Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-n2cncn2)c(C=O)c1
Temperature: 100 °C
Yield: 20.2 %

Procedure:
To a solution of 2-fluoro-5-methoxybenzaldehyde (200 mg, 1.29 mmol) in DMSO (10 mL) are added 1,2,4-triazole (134 mg, 1.95 mmol) and K2CO3 (359 mg, 2.60 mmol) at room temperature. The solution is heated to 100° C. for 2 hours. The solution is cooled and is extracted with H2O (30 mL) and EtOAc (3×15 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 50% EtOAc in heptane as the eluent to afford 5-methoxy-2-1,2,4-triazol-1-yl-benzaldehyde (53 mg, 20%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:8][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: COc1cccc(C(=N)N)c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: COc1cccc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)c1

Procedure:
The title compound, MS: m/e=374.8 (M+), was prepared from 3-methoxybenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[NH2:8]/[C:9](=[N:17]\[OH:18])/[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>N1C=CC=CC=1>[CH3:1][C:2]1[O:18][N:17]=[C:9]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=1
Reactant: CCOC(=O)C(C)/C(N)=N/O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1noc(C)n1

Procedure:
Acetic anhydride (4.6 mL, 49 mmol) was added to a pyridine (50 mL) solution of the intermediate from Step A (2.6 g, 16.2 mmol). The solution was heated at reflux for 1 hour and then at room temperature overnight. The solution was then concentrated to remove most of the pyridine. The concentrated solution was diluted with EtOAc and washed twice with water. The organic layer was concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR δ (ppm) (CHCl3-d): 4.19 (2H, dd, J=72, 3.6 Hz), 3.94 (1H, m, J=7.3 Hz), 2.58 (3H, s), 1.60 (3H, t, 7.3 Hz), 1.25 (3H, t, J=7.1 Hz). m/z=185.1 (M+H).
Reaction SMILES: Cl.[N:2]1([C:8]2[N:13]3[N:14]=[N:15][N:16]=[C:12]3[C:11]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:22](Cl)Cl.CO.C=O>C([O-])(O)=O.[Na+]>[CH3:22][N:5]1[CH2:4][CH2:3][N:2]([C:8]2[N:13]3[N:14]=[N:15][N:16]=[C:12]3[C:11]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][N:9]=2)[CH2:7][CH2:6]1
Reactant: ClCCl
Reactant: c1csc(-c2cnc(N3CCNCC3)n3nnnc23)c1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CN1CCN(c2ncc(-c3cccs3)c3nnnn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
A 100 mL round bottom flask was charged with 5-(piperazin-1-yl)-8-(thiophen-2-yl)tetrazolo[1,5-c]pyrimidine hydrochloride (0.16 g, 0.49 mmol), CH2Cl2 (20 mL), methanol (10 mL), 40% aqueous formaldehyde (2 mL) and NaBH3(CN) (0.1 g, 1.7 mmol). The resulting solution was stirred at room temperature for 0.5 h. Work-up: the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 1-10% MeOH in CH2Cl2 to afford 24 mg (16%) of the product as a white solid. 1H NMR (300 MHz, CD3OD) δ: 8.55 (s, 1H), 7.42 (dd, J=5.1, 1.2 Hz, 1H), 7.39 (dd, J=3.6, 1.2 Hz, 1H), 7.08 (dd, J=5.1, 3.6 Hz, 1H), 3.70-3.40 (br, 4H), 3.30-3.10 (br, 4H), 2.96 (s, 3H). MS m/z: 302 (M+H+).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:38]=1[CH2:39]O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1(C)C=CC=CC=1>[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:38]=1[CH2:39][N:26]=[N+:27]=[N-:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCc1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cc(C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 3 h
Yield: 84.1 %

Procedure:
DBU (1 mL, 6.62 mmol) and diphenyl phosphoryl azide (1.6 mL, 7.5 mmol) were added to a solution of 2-benzyloxy-5-trifluoromethyl-benzyl alcohol (1.24 g, 4.41 mmol) in anhydrous toluene (10 mL) at room temperature. After 3 hours, water was added and the mixture extracted with ethyl acetate (3×). The combined organic layers were washed with 1N HCl (1×), brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (3% ethyl acetate/hexanes) to afford 1.14 grams of the title compound as a colorless oil (84%). MS 280 (M−N2)+. 1H NMR (400 MHz, CDCl3) δ 7.6-7.3 (m, 7H); 7.01 (d, 1H, J=9.1 Hz); 5.18 (s, 2H); 4.42 (s, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([CH3:26])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[CH3:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[NH:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1
Reactant: Cc1cncc2cccc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: Cc1cncc2cccc(N[C@H]3CC[C@H](N)CC3)c12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 95 (389 mg) and 10% hydrogen chloride/methanol solution (10 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (2 ml) and diethyl ether (6 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (355 mg) as light yellow powdery solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[N:8]=[C:9]([Cl:24])[C:10]2[CH2:19][C@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:20][CH2:21][CH3:22])[CH2:12][C:11]=2[N:23]=1>>[ClH:3].[NH2:6][C:7]1[N:8]=[C:9]([Cl:24])[C:10]2[CH2:19][C@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:20][CH2:21][CH3:22])[CH2:12][C:11]=2[N:23]=1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN1CCC[C@H]2Cc3nc(N)nc(Cl)c3C[C@@H]21
Product: Cl

Procedure:
The 4-hydroxy product thus obtained was refluxed with 4 ml. of phosphorous oxychloride. The reaction mixture, containing trans-(±)-2-amino-4-chloro-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-quinoline formed in the above reaction, was poured onto ice and the resulting aqueous mixture made basic. The basic mixture was filtered and the insoluble material dissolved in 0.1N aqueous hydrochloric acid. The hydrochloride salt thus prepared was recrystallized from ethanol to yield trans-(±)-2-amino-4-chloro-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline hydrochloride having the following physical characteristics. Mass spectrum, molecular ion at 280, smaller peak at 282.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH3:23][NH2:24]>CO.C(Cl)Cl>[CH3:23][NH:24][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with methylamine HCl (2.0 equiv, 23 mg, 0.34 mmol) as described in General Procedure X to afford 5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide, Ic (18 mg, 34.6%) as a yellow solid, tlc Rf=0.2 (15% MeOH/CH2Cl2), m/z obs312 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]23[CH2:15][C@H:14]2[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:9]3)[CH:7]=1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1)#[N:26]>>[C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]34[CH2:15][C@H:14]3[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:9]4)[CH:7]=2)=[O:34])=[N:31][CH:32]=1)#[N:26]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)C[C@H]2CCS1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(C#N)cn4)ccc3F)C[C@H]2CCS1
Yield: 46.5 %

Procedure:
Prepared in an analogous manner as described for intermediate rac-A9a from tert-butyl (1S,7S)-1-(5-amino-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate (−)-A8a) (86.7 mg, 247 μmol) and commercially available 5-cyanopicolinic acid to give the tert-butyl (1S,7S)-1-(5-(5-cyanopicolinamido)-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (65 mg, 135 μmol, 46.5% yield) as a yellow oil. MS (ISP): m/z=482.1 [(M+H)+].
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH2:7][CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:42]2[C@H:43]([CH3:66])[C@H:44]3[C@@H:61]([C@H:62]([OH:64])[CH3:63])[C:60](=[O:65])[N:45]3[C:46]=2[C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16]([C:14]1[N:15]=[C:11]([N:8]2[CH2:7][CH2:6][CH:5]([S:4][C:42]3[C@H:43]([CH3:66])[C@@H:44]4[C@@H:61]([C@H:62]([OH:64])[CH3:63])[C:60](=[O:65])[N:45]4[C:46]=3[C:47]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=3)=[O:48])[CH2:10][CH2:9]2)[S:12][CH:13]=1)=[O:17])[CH3:20]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CCOC(=O)c1csc(N2CCC(SC(C)=O)CC2)n1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1csc(N2CCC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CC2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 37.8 %

Procedure:
To a solution of 4-acetylthio-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)piperidine (400 mg, 1.27 mmol) (obtained as described in Reference Example 13) in dimethylformamide (12 ml) was added hydrazine acetate (152 mg, 1.65 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 2.5 hours. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (755 mg, 1.27 mmol) in acetonitrile (21 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.11 ml, 6.37 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1:2) and ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)piperidin-4-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (296 mg, yield 38%).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:17]3[CH:16]=[N:15][CH:14]=[C:13]([O:12][CH3:11])[CH:18]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1nn2c(I)cnc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cncc(-c2nn3c(I)cnc3s2)c1
Temperature: 110 °C
Yield: 24 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (100 mg, 0.303 mmol, 1 eq), 3-methoxypyridine-5-boronic acid pinacol ester (78 mg, 0.333 mmol, 1 eq), PdCl2(dppf) (25 mg, 0.030 mmol, 0.1) and sat K2CO3 (0.6 mL) in dioxane (4 mL) was heated at 110° C. for 2 days. Additional amount of catalyst (0.05 eq) was added and the reaction mixture was heated under microwave irradiation at 130° C. for 2 h. The solvent was removed, the residue was diluted with EtOAc, sonicated and flushed through a plug of Celite. The filtrate was concentrated and the residue was purified by column chromatography (MeOH in DCM, 0 to 10%) to give the desired product (26 mg, 24%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=3.97 min, [M+H]+ m/z 359.0.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: COc1cccc(B(O)O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cc(C=O)c(C)o2)c1F
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.3 g), 2-fluoro-3-methoxyphenylboronic acid (1.4 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.5 g, 93%) as a yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH:12]=[CH:11][C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N)nc(N)c1-c1cc(N)ccc1Cl
Solvent: c1ccncc1
Product: Cc1nc(N)nc(N)c1-c1cc(NS(C)(=O)=O)ccc1Cl

Procedure:
This compound was prepared from 2,4-diamino-5-(2-chloro-5-aminophenyl) -6-methylpyrimidine from Example 54 by reaction with methanesulphonylchloride in pyridine, mp. 234°-240° C.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:9]1[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:12]=[C:8]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:34])[CH3:37]
Reactant: CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCOC(=O)CCCCCCCBr
Product: CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCCCC(=O)OCC
Yield: 84.7 %

Procedure:
2-Heptyl-4,5-diphenylimidazole (1 g) was reacted with ethyl 8-bromooctanoate (1.6 g) in a method similar to Example 9 with a reaction time of 48 hours. Chromatography on silica gel (hexane/ethyl acetate) gave 1-(7-ethoxycarbonyl-heptyl)-2-heptyl-4,5-diphenylimidazole (1.3 g, 87%) as an oil. Found: C, 78.98; H, 9.22; N, 5.76%; C32H44N2O2 requires: C, 78.64; H, 9.08; N, 5.73%;
Reaction SMILES: COC1C=CC(/C=[C:16]2/[C:17]([NH:19][C:20]([S:22]/2)=[NH:21])=[O:18])=CC=1OC1CCCC1.C(O[Na])(C)=O.[CH:28]([C:30]1[N:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34]([C:40]#[N:41])=[C:33]2[O:42][CH:43]([CH3:45])[CH3:44])=O>CC(O)=O>[NH2:21][C:20]1[S:22][C:16](=[CH:28][C:30]2[N:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]=[CH:35][C:34]([C:40]#[N:41])=[C:33]3[O:42][CH:43]([CH3:45])[CH3:44])[C:17](=[O:18])[N:19]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(N)=NC3=O)nc12
Temperature: 90 °C
Yield: 22.8 %

Procedure:
To a mixture of pseudothiohydantoin (Aldrich, 97%, 23.2 mg, 0.20 mmol), AcONa (160 mg, 1.95 mmol), molecular sieves, and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (53.1 mg, 0.22 mmol) (prepared as described below) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 85-95° C. for 1.5 h. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in hot DMF (20 mL) and filtered again. The filtrate was concentrated to give a brown solid: 55.8 mg, which was then purified by Biotage flash column (1%-6% MeOH in CH2Cl2) to give 6-(2-amino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile as a yellowish solid (15.5 mg, 22.8%). HR-ES (+) m/e calcd for C16H13N5O2S (M+H)+ 340.0863. found 340.0863.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:22])([F:21])[S:5]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)(=[O:7])=[O:6]>CCO.O>[F:21][C:4]([F:3])([F:22])[S:5]([O:8][C:9]1[C:18]([CH2:19][OH:20])=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)(=[O:6])=[O:7]
Reactant: O=Cc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(Oc1cc2c(cc1CO)CCCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 112 h

Procedure:
Sodium borohydride (36.3 mg, 0.959 mmol) was added to a stirred solution of 3-formyl-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (98.5 mg, 0.320 mmol) in EtOH (5 mL) at room temperature. The reaction was stirred for 112 h at room temperature. The reaction mixture was diluted with water (20 mL) washed with brine and dried (Na2SO4) then concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-30% EtOAc in hexanes gradient) to afford 3-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate. Rf=0.49 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ 7.25 (s, 1H); 6.95 (s, 1H); 4.69 (d, J=4.9 Hz, 2H); 2.76 (br s, 4H); 2.25 (t, J=5.4 Hz, 1H); 1.80-1.77 (m, 4H).
Reaction SMILES: [C:1]([NH:4][N:5]1[CH2:10][C:9]([CH:11]([OH:13])[CH3:12])=[N:8][N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]1=[O:21])(=[O:3])[CH3:2].C([O-])(O)=O.[Na+].[Na+].[Br-].[O-]Cl.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[C:1]([NH:4][N:5]1[CH2:10][C:9]([C:11](=[O:13])[CH3:12])=[N:8][N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)NN1CC(C(C)O)=NN(C(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NN1CC(C(C)=O)=NN(C(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-acetamido-6-(1-hydroxyethyl)-3-oxo-5H-1,2,4-triazine-2-carboxylate (601 mg, 1.50 mmol) in ethyl acetate (3.9 mL) was added a solution of NaHCO3 (378 mg, 4.50 mmol) and NaBr (170 mg, 1.65 mmol) in water (2.6 mL). After cooling of the biphasic mixture to 0° C., 2,2,6,6-Tetramethyl-piperidin-1-yl)oxyl (“TEMPO”) (12.0 mg, 0.0750 mmol) was added in one portion followed by dropwise addition of NaOCl (6 wt % in water, 2.79 mL, 2.25 mmol) to the vigorously stirred solution. After completion of the addition, stirring at 0° C. was continued for 30 min. Subsequently, a solution of aqueous Na2SO3 was added until the reaction mixture had completely discolored. Additional solid Na2SO3 was added to saturate the aqueous phase. The mixture was transferred to a separation funnel and the layers were separated. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. LCMS (Method I) RT 1.42 min. [(M-Boc)+Na]+ 221.
Reaction SMILES: [C:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC=CC=1.[BH4-].[Na+]>CCOCC.C(O)C.O>[CH:13]1([NH:12][CH2:11][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Br[Mg]C1CCCCC1
Reactant: N#CC1(c2ccccc2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(C2(CNC3CCCCC3)CCC2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A solution of 1-phenyl-1-cyclobutanecarbonitrile (30 g) in ether (100 ml) was added dropwise to a stirred solution of cyclohexylmagnesium bromide [prepared from cyclohexyl bromide (62.3 g) and magnesium (9.5 g) in ether (200 ml)]. The ether was replaced with toluene, and the mixture was stirred at 90° C. for 24 hours. Sodium borohydride (7.3 g) was added as a slurry in ethanol (200 ml) and the mixture was heated under reflux for 3 hours. The cooled mixture was acidified, basified, diluted with ether and water, and filtered (Celite). The organic layer was separated and the aqueous layer was extracted with ether. The combined extracts were washed, dried and the solvent removed by evaporation to give (cyclohexyl)(1-phenylcyclobutyl)methylamine which was isolated by conversion into a hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH2:19][C:18]2[CH:29]=[CH:30][C:15]([F:14])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)=[O:6]
Reactant: COCc1ccc(C(=O)O)c(N)n1
Reactant: NCc1ccc(OCc2ccc(F)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1ccc(C(=O)NCc2ccc(OCc3ccc(F)cc3)cc2)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 2-amino-6-methoxymethyl-nicotinic acid described in Preparation Example A-11 (10 mg, 0.055 mmol) and 4-(4-fluoro-benzyloxy)-benzylamine described in Preparation Example 155 (19 mg, 0.082 mmol) in N,N-dimethylformamide (1 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (29 mg, 0.066 mmol) and triethylamine (0.022 mL, 0.16 mmol), and the solution was stirred overnight at room temperature. Water was added to the reaction solution, the precipitated solid was filtered, and the title compound (13 mg, 0.033 mmol, 60%) was obtained as a colorless solid.