Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1)(=[O:10])[NH2:9].Cl[C:18]1[C:19]2[C:27]([CH3:28])=[CH:26][N:25]([C:29]3[C:33]([CH:34]([CH3:36])C)=[CH:32][S:31][C:30]=3[CH3:37])[C:20]=2[N:21]=[C:22]([CH3:24])[N:23]=1.[CH:38](N(C(C)C)CC)([CH3:40])[CH3:39].C(=O)([O-])O.[Na+]>C(O)C>[C:8]([C:11]1[CH2:16][CH2:15][N:14]([C:18]2[C:19]3[C:27]([CH3:28])=[CH:26][N:25]([C:29]4[CH:33]=[CH:34][C:36]([CH:38]([CH3:40])[CH3:39])=[CH:37][C:30]=4[S:31][CH3:32])[C:20]=3[N:21]=[C:22]([CH3:24])[N:23]=2)[CH2:13][CH:12]=1)(=[O:10])[NH2:9]
Reactant: NC(=O)C1=CCNCC1
Reactant: Cc1nc(Cl)c2c(C)cn(-c3c(C(C)C)csc3C)c2n1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CSc1cc(C(C)C)ccc1-n1cc(C)c2c(N3CC=C(C(N)=O)CC3)nc(C)nc21
Yield: 37.5 %

Procedure:
In 4 ml of ethanol, 0.25 g of 4-carbamoyl-1,2,3,6-tetrahydropyridine trifluoroacetate and 0.35 g of 4-chloro-2,5-dimethyl-7-(isopropyl-2-methylthiophenyl)-7H-pyrrolo[2,3-d]pyrimidine were dissolved, and 0.39 g of diisopropylethylamine were added thereto. The reaction mixture was heated under reflux for 7.5 hours, and subsequently, a saturated aqueous solution of sodium hydrogencarbonate was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subsequently dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform—methanol=60:1), followed by crystallization from a mixed solvent of ethyl acetate-diethyl ether to yield 0.17 g of 4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2,5-dimethyl-7-(4-isopropyl-2-methylthiophenyl)-7H-pyrrolo [2,3-d]pyrimidine.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][C:17]([CH3:32])([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[CH3:18])/[C:12](O)=[O:13])[N:10]=1)=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:34].CCCCCC>C(Cl)Cl>[ClH:1].[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][C:17]([CH3:32])([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[CH3:18])/[C:12]([Cl:34])=[O:13])[N:10]=1)=[O:4]
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(O/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: Cl

Procedure:
In 15 ml of methylene chloride is dissolved 1.445 g of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetic acid and under ice-cooling and stirring 686 mg of phosphorus pentachloride is added. The mixture is stirred under ice-cooling for 30 minutes, after which 4.5 ml of hexane is added. The resultant crystalline precipitate is collected by filtration and washed with hexane to give 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetyl chloride hydrochloride, m.p. 79°-82° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][S:8][CH2:9]Cl.C(N(CC)CC)C>>[C:1]([O:6][CH2:7][S:8][CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CSCOC(=O)C(C)C

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting isobutyric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 64° C./12 mm Hg, nD20 1.4470.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)#[N:2].Br[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH:22]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][NH:12][C:4]([NH:3][C:1]#[N:2])=[N:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:20][CH2:19]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#CNC(=Nc1ccncc1)NCCN1CCNCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CNC(=Nc1ccncc1)NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12.5 h
Yield: 50 %

Procedure:
N-cyano-N′-(2-piperazin-1-yl-ethyl)-N″-pyridin-4-yl-guanidine (273 mg, 1 mmol) (prepared using the procedure described in Example 7) and bromodiphenylmethane (247 mg, 1 mmol) was dissolved in dimethylformamide (1.5 mL), followed by the addition of triethylamine (0.21 mL, 1.5 mmol). The reaction solution was stirred at room temperature under nitrogen for 10-15 hours and then diluted with 100 mL ethyl acetate. The organic layer was washed with water (3×30 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give crude title product. The final product was further purified by flash column chromatography (SiO2, 10% MeOH in EtOAc). The pure product was obtained in 50% yield in two steps. 1H-NMR (CD3OD, ppm): 8.36 (d, 2H), 7.18-7.43 (m, 12H), 4.29 (s, 1H), 3.46 (t, 2H), 2.45-2.61 (m, 10H). ESMS 440.4 (M+1), 462.4 (M+23).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].O.[OH-].[Na+]>C(O)=O>[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccnc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: Nc1nccc(C=Cc2ccc([N+](=O)[O-])cc2)n1
Yield: 57.5 %

Procedure:
The starting compound is prepared as follows. A solution of 2-amino-4-methylpyrimidine (21.8 g) and p-nitrobenzaldehyde (30.2 g) in formic acid (45 ml) is refluxed (24 hours). After cooling, the reaction mixture is poured into water (1 liter), and the aqueous mixture is neutralized with a 5N sodium hydroxide solution. The crude product is extracted with chloroform, and the extract is dried over sodium sulfate and concentrated to dryness. The crude product is purified on a silica gel column to give 4-[2-(p-nitrophenyl)ethenyl]-2-aminopyrimidine (27.8 g), m.p. 214°-216° C., which is used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:25](OC)([N:27](C)C)[CH3:26].[NH2:32]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:32][NH:27][C:25]([CH3:26])=[C:10]2[N:9]=1
Reactant: NN
Reactant: COc1cc2c(cc1C)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: COC(C)(OC)N(C)C
Product: COc1cc2c(cc1C)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-3,7-dimethyl-8-methoxy-pyrazolo[3,4-b][1,4]benzodiazepine (IVz) was prepared by reacting 0.0005 moles of 5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-7-methyl-2H-1,4-benzodiazepin-2-thione (IIz) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=353.
Reaction SMILES: [CH:1]1([C:7]([CH3:11])([CH3:10])[CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:22]1([CH:8]([NH:19][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][CH:15]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)([CH3:11])[CH3:10])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C=O)C1CCCCC1
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C1CCCCC1)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
The product from Example 22A, 4-chlorobenzamide, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:22])[CH:8]=2)[N:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[CH2:53](Br)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.O>CN(C)C=O>[CH2:53]([O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:29][CH2:28]1)[C:2](=[O:1])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2=[O:21])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CCOC(=O)CCCCn1c(=O)c2cc(O)ccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCCCn1c(=O)c2cc(OCc3ccccc3)ccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 30.6 %

Procedure:
To a suspension of ethyl 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate (1.34 g, 2.13 mmol) obtained in Example 105 and potassium carbonate (354 mg, 2.56 mmol) in N,N-dimethylformamide (50.0 ml), benzyl bromide (305 ml, 2.56 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18.5 hours. The reaction mixture was combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4) the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (5:1, v/v) to give the ethyl ester of the title compound (450 mg, 29%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[N+:10]([C:12]([CH3:23])([CH3:22])[CH2:13][O:14][Si](C(C)(C)C)(C)C)[O-:11].N1C=CC=CC=1.F.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[N+:10]([C:12]([CH3:23])([CH3:22])[CH2:13][OH:14])[O-:11]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)[N+]([O-])=Cc1ccc(F)cc1F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(CO)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 69.2 %

Procedure:
A solution of α-(2,4-difluorophenyl)-N-[dimethyl(t-butyldimethylsiloxymethyl) methyl]nitrone (688.3 mg, 2.00 mmol) in THF (20 ml) was cooled to 0° C. in ice-water bath. To the mixture was added carefully hydrogen fluoride-pyridine (1 ml). The mixture was gradually warmed to room temperature and stirred for 7 hours. The mixture was added to sat. NaHCO3 aqueous solution and extracted three times with ethyl acetate and dried over MgSO4. The solvent was evaporated and the white crystals were washed with hexane to give the title compound (317.3 mg; 69%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[C:18]1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[Li+].C[Sn](C)(C)C>COCCOCCOC.C(Cl)(Cl)Cl.CO>[CH3:18][C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Agent: C[Sn](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: COCCOCCOC
Solvent: CO
Product: Cc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Temperature: 100 °C
Reaction time: 3 h
Yield: 166.3 %

Procedure:
A solution containing 5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (203 mg, 0.687 mmol), tris(dibenzylidineacetone)dipalladium (0) (33 mg, 0.036 mmol), tri(o-tolyl)phosphine (95 mg, 0.312 mmol), lithium chloride (241 mg, 5.69 mmol), and tetramethylstannane (1.0 ml, 1.3 g, 7.2 mmol) in 2-methoxyethyl ether (5 ml) was heated in a bath maintained at 100° C. After 3 h, a further portion of tetramethylstannane (1 ml, 1.3 g, 7.2 mmol) was added, and heating was continued overnight. The solution was filtered, and subjected to purification by HPLC using a gradient of 0-20% 1:1:2 7M methanolic ammonia:methanol:chloroform and chloroform to obtain the title compound (120 mg, 0.519 mmol, 76%) as a pale solid: electrospray MS (m/z, relative intensity) 231 ([MH]+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[CH3:32][NH:33][CH3:34]>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[N:33]([CH3:34])[CH3:32]
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cc2nc(-n3cc(C(=O)O)cn3)nc(N(C)C)c2cc1Oc1c(C)cccc1C

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI/CI): predicted mass C23H23N5O3, 417.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].ClCCl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:26](=[O:27])[C:25]([CH3:30])([CH3:29])[CH3:24])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(OC(=O)C(C)(C)C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
4-Hydroxypyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 28, (1.42 mg, 4.40 mmol) is dissolved in pyridine (22 mL). 4-Dimethylamino-pyridine (10 mg) is added followed by trimethylacetyl chloride (1.63 mL, 13.2 mmol). The reaction is stirred at ambient temperature for 12 hours. The cloudy reaction mixture is then concentrated in vacuo to afford a white residue. Dichloro-methane (75 mL) is added to the residue and the mixture washed with a 1.0 N aqueous solution of hydrochloric acid (75 mL). The aqueous layer is extracted with dichloro-methane (75 mL), the combined organic layers washed with a saturated aqueous solution of NaHCO3 (75 mL), water (75 mL), brine (75 mL), then dried, filtered and concentrated in vacuo to afford the crude product. The crude product is purified over silica (4:1 to 1:1 hexane/ethyl acetate) to afford 1.76 g (98% yield) of the desired product as a clear, viscous oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(C)=O)(C)C.[Cl-].[Na+].O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:33](=[O:34])[CH2:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccccc1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
To an ice cold suspension of NaH (13 mg, 320 umol) in DMF (3 ml) under an argon atmosphere was added a solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (100 mg, 310 μmol; example 11.1) in DMF (1 ml) within 10 min. The suspension was stirred for 1 h at 0° C. A solution of phenyl-acetyl chloride (40 μl, 340 μmol; [103-80-0]) in DMF (1 ml) was added within 5 min. The reaction mixture was stirred for 14 h at ambient temperature, poured onto ice water/brine 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (10 mg, 23 μmol; 7%) as off-white solid. MS: m/e=444.1 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[NH:20]1[CH:29]2[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][CH2:22][CH2:21]1>>[OH:17][C:15]1[CH:16]=[C:8]([CH:9]=[C:10]([C:11]([N:20]2[CH:29]3[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:23][CH2:22][CH2:21]2)=[O:13])[CH:14]=1)[O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=1
Reactant: C1CCC2NCCCC2C1
Reactant: N#Cc1ccc(Oc2cc(O)cc(C(=O)O)c2)cc1
Product: N#Cc1ccc(Oc2cc(O)cc(C(=O)N3CCCC4CCCCC43)c2)cc1
Yield: 72.4 %

Procedure:
3-(4-Cyano-phenoxy)-5-hydroxy-benzoic acid (1.5 g, 5.87 mmol) and decahydro-quinoline (0.89 g, 6.45 mmol) and other reagents as described in Example 9(e) were used to afford 1.6 g of the required product. NMR (DMSO-d6): δ 1.35 (6H, m), 1.80 (7H, m), 3.0 (1H, m), 3.6 (1H, m), 4.5 (1H, m), 6.44 (1H, s), 6.54 (2H, m), 7.16 (2H, d), 7.88 (2H, d), 10.1 (1H, brs).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@H:6]([C:11]([OH:13])=[O:12])[C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:14]O>>[ClH:3].[CH3:14][O:12][C:11](=[O:13])[C@H:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH2:5]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[C@H](N)C(=O)O
Product: COC(=O)[C@@H](N)C(C)(C)C
Product: Cl
Temperature: 25 °C
Yield: 92 %

Procedure:
To anhydrous methanol (15 mL) at -20° C. under nitrogen was added thionyl chloride (4 mL) dropwise. The solution was allowed to warm to room temperature and then tert-Leucine (4.00 g) was added. The reaction mixture was warmed at 50° C. for 5 hours, re-cooled to -20° C., and then additional thionyl chloride (3 mL) was added dropwise. The reaction mixture was heated an additional 2.5 hours at 50° C. and then concentrated under reduced pressure and chased twice with methanol (15 mL) to afford an amorphous solid. The solid was triturated with ether to afford the title compound in 92% yield. The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 146 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:15]([CH2:14][CH2:13][CH2:12][CH2:11][Cl:10])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: Cc1ccc(N)c(Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)CCCCCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.30 ml (10.7 mmol) 2-chloro-4-methyl-aniline are placed in 30 ml of pyridine, combined with 2.67 g (10.5 mmol) 75% m 4-chlorobutyl-sulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with 6-molar hydrochloric acid, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=9:1->7:3).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.O=S(Cl)[Cl:18]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:18])=[O:15]
Reactant: O=C(O)CCCCCCCCCCCBr
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCCCCCCCCCBr
Yield: 95 %

Procedure:
Following a general procedure for preparing 21 (Creager et al. (1994) J. Electroanal. Chem., 370: 203–211), a solution of 12-bromododecanoic acid (4.2 g, 15 mmol) in SOCl2 (50 mL) was heated at 50° C. under argon for 1 h. The excess SOCl2 was removed by water pump distillation with benzene (3×50 mL). 4.3 g (95%) of 12-bromododecanoyl chloride was obtained as a colorless oil and used in the subsequent reaction without further purification. In a 50 mL flask anhydrous AlCl3 (2.8 g, 21 mmol) was added to a stirred solution of 12-bromododecanoyl chloride (4.0 g, 13.6 mmol) in dry CH2Cl2 (30 mL) at 0° C. under argon for 20 min. Then the mixture was added dropwise over 10 min to a solution of ferrocene (2.6 g, 14 mmol) in CH2Cl2 (50 nL) at 0° C. The mixture was stirred and allowed to warm to rt. After 2 h water (30 mL) was added slowly into this mixture. Then the phases were separated, and the organic layer was washed with water (3×100 mL) and NaHCO3 (2×50 mL) and over (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica, petroleum ether/diethyl ether, 10:3) to afford a red oil (4.3 g, 85%). 1H NMR δ 1.28 (s, 16H), 1.64 (m, 2H), 2.63 (m, 2H), 3.29 (m, 2H), 4.19 (s, 5H), 4.48 (A2B2, J=1.5 Hz, 2H), 4.78 (A2B2, J=1.5 Hz, 2H); 13C NMR δ 25.0, 28.5, 29.0, 30.1, 30.9, 33.3, 34.5, 40.5, 70.0, 70.4, 72.9, 89.0, 205.0; FAB-MS obsd 446.0955, calcd exact mass 446.0958 (C12H31BrFeO).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[S:9](=O)(=[O:12])([OH:11])[OH:10]>C(Cl)CCl>[Br:1][C:2]1[CH:7]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[Br:8]
Reactant: O=S(=O)(O)O
Reactant: Brc1ccccc1Br
Solvent: ClCCCl
Product: O=S(=O)(O)c1ccc(Br)c(Br)c1
Reaction time: 2 h
Yield: 94 %

Procedure:
A 300-ml four-neck flask equipped with a stirring device, a condenser and a thermometer was prepared. Then, 120 g of 1,2-ethylene dichloride and 76 g (0.32 mols) of 1,2-dibromobenzene were placed in the flask, and 56 g (0.42 mols) of 60% fuming sulfuric acid was added thereto dropwise in a gentle stream of nitrogen gas and allowed to react therewith at 70° C. for 2 hours. After the resulting reaction product solution was cooled, a reaction product was filtered out and then dried. Thus, 95 g of crude 3,4-dibromobenzenesulfonic acid was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28]CC)=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[OH-].[Na+]>C1COCC1.CCO.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:31][CH2:32]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:40]=[CH:41][C:42]([Br:45])=[CH:43][CH:44]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1nc(O[C@H](c2ccc(Br)cc2)C(F)(F)F)cc(N2CCC3(CC2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C3)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (190 mg, 0.27 mmol) was added NaOH (100 mg, 0.26 mmol) in 15 mL THF/EtOH/H2O (2/1/2.5), and the reaction was stirred for 12 h at RT. Then, the reaction mixture was concentrated in vacuo to remove most of the organic solvents, and the pH was adjusted to 6 with 1 N HCl. EtOAc was added, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(benzyloxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid which was used without further purification.