Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:6][C:7](=[O:20])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[O:4][C:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:6][C:7](=[O:20])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:1].[O:4]1[CH:5]=[CH:6][C:7](=[O:20])[CH:8]=[CH:3]1
Reactant: CCOC(=O)CCCCCOc1c(CO)oc(COC(=O)C(C)(C)C)cc1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCOc1c(C=O)oc(COC(=O)C(C)(C)C)cc1=O
Product: O=c1ccocc1
Reaction time: 3 h
Yield: 577 %

Procedure:
To a solution of 2.3 g of 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone in 75 ml of acetone was added 4 g of activated manganese dioxide. The resulting suspension was stirred for 3 hr, at which time the mixture was filtered and the filtrate evaporated to an oil. The oil was chromatographed on silica gel to give the oily aldehyde, 2-formyl-3-(5-carboethoxypentyloxy)-6-trimethylacetoxymethyl)-4-pyrone weighing 1.6 g (70%). NMR (CDCl3): δ1.28 (3H, t, J=7 Hz), 1.30 (9H, s), 2.31 (2H, t, J=5.5 Hz), 4.17 (2H, q, J=7 Hz), 4.48 (2H, t, J=7 Hz).
Reaction SMILES: [F:1]C1C=CC(CC(=O)C)=CC=1.FC1C=CC(CC(=O)C)=CC=1S(Cl)(=O)=O.CO[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:39][C:38]([NH:40][C:41](=[O:43])[CH3:42])=[N:37][C:36]=2[CH3:44])=[CH:31][C:30]=1[S:45](=[O:48])(=[O:47])[NH2:46].COC1C=CC(CC(=O)C)=CC=1>>[F:1][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:39][C:38]([NH:40][C:41](=[O:43])[CH3:42])=[N:37][C:36]=2[CH3:44])=[CH:31][C:30]=1[S:45](=[O:48])(=[O:47])[NH2:46]
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1S(N)(=O)=O
Agent: CC(=O)Cc1ccc(F)c(S(=O)(=O)Cl)c1
Agent: COc1ccc(CC(C)=O)cc1
Product: CC(=O)Nc1nc(C)c(-c2ccc(F)c(S(N)(=O)=O)c2)s1

Procedure:
The title compound is prepared from 4-fluorophenyl acetone via 2-fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride (Example 47a) following an identical sequence of reactions used for the synthesis of N-[5-(4-methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 30) from 4-methoxyphenyl acetone.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[O:33][N:32]=[C:31]([CH2:34][CH3:35])[N:30]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:26][CH2:25][N:24]([C:55]([C:54]6[CH:58]=[CH:59][C:51]([C:45]7[C:46]8[CH:47]=[C:48]([O:49][CH3:50])[C:39]([O:38][CH2:36][CH3:37])=[CH:40][C:41]=8[C@H:42]8[CH2:63][S:62][CH2:61][CH2:60][C@H:43]8[N:44]=7)=[CH:52][CH:53]=6)=[O:56])[CH2:23][CH2:22]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[O:33][N:32]=[C:31]([CH2:34][CH3:35])[N:30]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc7c(c6)OCO7)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6-(1,3-benzodioxol-5-yl)-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (232 mg; compound B86) and 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (191 mg; compound C10) in DMF (10 ml) is added HOBt (74 mg) and EDCI (92 mg) and the reaction mixture is stirred at RT for 48 h. One additional equivalent of EDCI (92 mg) is added in order to complete the reaction. The reaction mixture is extracted for three times with DCM/H2O/saturated sodium chloride solution (150 ml/100 ml/35 ml). The organic phase is separated and dried with Na2SO4. After filtration and evaporation of all volatiles the resulting residue is purified by flash column chromatography [amino phase silica gel, eluation gradient: DCM/ethanol, 100/0/to 95/5 (v/v)] and by preparative HPLC to give the title compound as a solid.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[OH:24])[CH2:4][CH3:5])[CH3:2].[Cl:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>C1COCC1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[O:24][C:27](=[O:28])[CH2:26][Cl:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1OC(=O)CCl

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol with chloroacetyl chloride/triethylamine in THF at 0° C. to rt. 1H NMR(CDCl3) d 6.84(s,2H), 6.15(s,1H), 4.3(s,2H), 4.0(d,1H), 3.3(m,1H), 2.28(s,3H), 2.17(s,3H), 2.08(s,6H), ⅙–1.7(m,4H), 0.9(t,6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:13][CH2:12][CH2:11][O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:19].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:13](=[O:19])[CH2:12][CH2:11][O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccc(C2=NOCCS2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S1CCON=C1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,6-Dihydro-3-(3-fluorophenyl)-1,4,2-oxathiazine (19.7 g, 0.1 mol) was dissolved in chloroform, 50 ml). 3-Chloroperoxybenzoic acid (21 g) dissolved in chloroform (200 ml) was added dropwise at such a rate that the temperature of the reaction mixture remained at between 25° to 30° C. After the addition was complete, the reaction was left stirring at room temperature overnight. Saturated aqueous sodium bicarbonate was added and stirred until all gassing ceased. The chloroform solution was washed with water, dried over anhydrous magnesium sulphate and evaporated to leave a solid which was recrystallised from ether/ligroin, to give 5,6-dihydro-3-(3-fluorophenyl)-1,4,2-oxathiazine 4-oxide, mp 79° C.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH3:5][C:6](=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([N:9]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)C1C=CC=CC=1)=[O:8].[OH-].[Na+]>ClC1C=CC=CC=1>[ClH:1].[CH2:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:9]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[C:6]([CH3:5])[C:7]2=[O:8])[CH2:21][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(=Cc1ccccc1)C(=O)N(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Reactant: [Cl-]
Agent: [Al+3]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: Cc1cc2ccccc2n(C2CCN(Cc3ccccc3)CC2)c1=O
Product: Cl
Temperature: 110 °C
Yield: 74.2 %

Procedure:
To grinded aluminum chloride (26 g) are added chlorobenzene (26 ml) and N-(α-methylcinnamoyl)-N-(1-benzyl-4-piperidinyl)aniline (8.7 g) and the mixture is heated at 110° C. for 1 hour. After cooling, the reaction mixture is poured into ice-water and made alkaline with an aqueous sodium hydroxide solution. After extraction with dichloromethane, the extract is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; methylene chloride). The purified substance is converted into hydrochloride and then recrystallized from ethanol/water to give 1-(1-benzyl-4-piperidinyl)-3-methylcarbostyril hydrochloride (5.8 g) as colorless needles, m.p. 274°-276° C.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([O:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([O:34][C:33]3[CH:52]=[CH:53][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])=[CH:50][CH:49]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(OC3CCN(C(=O)NCc4ccc(F)cc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(F)cc1)N1CCC(Oc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 33.7 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)phenoxy]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.335 g, 0.43 mmol) was reacted according to Procedure H (eluant: 8:1 chloroform-methanol) to give the title compound (0.09 g, 0.145 mmol). The free base was treated with a solution of anhydrous hydrogen chloride in methanol, followed by diethyl ether and hexane. The precipitate was filtered and, after drying in vacuo overnight, yielded the title compound (0.17 g, 0.3 mmol)
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[C:12]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)(=[O:14])[CH3:13].C(=O)([O-])O.[Na+]>C(OCC)C>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:12]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)([OH:14])[CH3:13]
Reactant: Brc1nccs1
Reactant: CC(=O)c1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(O)(c1nccs1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 17.3 ml) was added dropwise to a stirred solution of 2-bromothiazole (6.5 g) in anhydrous diethyl ether (40 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylthiazole (5 g) in diethyl ether (10 ml) was added dropwise. After a further 1 hour, the mixture was allowed to warm to room temperature. After 1 hour, saturated aqueous sodium hydrogen carbonate solution was added and the organic phase was separated. Further processing in the usual fashion then gave the title compound. M.p. 146°-147° C. 13C Nmr (CDCl3) 31.4, 76.4, 120.3, 142.0 and 175.2 ppm. Found: C, 45.1; H, 3.5; N, 13.0. C8H8 N2OS2 requires C, 45.2; H, 3.8; N, 13.2%. Hydrochloride, m.p. 137°-140° C. (dec.). 13C Nmr (d6 -DMSO) 28.8, 75.4, 120.6, 142.0 and 176.0 ppm.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:33]2[CH:34]=[CH:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:32]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ccccc2c1
Yield: 71.6 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-Diisopropylethylamine (0.345 mL; 2 mmol) and naphthalen-2-ylboronic acid (0.258 g; 1.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.147 g (71%) of the title compound.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29](N5C=C(C(N)=O)CC=C5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[OH-:45].[Na+].C[CH2:48][O:49]CCOCCO>>[CH2:25]([O:24][P:21]([OH:23])([OH:20])=[O:22])[C@H:26]1[O:30][C@@H:29]([OH:45])[C@H:28]([OH:40])[C@@H:27]([OH:41])[C@@H:48]1[OH:49]
Reactant: CCOCCOCCO
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: [OH-]
Agent: [Na+]
Product: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h

Procedure:
To 0.5 ml G-6-PDH (2.5 mg/ml, 777 lV/mg) was added 20 mg G-6-PNa2, 20 mg NADH, 150 μl of carbitol and the NHS ester prepared above in 3 1 μl aliquots followed by a 0.05 μl aliquot over a period of about 3 hrs while maintaining the pH with 0.1 N NaOH between 8.55-8.77, to provide an amitriptyline-enzyme mole ratio of about 58.3. The reaction mixture was then chromatographed over Sephadex G-50 M (80 ml column) employing 0.05 M carbonate buffer (pH9.6) as eluent, collecting 20 drop fractions with fractions 16-21 pooled to provide a total volume of 8 ml. The max rate as determined by a G-6-PDH assay to be described was ΔOD/min 653.3 (% deactivation 82.8) and % inhibitability using saturating amounts of anti(amitriptyline) varied from 85.3 to 90.8 depending on the source of antibody.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5]2.C[O-].[Na+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>CO>[CH3:16][CH:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:3]=2)[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc2cc(OCc3ccc4ccccc4n3)ccc2c1
Temperature: 25 °C
Reaction time: 192 h
Yield: 151.1 %

Procedure:
To a solution of 6-hydroxy-α-methyl-2-naphthaleneacetic acid (10.8 g, 50 mmol) in methanol (100 ml) is added sodium methoxide (100 mmol). After 10 minutes the solvent is removed and replaced with dimethylformamide (250 ml). 2-(Chloromethyl)quinoline (17.8 g, 100 mmol) is then added and the reaction mixture is stirred for 8 days at room temperature. The reaction mixture is partitioned between water and methylene chloride, the organic layer is washed with water and evaporated to yield 27 g of an oil. Recrystallization of this oil twice from acetonitrile gives 10.6 g of white crystals of intermediate ether ester (42% yield, m.p. 106°-108° C.).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:38]5[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OC1CCNCC1
Agent: OC1CCNC1
Product: OC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 4-hydroxypiperdine. A yellow solid 119 was obtained (0.031 g, 63%). 1H-NMR (CDCl3, 400 MHz) δ 1.75-1.84 (m, 2H), 2.02-2.10 (m, 2H), 3.67-3.74 (m, 2H), 4.00-4.07 (m, 2H), 4.10-4.16 (m, 1H), 4.28-4.34 (m, 4H), 4.72-4.76 (m, 1H), 6.93-6.97 (m, 3H), 7.05 (dd, J=1.8 Hz, 8.0 Hz, 1H), 7.10 (d, J=1.8 Hz, 1H), 7.12 D, J=8.5 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.25 (d, J=6.3 Hz, 1H), MS (APCI) m/z 489 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([Cl:17])[N:9]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:17][C:10]1[N:9]=[C:8]([NH:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(C)(C)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
Add neopentylamine (18 mL, 150 mmol) to a suspension of 2,6-dichloro-3-nitropyridine (20 g, 103 mmol) and Na2CO3 (18.5 g, 175 mmol) in EtOH (1.6 mL/mmol) at RT and stir overnight. Concentrate and dilute the resultant slurry with water (100 mL) and slowly neutralize with concentrated HCl (approx. 40 mL) to pH=7. Cool the suspension at 0° C. for 1 h and collect solid by vacuum filtration. Wash the solid with ice water (4×50 mL) and air dry overnight. Recrystallize the material from EtOAc and hexanes to give the title compound as a yellow solid (21.23 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>CC#N>[CH:27]([O:26][C:24]([N:13]1[CH2:14][CH2:15][CH:10]([S:9][C:6]2[C:7]([CH3:8])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)[CH2:11][CH2:12]1)=[O:25])([CH3:29])[CH3:28]
Reactant: Cc1c(Cl)ncnc1SC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(Cl)ncnc1SC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
A mixture of 4-chloro-5-methyl-6-(piperidin-4-ylsulfanyl)-pyrimidine (HCl salt, 1.8985 g, 6.77 mmol) and triethylamine (2.825 mL, 0.02 mol) in 50 mL of CH3CN was stirred under room temperature. After 15 min, isopropyl chloroformate (1M in toluene, 8.13 mL, 8.13 mmol) were added slowly under 0° C. Mixture was stirred under room temperature. After 3 h, mixture was concentrated and residue was extracted with EtOAc and saturated NaHCO3. Organic phase was dried over MgSO4, filtered and concentrated to give 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid isopropyl ester as yellowish oil (1.9143 g, 85%). Exact mass calculated for C14H20ClN3O2S 329.1, found 330.3 (MH+).
Reaction SMILES: COC[N:4]1[C:8]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:7][C:6]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:33]=[C:32]([C:34]4[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=4)[N:31](COC)[N:30]=3)[CH2:24][CH2:23]2)=[N:5]1.C(OCC)(=O)C.[ClH:55]>C(Cl)(Cl)Cl>[ClH:55].[ClH:55].[CH3:45][O:44][C:36]1[CH:35]=[C:34]([C:32]2[NH:31][N:30]=[C:29]([CH2:28][N:25]3[CH2:24][CH2:23][N:22]([CH2:21][C:6]4[CH:7]=[C:8]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[NH:4][N:5]=4)[CH2:27][CH2:26]3)[CH:33]=2)[CH:39]=[C:38]([O:40][CH3:41])[C:37]=1[O:42][CH3:43]
Reactant: COCn1nc(CN2CCN(Cc3cc(-c4cc(OC)c(OC)c(OC)c4)n(COC)n3)CC2)cc1-c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)[nH]n4)CC3)n[nH]2)cc(OC)c1OC
Reaction time: 3 h

Procedure:
N,N′-Bis[[1-methoxymethyl-5-(3,4,5-trimethoxy-phenyl)pyrazol-3-yl]methyl]piperazine (71 mg) was dissolved in chloroform (3 mL), and to the solution an ethyl acetate solution (0.7 mL) of 4 M hydrochloric acid was added at room temperature, and the mixture was stirred for 3 hours. After concentrating the reaction mixture, the residue was sufficiently dried and recrystallized from methanol-diisopropyl ether to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:9][CH:10]=[CH2:11])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[C:12]1([C:4]([CH2:9][CH2:10][CH3:11])([CH2:1][CH2:2][CH3:3])[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCC(CC=C)(C(=O)OC)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(CCC)(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A solution of the product of Example 1A (7.5 g, 32.61 mmol) in ethyl acetate (125 mL) was treated with 10% palladium on carbon (600 mg) and stirred at 25° C. under hydrogen gas for 18 hours. The solution was filtered through celite® and the filtrate was concentrated in vacuo to give the title compound (7.63 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.27 (m, 5 H), 3.64 (m, 3 H), 1.96 (m, 4 H), 1.08 (m, 4 H), 0.89 (t, J=7.17 Hz, 6 H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14]C)[CH2:12]C)=[O:7])=[C:4]([O:19]C)[CH:3]=1.NC1C(Cl)=CC(C(NCCN(C)C)=O)=C(OC)C=1>>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:14])[CH3:12])=[O:7])=[C:4]([OH:19])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Agent: COc1cc(N)c(Cl)cc1C(=O)NCCN(C)C
Product: CN(C)CCNC(=O)c1cc(Cl)c(N)cc1O
Yield: 89 %

Procedure:
The general procedure of Preparation 1A was repeated except that the 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide utilized therein was replaced by 4-amino-5-chloro-N-[2-(dimethylamino)ethyl]-2-methoxybenzamide (prepared according to U.K. Patent Specification No. 1,793,771). The solvent (DMF) was removed in vacuo, and the residue treated with water and methylene chloride saturated with carbon dioxide, concentrated, and the crude product isolated in 89% yield by extraction with ethanol. A sample was chromatographed on a silica gel column using methylene chloride (97), methanol (3), ammonia (0.3) solvent system. The appropriate fractions were combined and concentrated in vacuo. The residue was crystallized from methanol to give the title compound as a colorless solid, mp. 163°-165°.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:21][CH:22]1[CH2:25][N:24]([CH2:26][C@H:27]([OH:32])[C:28](OC)=[O:29])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[Si:14]([O:21][CH:22]1[CH2:25][N:24]([CH2:26][C@H:27]([OH:32])[C:28]([NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=2)=[O:29])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: N#Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](O)C(=O)Nc2ccc(C#N)cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trimethylaluminium (7.95 mL, 15.89 mmol) was added to 6-aminonicotinonitrile (1.646 g, 13.82 mmol) in toluene (50 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-Methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (4.0 g, 13.82 mmol) in toluene (20 mL) was added and the resulting solution was allowed to warm to room temperature and then heated at 60° C. for 3 hours. The mixture was cooled to ˜10° C. and quenched by the addition of 20% Rochelle salt solution. It was then diluted with EtOAc (50 mL) and stirred for 2 hours. The organic phase was separated, washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica with EtOAc as eluent to afford the product containing some 6-aminonicotinonitrile (4.1 g). This was used without further purification.