Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[CH2:13]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(CNCc2ccccc2)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-cyanobenzene-1-sulfonyl chloride (600 mg, 3 mmol) was added to a solution of N-benzyl-1-(4-methoxyphenyl)methanamine (example 5-46b, 750 mg, 3.3 mmol) and triethylamine (500 mg, 3.6 mmol) in dichloromethane (15 mL). The reaction was stirred at ambient temperature for 4 hours then concentrated on the rotovap. The crude was purified on silica gel to afford N-benzyl-4-cyano-N-(4-methoxybenzyl)benzene-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.68 (s, 3H), 4.26 (s, 2H), 4.31 (s, 2H), 6.75 (d, J=8.4 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 7.07 (m, 2H), 7.21 (m, 3H), 7.98 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[O:3]1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:18]([O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH2:11][C:10]2=[O:12])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCI
Reactant: CC1(C)CC(=O)c2cc(O)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(c1)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
A solution of 50 g (0.26 mol) of 2,2-dimethyl-6-hydroxychroman-4-one (Example 28a) in 500 ml of DMF was added dropwise to a suspension of 9.0 g (0.3 mol) of 80% sodium hydride in 500 ml of DMF. After stirring at RT for 90 min, 49 g (0.265 mol) of iodobutane were added and the mixture was stirred at RT for a further 90 min. The reaction mixture was then concentrated in vacuo, the residue was treated with water and the mixture was extracted several times with EA. The organic phases were washed with 5 M sodium hydroxide solution, stirred with activated carbon and magnesium sulfate, filtered and concentrated. 57.6 g of 6-butoxy-2,2-dimethylchroman-4-one were obtained.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]([CH2:11][C:12]#[CH:13])[CH2:9][CH3:10])[CH3:7].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20].Cl>CCCCCC.O1CCCC1>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])([CH3:20])[C:13]#[C:12][CH2:11][N:8]([CH2:9][CH3:10])[CH2:6][CH3:7]
Reactant: C#CCN(CC)CC
Reactant: CC(=O)CCCCCl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CC)CC#CC(C)(O)CCCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.37 ml (19.8 mmol) of a 1.6 M solution of n-butyllithium in n-hexane were slowly added dropwise to a solution of 2.0 g (18 mmol) of N,N-diethyl-2-propynylamine (Example 1C1)) in 50 ml of tetrahydrofuran at -78° C. After one hour at -78° C., the mixture was warmed to room temperature, and 2.42 g (18 mmol) of 1-chloro-5-hexanone were added. Stirring at room temperature for one hour was followed by adjustment to pH 7 with 2 N hydrochloric acid and partitioning between 5% strength sodium bicarbonate solution and dichloromethane. The organic phase was dried over magnesium sulfate, the solvent was removed under reduced pressure. Yield: 4.38 (99% of theory); oily product
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)([O-:10])=[O:9].N1CCCCC1.[NH2:25]/[C:26](/[CH3:31])=[CH:27]\[C:28]([O-:30])=[O:29]>C1C=CC=CC=1>[CH3:5][C:3]1[NH:25][C:26]([CH3:31])=[C:27]([C:28]([OH:30])=[O:29])[CH:14]([C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=2)[C:2]=1[C:1]([OH:7])=[O:6]
Reactant: C/C(N)=C/C(=O)[O-]
Reactant: CC(=O)CC(=O)[O-]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)O)=C(C)N1

Procedure:
In 100 ml of benzene were dissolved 6 g of 2-nitratopropyl acetoacetate, 4.42 g of 3-nitrobenzaldehyde and 0.4 ml of piperidine. The solution was subjected to reflux, extraction, washing, dryness and evaporation of the solvent in the manner described in Example 9 to give a residue, to which 5.97 of 3-nitratopropyl 3-aminocrotonate was added. The mixture was treated in the manner described in Example 9 to give a residue, which was then subjected to column chromatography on silica gel (eluted with n-hexane-ethyl acetate=5:1) and recrystallized from ether to obtain 7.7 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nitratopropyl) ester-5-(3-nitratopropyl) ester.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.C(=O)(O)[O-].[K+].[C:37]([O:43][CH2:44]Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C)C=O>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 81.6 %

Procedure:
3-Methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylic acid (69.6 g., 0.2 mole) was dissolved in 300 ml. of dimethylformamide and reacted in sequence with triethylamine (20.2 g., 0.2 mole), potassium bicarbonate (40 g., 0.4 mole) and chloromethyl pivalate (33 g., 0.22 mole) according to procedures detailed in Preparation B 1. To isolate the product, the reaction mixture was diluted with 3 l. of ether, and the organic solution washed, dried and evaporated to dryness, as detailed in Preparation 1, affording pivaloyloxymethyl 3-methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylate [75.5 g., 82%; ir (CH2Cl2) 1776, 1750, 1685 cm-1 ].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([NH2:11])[CH3:10].[BH4-].[Na+].O>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:11][CH2:9][CH3:10])=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNCc1ccncc1

Procedure:
15.70 g (0.147 mol) of 4-pyridine-formaldehyde was dissolved in 200 mL of ethanol, added under stirring in cold-water-bath with 21 g (0.296 mol) of 65-70% ethylamine aqueous solution, reacted for 0.5 h, monitored with TLC until the reaction was almost completed. Added carefully with 5.6 g (0.148 mol) of sodium borohydride in several batches, small amount in each batch, after the end of addition, added with 30 mL of water, reacted overnight (20 h), the reaction was completed according to TLC monitoring. Evaporated to remove solvent, added with water, extracted with dichloromethane, washed with water and saturated saline in order, dried with anhydrous sodium sulfate, evaporated to remove solvent to obtain yellow thick liquid, 30 g, crude yield 73.4%. 1H NMR(CDCl3, 400 MHz)δ: 1.14(t, 3H, J=7.00 Hz), 2.66(q, 2H, J=7.00 Hz), 3.81(s, 2H), 7.26-7.27(m, 2H), 8.52-8.54(m, 2H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O:25]([CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:44])[CH2:42]Cl)=[CH:37][CH:36]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O(CCOC1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1>>[O:44]=[C:41]([C:38]1[CH:39]=[CH:40][C:35]([O:34][CH2:33][CH2:32][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:36][CH:37]=1)[CH2:42][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5]
Reactant: O=C(CCl)c1ccc(OCCOc2ccccc2)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C(O)c1ccc(OCCOc2ccccc2)cc1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(OCCOc2ccccc2)cc1

Procedure:
Using the procedure described in Example 5, treatment of L-proline-L-isoleucine benzylamide (200 mg, 0.63 mmol) with 4'-phenoxyethoxy-2-chloroacetophenone, (275 mg, 0.95 mmol, 1.5 eq; prepared from 4-(2-phenoxyethoxy)benzoic acid by the method described in example 1), provided 80 mg of L-isoleucine, N-[1-{2-oxo-2-[4-(2-phenoxyethoxy)-phenyl]-ethyl}-L-prolyl] benzylamide as a crystalline solid.
Reaction SMILES: ClC1C=CC(C2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12]C=2)=CC=1.[NH:16]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[O:15]1[CH2:14][CH2:9][CH:10]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17]2)[CH2:11][CH2:12]1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCOCC2)C1

Procedure:
The title compound was prepared by substituting dihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and (S)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=1.C1C=C[C:19]2N(O)N=[N:22][C:20]=2[CH:21]=1.C(Cl)CCl.C1(N)CC1>ClCCl>[CH:20]1([NH:22][C:13]([C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[O:12][N:11]=2)=[O:15])[CH2:21][CH2:19]1
Reactant: O=C(O)c1cc(-c2ccccc2O)on1
Reactant: On1nnc2ccccc21
Agent: NC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC1CC1)c1cc(-c2ccccc2O)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a 20 mL flask was added the crude acid from step 3 (20 mg, 0.1 mmol), HOBt (16 mg, 0.12 mmol), and EDC (23 mg, 0.12 mmol). To this was added dichloromethane (3 mL) and the resulting heterogeneous mixture was stirred for 30 minutes at room temperature. To the resulting solution was added cyclopropylamine (9.0 mg, 0.15 mmol) and the reaction was monitored by HPLC for product formation. After 2 hours, the reaction was complete and concentrated to a thick oil. This oil was partitioned between EtOAc (3 mL) and water (2 mL) with stirring for 10 minutes. The layers were then allowed to separate and the aqueous layer was discarded. The organic layer was then washed with water (2 mL), brine (2 ml) and dried over Na2SO4. Concentration gave an oil that was purified by column chromatography (30% EtOAc in hexanes) to give 6.1 mg (25% yield) of the desired isoxazole 6; 1H NMR (400 MHz, d6-DMSO)S 8.85 (d, 1H), 7.78 (d, 1H), 7.32 (t, 1H), 7.08 (s, 1H), 7.01 (d, 1H), 6.94 (t, 1H), 2.82 (m, 1H), 0.67 (m, 2H), 0.59 (m, 2H). LC/MS (electrospray ionization, positive mode) M+H=245.0.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:45])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH:42](C)C)[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:45])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1)[CH3:42]
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [2-{3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M243) (0.31 g, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (140 mg, 55%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([CH:10]([OH:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(=O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 93.8 %

Procedure:
Following a procedure similar to that described in Example 74(b), but using 4.03 g of 2-butyl -4-pivaloyl -1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (a) above] and 0.22 g of sodium borohydride, 3.79 g of the title compound was obtained as crystals, melting at 134°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[S:30][C:15]3([CH2:20][CH2:19][N:18](C(OC4C=CC=CC=4)=O)[CH2:17][CH2:16]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>C(O)CO.CCOCC>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[S:30][C:15]3([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Product: Fc1cccc(C2SC3(CCNCC3)c3ccccc32)c1
Temperature: 160 °C
Reaction time: 0.75 h

Procedure:
To 6.97 g of 3-(3-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine] of Example 57 in 100 ml of ethylene glycol, under nitrogen, at 150° C. is added 16 g of 85% potassium hydroxide pellets. The reaction is stirred in a 160° C. bath for 45 minutes. The solution is then poured into 225 ml of ice-water, diluted to 500 ml and extracted with three 175 ml portions of dichloromethane. The combined dichloromethane extracts are washed with 200 ml portions of water and one 50 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give a solid free base. The free base in ether is treated with ethereal maleic acid to give a salt. The salt is washed with ether and recrystallized from methanol-acetone-ether to give a white powder of 3-(3-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine] maleate, m.p. 188°-188.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[O:15]1[CH2:20][CH2:19][N:18]([C@@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.F[C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40].C(N(CC)CC)C>O1CCCC1>[O:15]1[CH2:16][CH2:17][N:18]([C@@H:21]2[CH2:22][CH2:23][C@H:24]([NH:27][C:29]3[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=3[N+:39]([O-:41])=[O:40])[CH2:25][CH2:26]2)[CH2:19][CH2:20]1
Reactant: N[C@H]1CC[C@@H](N2CCOCC2)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(N[C@H]2CC[C@@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of EXAMPLE 39B (0.40 g), 4-fluoro-3-nitrobenzenesulfonamide (0.478 g) and triethylamine (2 mL) in tetrahydrofuran (10 mL) was stirred for 3 days at room temperature. The reaction mixture was concentrated and purified by flash chromatography (silica gel, 0-30% methanol/dichloromethane) providing the product.
Reaction SMILES: [F-:1].[K+].CS(O[CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:23](=[O:25])[CH3:24])[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Br:21])=[C:16]([CH3:22])[CH:15]=1)(=O)=O>C(OCC)(=O)C>[Br:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([N:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][F:1])[C:23](=[O:25])[CH3:24])=[CH:15][C:16]=1[CH3:22]
Reactant: CC(=O)N(CCOCCOS(C)(=O)=O)c1cc(C)c(Br)c(C)c1
Reactant: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)N(CCOCCF)c1cc(C)c(Br)c(C)c1
Yield: 69.7 %

Procedure:
Potassium fluoride (180 mg, 3.11 mmol) was added to a solution of 2-[2-[acetyl-(4-bromo-3,5-dimethyl-phenyl)amino]ethoxy]ethyl methanesulfonate (254 mg, 0.622 mmol) in PEG200 (2 ml), and the mixture was irradiated with microwaves at 100° C. for 10 minutes. The reaction solution was diluted with ethyl acetate, and the organic layer was sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give N-(4-bromo-3,5-dimethyl-phenyl)-N-[2-(2-fluoroethoxy)ethyl]acetamide (144 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6]([CH2:15][CH:16]=O)([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[CH2:7][C:6]([CH2:15][CH2:16][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([CH3:19])[CH:21]=2)([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1
Reactant: Cc1ccc(C2(CC=O)CCOC(C)(C)C2)cc1
Reactant: Cc1cccc(CN)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(C2(CCNCc3cccc(C)c3)CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]acetaldehyde (61.6 mg, 0.25 mmol), 3-methylbenzylamine (63 μl, 0.5 mmol) and acetic acid (50 μl, 8.6 mmol) in CH2Cl2 (3 ml) was stirred at rt for 1 h before it adding sodium triacetoxyborohydride (106 mg, 0.50 mmol). The resulting mixture was stirred at rt for 18 h. The mix was concentrated and dissolved in MeOH and purified by HPLC to give {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(3-methylphenyl)methyl]amine as a white solid (35 mg, 40%, m/z: 352.3 [M+H]+ observed).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].C(N(CC)CC)C.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>C(OCC)C>[CH3:1][N:2]([CH3:4])[NH:3][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(C)N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
A 500-mL round bottomed flask was charged with 1,1-dimethylhydrazine (3.88 mL, 50 mmol), triethylamine (7.52 mL, 53 mmol), and diethyl ether (250 mL). To this stirred solution at 0° C. was slowly added pivaloylchloride (6.28 mL, 50 mmol). The resultant white suspension was stirred at ambient temperature for 18 h. This suspension was then filtered through a sintered glass funnel to afford a colorless solution. The volatile components were then removed and the resultant white solid was sublimed at 65° C./0.05 Torr to afford LtBu,NMe2H as colorless crystals (6.95 g, 96%): mp 120-122° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.N1C=CC=CC=1.O.[NH2:21][NH2:22]>O>[NH:21]([C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:22]
Reactant: Clc1ncc(-c2ccccc2)cn1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccccc2)cn1

Procedure:
To a solution of 5.4 g. of 2-chloro-5-phenylpyrimidine in 25 ml. of pyridine is added 25 ml. of hydrazine hydrate. The mixture is heated on a steam bath for one hour with occasional swirling. Water is added and the material that is separated is collected and crystallized from methanol to give 4.5 g. of the product of the Example, m.p. 155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]1[CH2:14][O:13][CH2:12][CH2:11]1.C(OCC)(=[O:17])C.C1CCCCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([OH:17])([CH3:14])[CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C1CCOC1
Solvent: C1CCCCC1
Product: CC(O)(CCO)c1ccc(F)cc1

Procedure:
The molecular sieves were removed by filtration. At a temperature of −60° C. 13 mL of 0.83M 4-fluorophenylmagnesium bromide in THF (10.8 mmol, 2.00 eq) were added. The conversion was determined by TLC (eluent: ethyl acetate/cyclohexane 1+1). The reaction was quenched after 45 minutes by addition of 10 mL of 2.5M aqueous NaOH. The layers were separated and the organic layer was washed twice with 10 mL of 1M aqueous KHSO4, and once with 10 mL of sat. aqueous NaHCO3.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].[BrH:14]>>[BrH:14].[BrH:14].[NH2:10][CH2:11][CH2:12][S:13][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: NCCS
Reactant: OCc1ccccn1
Agent: Br
Agent: Cl
Product: NCCSCc1ccccn1

Procedure:
(a) A solution of 2-hydroxymethyl pyridine (5.45 g.) and cysteamine hydrochloride (6.2 g.) in aqueous hydrobromic acid (110 ml., 48%) was heated under reflux overnight. After cooling, the solution was evaporated to dryness and the residual solid washed with ethanol/ether and recrystallised from aqueous ethanol to give 2-[(2-aminoethyl)thiomethyl]pyridine dihydrobromide m.p. 191°-193°.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl.[NH:34]1[CH2:37][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH2:35]1>C(O)(C)C.CO>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:34]3[CH2:37][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH2:35]3)=[O:14])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)C1CNC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCN(C2CCC2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 85 °C
Yield: 42.9 %

Procedure:
To a stirred solution of 4-nitrophenyl 4-cyclobutyl-1,4-diazepane-1-carboxylate (2.4 g, 7.5 mmol) in isopropyl alcohol (6 ml) and methanol (3 ml) was added DIPEA (3.80 ml, 24 mmol) followed by methyl azetidine-3-carboxylate hydrochloride (1.70 g, 11 mmol) portion wise over 2 minutes. The resulting suspension was heated at 85° C. for 72 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with 1M sodium carbonate solution (3×30 ml), dried (Na2SO4), filtered and evaporated at reduced pressure. Purification by FCC on silica provided the title compound as pale yellow oil (0.95 g, 43%).