C
Reactant: CCNCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C#C[Si](C)(C)C)c2nsnc12
Temperature: 45 °C
Reaction time: 20 h

Procedure:
4,7-Dibromobenzo[c][1,2,5]thiadiazole (1.02 g, 3.47×10−3 mol), Pd(PPh3)4 (0.207 g, 1.79×10−4 mol), CuI (0.029 g, 1.5×10−4 mol), THF (30 ml), diethylamine (3.0 ml) and (trimethylsilyl)acetylene (6.00 ml, 4.25×10−2 mol) were added to a 100-ml Schlenk tube. N2 was bubbled through the mixture for 5 min, following which the reaction was stirred at 45° C. for 20 h under N2. After cooling, the solvent was evaporated and the residue was chromatographed on silica gel with 1:1 hexanes:CHCl3 as the eluant. Yield=1.05 g (92% based on 1.02 g of 4,7-dibromobenzothiadiazole). 1H NMR (360 MHz, CDCl3): δ 7.70 (s, 2H, Ph-H), 0.33 (s, 18H, —Si—CH3). Chemical Ionization MS m/z: 328.0880 (M+) (calcd 328.089).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])(C)C)=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)[F:35])=O.C(N(C(C)C)CC)(C)C.ClC(OCCF)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH2:31][F:35])=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Cl)OCCF
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OCCF)CC3)cn2)cc1

Procedure:
The title compound (0.105 g, 90%) was prepared as a white solid from 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.12 g, 0.27 mmol) and TFA (0.20 mL) in CH2Cl2 (6 mL) then diisopropylethylamine (1.2 mL) and 2-fluoroethyl chloroformate (42 μL, 0.32 mmol) in a manner similar to Example 74. The crude material was purified by chromatography on a silica gel column eluted with 1:7 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.7 Hz), 8.13 (d, 2H, J=8.3 Hz), 8.00 (d, 2H, J=8.5 Hz), 7.73 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H, 4.70-4.55 (m, 2H), 4.40-4.15 (m, 4H), 3.91 (d, 2H, J=6.4 Hz), 3.06 (s, 3H), 2.84 (bs, 2H), 2.10-1.95 (m, 1H), 1.95-1.80 (m, 2H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 437 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:22]C(=O)C(F)(F)F)[CH3:2].[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH2:22])[CH3:2]
Reactant: CCOc1cc(C2CCN(CCS(C)(=O)=O)CC2)ccc1NC(=O)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C2CCN(CCS(C)(=O)=O)CC2)ccc1N
Yield: 93.9 %

Procedure:
To N-(2-(ethyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}phenyl)-2,2,2-trifluoroacetamide (1.4 g, 3.3 mmol) in THF (25 mL) and H2O (25 mL) was added LiOH (0.21 g, 5.0 mmol). The mixture was stirred for two h and then more LiOH (0.21 g, 5.0 mmol) was added. After stirring for one h, the product was extracted with EtOAc. The organic layer was dried (MgSO4), filtered and rotovaped to provided the title compound of step G as a colorless oil (1.0 g, 3.1 mmol, 94%). 1H NMR (400 MHz, DMSO-d6) δ 6.66-6.56 (m, 3H), 4.02 (q, J=7.0 Hz, 2H), 3.15 (t, J=6.6 Hz, 2H), 3.03 (s, 3H), 2.99 (d, J=11.5 Hz, 2H), 2.88 (t, J=6.6 Hz, 2H), 2.42-2.32 (m, 1H), 2.13 (dd, J=11.9, 11.7 Hz, 2H), 1.82 (d, J=13.0 Hz, 2H), 1.70-1.58 (m, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.ON1C2C=CC=CC=2N=N1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:26]([CH:29]=1)[C:27]#[N:28]>C(O)C>[C:27]([C:26]1[CH:29]=[C:22]([NH:21][C:8]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])=[O:10])[CH:23]=[CH:24][C:25]=1[O:30][CH2:31][CH:32]([CH3:33])[CH3:34])#[N:28]
Reactant: CC(C)COc1ccc(N)cc1C#N
Reactant: Cc1c(C(=O)O)cnn1C
Agent: On1nnc2ccccc21
Solvent: CCO
Product: Cc1c(C(=O)Nc2ccc(OCC(C)C)c(C#N)c2)cnn1C
Temperature: 78 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
1-Hydroxybenzotriazole 1,5-dimethylpyrazole-4-carboxylate (2 g) and 5-amino-2-isobutoxybenzonitrile (1.9 g) were added to ethanol (25 ml) and the mixture was stirred at 78° C. for 3 h. After evaporation of the solvent, the residue was purified by silica gel column chromatography (mobile phase:chloroform:methanol=50:1) to give the title compound (0.8 g), melting point: 160–162° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21]>>[CH2:9]([N:8]([CH2:17][CH2:18][CH2:19][C:20]#[N:21])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: N#CCCCBr
Product: N#CCCCN(Cc1ccccc1)Cc1ccccc1

Procedure:
By a method analogous to Example 1 dibenzylamine was reacted with 4-bromobutyronitrile to give 4-(N,N-dibenzylamino)butyronitrile, mp. 45°-46° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]>Cl.C1C=CC=CC=1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: C1=COCCC1
Reactant: N#CCCCCCCO
Agent: Cl
Solvent: c1ccccc1
Product: N#CCCCCCCOC1CCCCO1
Yield: 86.8 %

Procedure:
3,4-Dihydro-2H-pyran (272 g., 3.35 mole) was added dropwise at 40°C. with stirring to 7-hydroxyheptanenitrile (284 g., 2.24 mole) and concentrated hydrochloric acid (10 drops). The temperature was allowed to rise to 65°C. and was maintained at this level for one hour. The solution was cooled and benzene (500 ml.) was added. The solution was washed with aqueous sodium bicarbonate and then water, and dried over sodium sulphate. The solvent was removed in vacuo, and the residue distilled under reduced pressure to give 7-(2-tetrahydropyranyloxy)heptanenitrile (411 g., 87%), b.p. 100°-130°C./0.1 mm.Hg, nD25 1.455.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:11]([OH:12])[C:10]=1[OH:19])([O-:8])=[O:7]>CC(OC(C)=O)=O>[C:11]([O:12][C:11]1[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:9]([N+:6]([O-:8])=[O:7])[C:10]=1[O:19][C:10](=[O:19])[CH3:9])(=[O:12])[CH3:13]
Reactant: O=[N+]([O-])c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1OC(C)=O
Temperature: 0 °C

Procedure:
A catalytic amount of concentrated sulfuric acid was added to a solution containing 2.0 g of 3,5-dinitrocatechol in 15 ml of acetanhydride and the solution was mixed for 1/2 hours in 50°-60° C. Ice water was added to the reaction mixture and the solution was mixed in 0° C. whereby the product was crystallized. The product was filtered and washed with water and dried. Yield 2.75 g (97%), m.p. 115°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:11]1([C:14](=[O:21])[CH2:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH2:13][CH2:12]1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:21])[C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])=[CH:5][CH:4]=1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=C(C(=O)C2CC2)C(=O)C2CC2)cc1

Procedure:
The procedure described in Example 19 was repeated by using 0.68 g 4-methoxybenzaldehyde and 0.77 g 1,3-dicyclopropyl-1,3-propanedione. Yield 0.46 g, mp 60.5°-61.5° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32]Cl)[C:26]([CH2:34][CH3:35])=[CH:25][C:24]=1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C>CS(C)=O.CN(C)C1C=CN=CC=1.O>[CH2:15]([O:22][C:23]1[C:24]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[CH:25][C:26]([CH2:34][CH3:35])=[C:27]([CH:28]=1)[O:29][CH2:30][CH2:31][CH2:32][O:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCc1c(O)cccc1C(=O)OC
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1C(=O)OC
Temperature: 60 °C
Reaction time: 87 h
Yield: 107.3 %

Procedure:
To a solution of methyl 3-hydroxy-2-propyl-benzoate (40.0 g, 206 mmol) and 1-benzyloxy-5-(3-chloropropoxy)-4-ethyl-2-(4-fluorophenyl)benzene (prepared according to Org. Process Res. Dev. (2009), 13: 268-275) (82.15 g, 206 mmol) in dimethylsulfoxide (240 mL) add potassium carbonate (30.2 g, 219 mmol) and N,N-dimethylpyridin-4-amine (2.0 g, 16 mmol) in succession. Stir the suspension for 87 h at 60° C. and then allow it to cool. Dilute the mixture with water (600 mL) and with methyl-tert-butylether (100 mL) and stir for 15 min. Separate the phases and wash the aqueous portion with methyl-tert-butylether (3×30 mL). Wash the combined organic extracts with water and brine. Concentrate the organic portion in vacuo to yield the title compound (123.0 g, quantitative) as a brown oil. ES/MS m/z 557 (M+1).
Reaction SMILES: [C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25])([O-:16])=[O:15]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:28][CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15])[C:24]([CH3:25])([CH3:26])[CH3:27])=[O:11]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Reactant: CC(C)(C)C(O)c1ccccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
Under a nitrogen atmosphere, (1S)-camphanic acid chloride (3.37 g, 15.6 mmol) was added to a solution of (RS)-1-(2-nitrophenyl)-2,2-dimethyl-1-propanol (2.71 g, 13 mmol) and DMAP (80 mg, 0.65 mmol) in anhydrous pyridine (50 mL). The mixture was stirred for 24 hours at room temperature. Solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (50 mL), washed with 0.5 M HCl (20 mL) twice followed with saturated NaHCO3 solution (20 mL). The organic phase was dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield (RS)-1-(2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (4.11 g, 81%, 1:1 mixture of diastereomers) as a yellow solid. 1H NMR (400 MHz, CDCl3) for diastereomers: δ 7.91 (m, 1H, Ph-H), 7.62 (m, 2H, Ph-H), 7.46 (m, 1H, Ph-H), 6.66 and 6.62 (2 s, 1H, Ph-CH), 2.38 (m, 1H), 2.10-1.9 (m, 2H), 1.71 (m, 1H), 1.13, 1.11, 1.08, 1.04, 1.03, 0.87 (6 s, 9H, CH3×3), 0.97 (s, 9H, (CH3)3C).
Reaction SMILES: ClC1C=C(Cl)C=CC=1O[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[CH:8]=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21].[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:20]([C:6]1[CH:7]=[CH:8][C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[CH:10][C:5]=1[NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])([O-:22])=[O:21]
Reactant: NCCC(=O)O
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)CCNc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Amounts of 8.90 g of 2,4-bis(2,4-dichlorophenoxy)nitrobenzene, 5.35 g of β-alanine and 11.06 g of K2CO3 were added to 50 ml acetonitrile. The reaction mixture was refluxed for 5 days. After evaporating the solvent the residue was stirred with 150 ml of water and 100 ml of diethylether for 1 hour. The water phase was acidified with conc. hydrochloric acid and extracted with methylene chloride. After drying and evaporating the solvent the organic layer yielded the desired product as a yellow crystalline material; melting-point 115° C.; yield 2.64 g.