Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:26][O:27][Si](C(C)(C)C)(C)C)[C@@H:10]([NH:19][S@](C(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.COC1C=CC(C=O)=CC=1.[O:46](C(OC(C)(C)C)=O)[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=O>C(OCC)C.CCO>[Si:1]([O:8][C@H:9]([CH2:26][OH:27])[C@@H:10]([NH:19][C:47](=[O:46])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cccc(F)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 500 mL RBF containing (S)—N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (2.600 g, 4.9 mmol) was added EtOH (25 ml) and the mixture was allowed to stir at 0° C. for 15 min. At this time, HCl (4N in dioxane) (3.7 ml, 15 mmol) was added via syringe. The reaction was monitored at 1 h by LC/MS 76877-2-1 and tlc (100% EtOAC amino bis TBS; Rf=0.80 UV active stains orange to anisaldehyde amine with primary alcohol deprotected Rf=0.45 to 0.1 streak, UV active and stains white to anisaldehyde). The reaction was allowed to stir for 3 h at 0° C. and then TEA (4.1 ml, 29 mmol) was added fast dropwise and a white solid formed. An LC/Ms was obtained to confirm that the secondary TBS ether was not removed during the TEA neutralization process. Approximately 15 mL of EtOH were removed by rotary evaporator and then DCM (10 mL) was added and the solid went into solution. At this time, (BOC)2O (2.3 ml, 9.8 mmol) was added in one portion and the reaction was allowed to stir for 1 h and then poured into diethyl ether (300 ml). The organic layer was washed with ammonium chloride (3×150 mL, sat) and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated to give a colorless crude oil. The desired product has an Rf=0.40 in 35% EtOAc in hexanes, UV active, stains white to anisaldehyde and purple to moly stain. The crude oil was purified on a 120 g Isco column (10 to 35% EtOAc in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C1CCCCC1.[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20].CI>O1CCCC1>[CH2:19]([O:21][C:22]([C:24]1([CH3:1])[CH2:25][CH2:26][N:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1CCN(c2ccc(C(C)(C)C)cc2)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCN(c2ccc(C(C)(C)C)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (113 μL, 0.81 mmol) was diluted with tetrahydrofuran (1 mL). The resulting solution was cooled to 0° C., and a solution of n-butyllithium in cyclohexane (400 μL, 2M, 0.80 mmol) was then added. The mixture was stirred at 0° C. for 30 min. The mixture was then cooled to −78° C., and a solution of the 1-(4-Tert-butyl-phenyl)-piperidine-4-carboxylic acid ethyl ester (118 mg, 0.41 mmol, prepared in accordance with Example 48) in tetrahydrofuran (3 mL) was added. After 30 min, methyl iodide (57 μL, 0.41 mmol) was added. Afterward, the mixture was maintained at −78° C. for 1 hr. The mixture was then allowed to increase to room temperature, and maintained at that temperature for 1 hr. The mixture was then quenched with saturated aqueous ammonium chloride (15 mL). The organic phase was extracted with ethyl acetate (20 mL). The organic phase was then dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as an oil (155 mg, quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.F[C:11]1[C:16]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)=[CH:15][C:14]([CH2:43][N:44]2[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@@H:45]2[CH3:54])=[CH:13][N:12]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:51])=[O:52])[CH2:46][C@@H:45]3[CH3:54])=[CH:13][N:12]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Reactant: COc1ncc(N)cn1
Product: COc1ncc(Nc2ncc(CN3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared from 2-methoxypyrimidin-5-amine (Aces Pharma, Inc.) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (preparation similar as reported in Example 316, Steps 1 to 2; from (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Sigma Aldrich, Inc.)) via similar steps as previously described in Example 316 and isolated as a yellow solid. m/z (ESI, +ve ion) 501 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.77 (s, 1H) 9.03 (s, 2H) 8.71 (d, J=1.96 Hz, 1H) 8.24 (d, J=2.15 Hz, 1H) 7.90 (br. s., 1H) 7.74 (br. s., 1H) 3.91 (s, 3H) 3.24 (d, J=13.50 Hz, 2H) 2.86-2.96 (m, 1H) 2.85 (s, 3H) 2.55-2.79 (m, 4H) 2.44 (s, 3H) 2.11-2.37 (m, 2H) 1.16 (d, J=6.26 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:9]([CH:10]=[O:11])=[CH:8][C:7]([CH3:12])=[CH:6][N:5]=1>CO>[Cl:3][C:4]1[C:9]([CH2:10][OH:11])=[CH:8][C:7]([CH3:12])=[CH:6][N:5]=1
Reactant: Cc1cnc(Cl)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(Cl)c(CO)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
Sodium borohydride (0.65 g, 0.0167 moles) was added slowly to a well-stirred solution of 2-chloro-5-methylpyridine-3-carbaldehyde (1.3 g, 0.0084 moles) in methanol (20 ml) at 0° C. temperature over a period of 15 minutes. The reaction mass was further stirred for 2 hours at the same temperature. The solvent was removed under reduced pressure and the mass was quenched with water (25 ml). The mass was extracted with ethyl acetate (2×50 ml) and the layers separated. The organic layer was removed under reduced pressure. The residue so obtained was subjected to chromatographic purification on silica gel to give 2-chloro-3-hydroxymethyl-5-methylpyridine as a solid in 88 % yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:32])([CH3:31])[CH:28]([CH3:30])[CH3:29])[O:23][SiH:24]([CH3:26])[CH3:25])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:41]=[O:42]>C1(C)C=CC=CC=1.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:32])([CH3:31])[CH:28]([CH3:30])[CH3:29])[O:23][SiH:24]([CH3:26])[CH3:25])=[C:14]([CH:41]=[O:42])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 26.5 g (0.049 mol) (4R,9aR)-7-bromo-6-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 800 ml toluene was added at −78° C. during 10 minutes 50 ml of a 1.5 M solution of tert. butyllithium in pentane. The reaction mixture was stirred at −78° C. for 30 minutes. To the resulting orange solution was added 30 ml dimethylformamide during 3 minutes. The reaction mixture was stirred at −78° C. for 30 minutes and the cooling bath was then removed and the mixture was stirred for 30 min at ambient temperature. The reaction was quenched by addition of 300 ml of a 10% aqueous solution of citric acid and extracted with ethyl acetate. The organic phase was washed with a 10% aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, evaporated under aspirator vacuum and purified by chromatography on silica gel with heptane:ethyl acetate=4:1 to 3:1. to yield 22.70 g (94.6%) of the title compound as yellow foam (MS: 490 (M+H+)).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[Br:12]Br.[BrH:14]>O>[BrH:12].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:14])[CH:9]=2)[CH2:4]1
Reactant: NC1Cc2ccccc2C1
Reactant: BrBr
Agent: Br
Agent: Cl
Solvent: O
Product: NC1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 2-amino-2,3-dihydro-1H-indene hydrochloride salt (10.0 g, 58.9 mmol) in water (50 mL) was warmed to 60° C. Next, bromine was added dropwise (3.50 mL, 67.9 mmol) over a 50 min period. Stirred for 1 hour, cooled to RT, stirred 1 hour, treated with 5 mL of 48% HBr (aq) and filtered. The residue was dried in a vacuum oven overnight (40° C.) to give 2-amino-5-bromo-2,3-dihydro-1H-indene hydrobromide salt (14.5 g, 84% yield) as a single isomer: 1H NMR (600 MHz, DMSO-d6) δ 8.08 (br s, 3H), 7.47 (s, 1H), 7.35 (dd, J=7.9, 0.9 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 3.97 (br s, 1H), 3.18-3.26 (m, 2H), 2.85-2.94 (m, 2H).
Reaction SMILES: BrC1C(=O)C(C(O)=O)=CN(C(C)C)C=1C.[Br:16][C:17]1[C:18](=[O:31])[C:19]([C:28]([OH:30])=O)=[CH:20][N:21]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[C:22]=1[CH3:23].Cl.CS(C1C=CC(CN)=CC=1)(=O)=O.[CH3:45][C:46]1[O:50][C:49]([CH2:51][NH2:52])=[N:48][N:47]=1.BrBr>>[CH3:45][C:46]1[O:50][C:49]([CH2:51][NH:52][C:28]([C:19]2[C:18](=[O:31])[C:17]([Br:16])=[C:22]([CH3:23])[N:21]([CH:24]3[CH2:25][CH2:26][CH2:27]3)[CH:20]=2)=[O:30])=[N:48][N:47]=1
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C1CCC1
Reactant: Cc1nnc(CN)o1
Agent: BrBr
Agent: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Product: Cc1nnc(CNC(=O)c2cn(C3CCC3)c(C)c(Br)c2=O)o1

Procedure:
Preparation 24 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 7b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine. ESI mass spectrum: [M+H]+=381 (bromine isotope pattern); Retention time HPLC: 0.69 min (Z003_001).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:23][C:24]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][C:28](=O)[CH2:29]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:32]([CH3:34])=[CH:33][C:24]=3[CH3:23])[CH2:29]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: Cc1cc(C)c2c(c1)CC(=O)CC2
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1CCc2c(C)cc(C)cc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 5,7-dimethyl-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 21.0, 24.3, 25.3, 25.6, 26.6, 29.7, 30.7, 36.6, 37.1, 38.0, 53.0, 53.3, 56.0, 59.1, 60.4, 60.8, 67.3, 104.7, 127.9, 28.0, 128.6, 128.7, 131.1, 131.3, 131.6, 134.6, 135.1, 135.2, 136.4, 137.3, 172.5, 172.6; MS m/z 466.5 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:26]([F:29])([F:28])[F:27])=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:30]1([CH:33]=O)[CH2:32][CH2:31]1.C(N1CCC2C(C(N3CCC(C4C=CC=C(F)C=4C(F)(F)F)CC3)=O)=NNC=2C1)C>>[CH:30]1([CH2:33][N:22]2[CH2:23][CH2:24][C:25]3[C:17]([C:15]([N:12]4[CH2:11][CH2:10][CH:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[C:4]=5[C:26]([F:29])([F:27])[F:28])[CH2:14][CH2:13]4)=[O:16])=[N:18][NH:19][C:20]=3[CH2:21]2)[CH2:32][CH2:31]1
Reactant: O=CC1CC1
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cccc(F)c2C(F)(F)F)CC1
Agent: CCN1CCc2c(C(=O)N3CCC(c4cccc(F)c4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Product: O=C(c1n[nH]c2c1CCN(CC1CC1)C2)N1CCC(c2cccc(F)c2C(F)(F)F)CC1

Procedure:
Following general procedure GP-G1, ((4-(3-fluoro-2-(trifluoro-methyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (30) and cyclopropane carbaldehyde were converted to (6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluormethyl)phenyl) piperidin-1-yl)methanone as a white solid (23 mg, 34%): 1H NMR (300 MHz, DMSO-d6) δ 12.74 (br s, 1H), 7.72-7.65 (m, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.34-7.27 (m, 1H), 4.92-4.63 (m, 2H), 3.59-3.53 (m, 2H), 3.32-3.09 (m, 2H), 2.90-2.39 (m, 7H), 1.81-1.62 (m, 4H), 0.92-0.85 (m, 1H), 0.52-0.48 (m, 2H), 0.14-0.10 (m, 2H); ESI MS m/z 451 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]([O:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].C1COCC1.[NH2:22][OH:23].[C-]#N.[K+]>O.CO>[OH:23][NH:22][C:3](=[O:2])[CH2:4][CH2:5][CH:6]([O:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13]
Reactant: NO
Reactant: COC(=O)CCC(OC)c1ccccc1C
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(CCC(=O)NO)c1ccccc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution prepared by dissolving 4-methoxy-4-o-tolyl-butyric acid methyl ester (230.0 mg, 1.03 mmol) into 3 mL of a mixture of THF, methanol, and 50 wt % NH2OH in H2O (2:2:1) was added KCN (6.0 mg, 0.03 mmol). The reaction mixture was stirred for 3 days at room temperature and then quenched by the addition of 10 mL of 1M aqueous HCl. The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers washed with brine (2×10 mL). The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to afford 184 mg of the title compound as a yellow oil.
Reaction SMILES: ClC1C=C(S([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=O)=O)C=C(Cl)C=1>CO>[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2
Reactant: O=C1Cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2N1
Solvent: CO
Product: Nc1ccc2c(c1)CC(=O)N2

Procedure:
The reaction is carried out in methanol. The crude product is further reacted directly in V (6).
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][N:4]1C(=O)CCC1=O.[ClH:19]>C(O)C.O>[ClH:19].[NH2:4][CH2:3][CH:2]([OH:1])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1CC(O)COc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NCC(O)COc1ccccc1

Procedure:
A solution of 1-(2-hydroxy-3-phenoxypropyl)pyrrolidine-2,5-dione (3.5 g, 13.1 mmol) (as shown at 3 above) in HCl (12N, 20 mL) and ethanol (20 mL) was heated to reflux for 6 hours. After thin layer chromatography (TLC) showed the reaction was complete, the mixture was concentrated in vacuum to give a white residue, which was taken up in water (20 mL) and washed with ether (3*50 mL). The aqueous phase was concentrated to give crude product, which was crystallized from methanol to give 2.9 g of 1-amino-3-phenoxypropan-2-ol hydrochloride (as shown at 4).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[CH2:4][CH2:3]1.[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+]>CC#N>[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]2[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[CH2:4][CH2:3]2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=S1(=O)CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CN2CCS(=O)(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing thiomorpholine 1,1-dioxide hydrochloride (0.65 g, 3.8 mmol) in CH3CN is added 4-nitrobenzylbromide (1.1 g, 5.1 mmol) and K2CO3 (1.9 g, 13.7 mmol). The mixture is then allowed to stir at room temperature overnight. After aqueous work up, the product is obtained through chromatography. MS (ESI): 271.1 (M+1)+1
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1>C(#N)C>[OH:28][CH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:20]([C:10]2[N:11]=[C:6]([CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([CH3:1])[CH:3]=3)[NH:7][C:8](=[O:16])[C:9]=2[C:14]#[N:15])[CH2:21][CH2:22]1
Reactant: CSc1nc(Cc2cccc(C)c2)[nH]c(=O)c1C#N
Reactant: OCCC1CCNCC1
Solvent: CC#N
Product: Cc1cccc(Cc2nc(N3CCC(CCO)CC3)c(C#N)c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(3-methylbenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.142 g (1.16 mmol) of 2-(4-piperidinyl)ethan-1-ol in 3 ml of acetonitrile at 90° C. under argon for seven days. After cooling to room temperature, the crude product is purified by preparative HPLC. 0.047 g (36% of theory) of the title compound is obtained as a colourless solid.
Reaction SMILES: C(N(CC)C(CCCC(NF)C)CC)C.CCN([C:21]1[CH:26]=[CH:25][C:24]2[C:27]3([C:37]4[CH:43]=[C:42](Cl)[CH:41]=[CH:40][C:38]=4[O:39][C:23]=2[CH:22]=1)OC(=O)C1C3=CC=CC=1)CC.CC1C=C2OC3C=C(N4CCCCC4)C=CC=3C3(OC(=O)C4C3=CC=CC=4)C2=CC=1NC1C=CC=CC=1>>[CH:43]1[C:37]2[CH2:27][C:24]3[C:23](=[CH:22][CH:21]=[CH:26][CH:25]=3)[O:39][C:38]=2[CH:40]=[CH:41][CH:42]=1
Reactant: CCN(CC)c1ccc2c(c1)Oc1ccc(Cl)cc1C21OC(=O)c2ccccc21
Agent: CCC(CCCC(C)NF)N(CC)CC
Agent: Cc1cc2c(cc1Nc1ccccc1)C1(OC(=O)c3ccccc31)c1ccc(N3CCCCC3)cc1O2
Product: c1ccc2c(c1)Cc1ccccc1O2

Procedure:
Rhodamine B anilinolactam, Rhodamine B-p-chloroanilinolactam, 3-diethylamino-7-dibenzylaminofluoran, 3-diethylamino-7-octylaminofluoran, 3-diethylamino-7-phenylfluoran, 3-diethylamino-7-chlorofluoran, 3-diethylamino-6-chloro-7-methylfluoran, 3-diethylamino-7-(3,4-dichloroanilino)fluoran, 3-diethylamino-7-(2-chloroanilino)fluoran, 3-diethylamino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tolyl)amino-6-methyl-7-anilinofluoran, 3-piperidino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tolyl)amino-6-methyl-7-phenethylfluoran, 3-diethylamino-7-(4-nitroanilino)fluoran, 3-dibutylamino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-propyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-isoamyl)amino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-cyclohexyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tetrahydrofuryl)-amino-6-methyl-7-anilinofluoran, etc.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([CH3:47])[C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C@H:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH3:40])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br>ClCCl.C(O)(=O)C.C(OCC)C>[C:41]1([C@@H:39]([NH:38][C:34]2[N:33]=[C:32]([C:19]3[N:18]([CH3:47])[C:17]([CH:14]4[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]4)=[N:21][C:20]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[CH:37]=[CH:36][N:35]=2)[CH3:40])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C[C@H](Nc1nccc(-c2c(-c3cccc(C(F)(F)F)c3)nc(C3CCN(C(=O)OCc4ccccc4)CC3)n2C)n1)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-c2c(-c3cccc(C(F)(F)F)c3)nc(C3CCNCC3)n2C)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To a solution of (S)-4-[5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-methyl-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester(12.5 gm, 0.0195 mole) in dichloromethane (170 mL) at 0° C., under argon, was slowly added 30% hydrogen bromide in acetic acid (170 mL). The solution was allowed to stir for 1.5 h at 0° C. and then diluted with diethyl ether (2.0 L). The resulting solid was filtered under argon, washed with diethyl ether (500 ml) and sucked dry under argon. The solid was then dissolved in dichloromethane (500 mL) and 10% aqueous sodium bicarbonate (500 mL) and mixed well. The dicholormethane solution was removed and the aqueous layer washed with dichloromethane (200 mL). The dichloromethane extracts were dried over anhydrous sodium sulfate, concentrated and the resulting foam (9.6 gm) chromatographed on silica using (dichloromethane/methanol/acetic acid/water--90/10/1/1). The resulting product containing fractions were washed with 10% aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to give (S)-4-[5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-methyl-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine (9.4 gm). The solid was dissolved in ethyl acetate (400 ml) filtered and then treated with a solution of hydrochloric acid/ethyl acetate (84 mL, 0.033 gm HCl/mL, 4 eq.). The resulting solid was filtered, dissolved in water (100 ml) and lyophilized to give (S)-4-[5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-methyl-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine trihydrochloride (12.0 gm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][S:10](=[O:12])(=[O:11])[NH2:13]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1F
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccccc1F
Yield: 38.2 %

Procedure:
This compound was prepared according to the procedure of Example 56. A mixture of 11.2 g (0.1 mole) of 2-fluorophenol and 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate in 50 ml of toluene gave 7.3 g (38%) of the title compound as a white solid, mp 63°-64° (benzene).
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[C:19]1[NH2:29]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[C:19]1[NH2:29])=[NH:5]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: Nc1nc(-c2ccccc2)cn1N
Agent: Cl
Solvent: CC(C)O
Product: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccccc2)nc1N
Temperature: 80 °C
Reaction time: 5 h

Procedure:
6 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are added, with stirring, to a mixture of 4.1 g (0.02 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 3.5 g (0.02 mol) of 1,2-diamino-4-phenyl-imidazole (see Beyer H. et al., Chem. Ber. 101, 3151 (1968)) and 150 ml of isopropanol, and the mixture is stirred at 80° C. for 5 hours. During that time, the starting materials dissolve and the title compound gradually crystallizes out. At the end of the reaction time, the mixture is cooled. The product that has crystallized out is filtered off with suction, washed with isopropanol and dried. The product crystallizes with one mole of isopropanol, m.p. 238°-240° C., 1H-NMR (DMSO/D2O): δ=8.24 (d, 1H); 7.88 (s, 1H); 7.73 (d, 1H); 7.55-7.68 (m, 3H); 7.34-7.5 (m, 3H); 3.26 (s, 4H).