Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[C:7](N)[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[N:10]=2)[CH:6]=1.BrCCCC(Cl)=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:14]1[C:8]2[C:9](=[N:10][C:4]3[C:5]([CH:7]=2)=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH2:11][CH2:12][CH2:13]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Agent: O=C(Cl)CCCBr
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: c1ccc2nc3c(cc2c1)CCCC3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tacrine (4 g, 20.17 mmoles) in chloroform (50 ml) and N,N-dimethylformamide (15 ml), 4-bromobutyroylchloride (3.5 ml, 30.25 mmoles) is added. The reaction mixture is maintained under stirring at room temperature for 6 hours and then diluted with chloroform and washed with water. The organic phase, anhydrified with sodium sulphate, is evaporated at reduced pressure. The crude product is purged by chromatography on silica gel, eluting with n-hexane/ethyl acetate 8/2 (ratio by volume). 9-[4-bromo)butyroylamino]-1,2,3,4-tetrahydroacridine is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]3[CH2:23][CH2:22][OH:21])=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: OCCC1CCCCN1
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCCCC3CCO)nc21

Procedure:
The title compound, m.p. 234°-237° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 2-(hydroxyethyl)piperidine using procedures analogous to those described above, except that the mixture was heated at reflux for 1.25 hrs, and the product was crystallized from ethyl acetate/ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[N:23][CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[N:23][CH:24]=[C:19]([F:18])[CH:20]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1cncc(F)c1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3cncc(F)c3)cc2sc1=O

Procedure:
7-(5-Fluoro-pyridin-3-yl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 5-fluoro-3-pyridyl-boronic acid under conditions analogous to Example 14(a). MS ESI(+) m/e: 332.08 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][S:11][C:10]=2[CH:13]=1
Reactant: Oc1ccc2c(-c3ccc(F)cc3)csc2c1
Reactant: BrCCCCBr
Product: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1

Procedure:
In analogy to example 27.1, 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene, MS: 378 (M, 1Br).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][O:12][CH2:11]1.O>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:14](=[O:15])[CH2:13][O:12][CH2:11][C:10]([OH:17])=[O:16]
Reactant: Cc1cccc(CN)c1
Reactant: O=C1COCC(=O)O1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(CNC(=O)COCC(=O)O)c1
Reaction time: 1 h

Procedure:
N-(3-methylbenzyl)-diglycolic acid, monoamide was prepared as follows: 2.4 g (0.02 moles) of 3-methylbenzylamine (Aldrich Chemical) was added to 3.0 g (0.026 mole) of diglycolic anhydride (Aldrich) dissolved in 15 mL dioxane. The solution was warmed, with stirring, at 70°-80° C. for 60 min. After cooling slightly, water was added to near the cloud point. After standing 60 minutes at room temperature, the crystals were filtered by suction, washed with water, and air dried. Recrystallized from water-ethanol.
Reaction SMILES: [H-].[Na+].C[N:4](C=O)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=1)=[O:12])[CH3:9].[N+](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>O>[CH2:8]([O:10][C:11]([C:13]1[N:14]([NH2:4])[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)[nH]1
Reactant: CN(C)C=O
Agent: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(C(=O)OCC)n1N
Reaction time: 1 h

Procedure:
NaH (60% in mineral oil, 154.3 mg, 3.86 mmol) was rinsed with hexanes (5 ml), then anhydrous DMF (10 ml) was added, to this suspension 406B (0.68 g, 3.22 mmol) was added portionwise at 0° C., and the mixture was stirred for 1 h from 0° C. to rt. O-(2,4-dinitro-phenyl)-hydroxylamine (705.6 mg, 3.54 mmol) was added in two portions at 0° C., the reaction mixture was stirred at rt overnight. Water (50 ml) was added, the mixture was extracted with EtOAc (3×25 ml), the combined organic layer was washed with water (4×20 ml) and brine (1×20 ml), dried and concentrated. The residue was purified by silica gel flash column chromatography to give 406C (480 mg, 66%) as a yellow solid (25% EtOAc—hexanes).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[CH:11]([OH:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([O:4][CH2:5][C:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc2c1CCc1ccccc1C2O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)OCc1cccc2c1CCc1ccccc1C2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.7 %

Procedure:
3.5 g of (5-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate prepared in Example 1-d was dissolved in 50 ml of dichloromethane and 10 g of manganese dioxide was added, followed by stirring at room temperature for 2 days. The reaction mixture was filtered through Celite, and the filtrate was washed with ethyl acetate and the solvent was evaporated, to give 2.7 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[F:23])=[CH:7][C:3]=1[C:4](O)=[O:5].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.C(OC([N:50]1[CH2:55][CH2:54][CH:53]([S:56]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[N:71]=[CH:70][C:69]([NH2:72])=[CH:68][N:67]=3)=[CH:61][CH:60]=2)(=[O:58])=[O:57])[CH2:52][CH2:51]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][C:14]=2[F:23])=[CH:7][C:3]=1[C:4]([NH:72][C:69]1[CH:70]=[N:71][C:66]([NH:65][C:62]2[CH:63]=[CH:64][C:59]([S:56]([CH:53]3[CH2:54][CH2:55][NH:50][CH2:51][CH2:52]3)(=[O:57])=[O:58])=[CH:60][CH:61]=2)=[N:67][CH:68]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cc(C(F)(F)F)ccc1F
Agent: COc1nc(Cl)nc(OC)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCNCC4)cc3)nc2)c1)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.7 %

Procedure:
Intermediate 18 (Example 26) (0.159 g, 0.44 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were diluted with DCM (4 mL) and treated with TFA (0.2 mL). After 2 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.017 g, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:16]([O-:18])=[O:17])[NH:9][C:8]=2[CH3:19])=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:16]([O-:18])=[O:17])[N:9]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]c2cccc([N+](=O)[O-])c2c1Oc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2c([N+](=O)[O-])cccc21
Reaction time: 0.17 h

Procedure:
The product from step (ii) (6.0 g) was dissolved in THF (100 ml), sodium t-butoxide (2.1 g) added, stirred for 10 min, ethyl bromoacetate (2.45 ml) added and stirred for a further 20 min. The reaction was quenched with 1M hydrochloric acid, extracted with EtOAc, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with 20% ethylacetate/iso-hexane. Yield 6 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:27]([CH3:26])(=[O:29])=[O:28])[C@H:9]1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[F:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)NCc1cccc(Cl)c1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of (2S,3S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.98 g, 2.64 mmol) in dry pyridine (13 mL) was added methanesulfonyl chloride (0.31 mL, 3.96 mmol). The reaction was stirred at 0° C. for 2 h and then at RT for 72 h. The volatiles were evaporated in vacuo and the residue was partitioned between water and EtOAc. The aqueous layer was repeatedly extracted with EtOAc, the combined organics were washed with 0.1N HCl and brine, dried (phase separator) and concentrated in vacuo to afford the title compound. Brown oil. MS (LC-MS): 451 [M+H]+, 395 [MH−tBu]+, 351 [MH−Boc]+; tR (HPLC conditions c): 5.08 min. The material thus obtained was used without any purification.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Product: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12

Procedure:
deprotection of 9-benzenesulfonyl-9H-carbazol-4-ol to give 4-hydroxy-carbazole reaction of 4-hydroxy-carbazole with epichlorohydrin under basic conditions to give 4-oxiranylmethoxy-9H-carbazole;
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:13]([C:4]1[CH:3]=[C:2]([NH:1][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 43.3 %

Procedure:
In the manner described in Example 161C, using ethyl 2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)acetate (1.68 g, 7.46 mmol), phenyl chloroformate (1.284 g, 8.2 mmol), and K2CO3 (1.52 g, 11 mmol) in THF (20 mL), which was purified by silica gel chromatography with 0-40% EtOAc/hexane as eluants to afford ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate as solid (1.115 g, 43%). 1H NMR (300 MHz, CDCl3) δ 7.37-7.43 (m, 2H), 7.25-7.27 (m, 2H), 7.21 (m, 2H), 6.25 (s, 1H), 4.88 (s, 2H), 4.28 (q, 2H), 1.33 (t, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 346 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]2[CH3:11].[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:23][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]3[CH3:11])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCC1
Reactant: Cn1c(-c2ccccc2)nc2c(Cl)ncnc21
Product: Cn1c(-c2ccccc2)nc2c(NC3CCCC3)ncnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-chloro-9-methyl-8-phenylpurine (1.0 mmol) was added to cyclopentylamine (10 mL). The reaction mixtures were stirred at room temperature for 5 hours. After that, the solvent was evaporated and pure cyclopentyl(9-methyl-8-phenylpurin-6-yl)amine, a compound of Formula (I), was obtained after silica gel chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([NH2:24])=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([NH2:24])=[N:21][C:22]([O:25][C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)nc(N)nc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4C#N)nc(N)nc32)CC1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
A mixture of: 4-(6-amino-4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 33; 224 mg, 0.64 mmol), 2-hydroxybenzonitrile (available from Alfa Aesar, Ward Hill, Mass., USA; 95.2 mg, 0.8 mmol), and potassium carbonate (220 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL) was heated at 80° C. for 3 h, and then cooled. Volatiles were evaporated and the residue was chromatographed (50-65% ethyl acetate/hexanes) to give 4-[6-Amino-4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (261 mg, 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:21]=[CH:20][C:13]3[O:14][CH:15]([CH2:18][OH:19])[CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([SH:24])[N:3]=1.[OH:25][CH2:26][CH2:27]Br.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:21]=[CH:20][C:13]3[O:14][CH:15]([CH2:18][OH:19])[CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:27][CH2:26][OH:25])[N:3]=1
Reactant: OCCBr
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc2c(c1)OCC(CO)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCCO)c(C#N)c1-c1ccc2c(c1)OCC(CO)O2

Procedure:
30 mg (0.09 mmol) of 2-amino-6-sulfanyl-4-[2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)], 22 mg (0.18 mmol) of 2-hydroxyethyl bromide and 29 mg (0.35 mmol) of sodium bicarbonate are stirred in 1.5 ml of DMF at room temperature overnight. The reaction solution is purified directly by preparative HPLC on reversed-phase silica gel.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([F:19])[CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([O:13][C:12]([NH:11][C@H:8]1[C:9]2[C:5](=[C:4]([F:19])[CH:3]=[C:2]([C:12]([O:13][CH3:14])=[O:18])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(F)cc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COC(=O)c1cc(F)c2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Reaction time: 16 h
Yield: 83 %

Procedure:
(R)-tert-Butyl 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-ylcarbamate (1.1 g, 3.33 mol, 1.0 eq.) was dissolved in MeOH (35 ml) and DMSO (30 ml), and the mixture was degassed for 30 minutes with argon. Pd(OAc)2 (0.038 g, 0.166 mmol, 0.05 eq.), 1,3-bis(diphenylphosphino)-propane (0.068 g, 0.166 mmol, 0.05 eq.) and TEA (1.39 ml, 9.99 mmol, 3.0 eq.) were then added, and stirring was carried out for 16 hours in a pressure vessel at 75° C. under CO pressure (80 psi). The reaction mixture was concentrated, diluted with water (50 ml) and extracted with ethyl acetate (2×75 ml). The combined org. phases were washed with sat. NaCl solution (60 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 10% ethyl acetate in hexane). Yield: 83% (0.86 g, 2.783 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:19](=[O:23])(=[O:22])([OH:21])[OH:20]>>[S:19]([OH:23])([OH:22])(=[O:21])=[O:20].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3([CH2:14][CH2:15][CH2:16][CH2:17]3)[NH:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCCNC12CCCC2
Agent: O=S(=O)(O)O
Product: Clc1ccc(C2=CCCNC23CCCC3)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10-(4-Chlorophenyl)-10-hydroxy-6-azaspiro[4.5]decane (1.6 g) was dissolved in concentrated sulphuric acid (18 ml) and stirred at ambient temperature for 1.5 hours. The mixture was poured cautiously onto ice-water (35 ml), stirred at 0° C. for 1 hour and allowed to stand at 4° C. for 24 hours. The product was collected by filtration, washed with water and dried in vacuo at ambient temperature to give 10-(4-chlorophenyl)-6-azaspiro[4.5]dec-9-ene sulphate as an off-white solid. Yield 1.7 g, mp 184°-190° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([O-:3])=[O:2].[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:23]([O:22][C:21](=[O:27])[NH:20][CH2:19][CH2:18][NH:17][CH:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:11][CH2:12]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8 (945 mg, 4.29 mmol), 1 (695 mg, 4.33 mmol), and acetic acid (1.31 g, 21.8 mmol) in methanol (10 mL) was treated with sodium cyanoborohydride (270 mg, 4.29 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6 mm, 10% EtOH-90% CHCl3) afforded the title compound (9).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: COc1ccnc(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccnc(-c2ccc(Cl)c(N)c2)c1
Yield: 98.1 %

Procedure:
To a suspension of 1-chloro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (200 mg) in ethanol (6 ml) and water (0.6 ml) were added iron powder (206 mg) and ammonium chloride (28 mg), and the mixture was refluxed for 3 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. To the residue were added ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 2-chloro-5-(4-methoxypyridin-2-yl)aniline (174 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>C(OCC)(=O)C.O>[N:4]([C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
To a 0° C. solution of 2,6-dichloroaniline (2.00 g) in ethyl acetate (40 mL) is added concentrated hydrochloric acid (12 mL). The reaction is stirred for 10 min. To this solution is added a solution of sodium nitrite (2.55 g) in water (7.5 mL) over 3 min. Upon completion of the addition, the reaction is stirred for an additional 30 min. A solution of sodium azide (2.41 g) in water (8 mL) is added over 5 min. After 30 min, pH 7 buffer (50 mL) is added and the reaction is transferred to a separatory funnel. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.11 g). 1H NMR (400 MHz, CDCl3) δ 7.3-7.27 (d, 2H), 7.07-7.02 (t, 1H)
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].[F:5][C:6]([F:13])([F:12])[C:7]([F:11])=[C:8]([F:10])[F:9]>>[F:5][C:6]([F:13])([F:12])[CH:7]([F:11])[C:8]([F:10])([F:9])[C:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CC(C)C
Product: CC(C)(C)C(F)(F)C(F)C(F)(F)F

Procedure:
Isobutane (1.98 g., 34.2 mmole) and hexafluoropropene (1.71 g., 11.4 mmole) were heated at 295° for 4 days to give: (i) isobutane (1.42 g., 24.4 mmole; 71% recovery); (ii) hexafluoropropene (0.51 g., 3.4 mmole; 30% recovery); (iii) 1,1,1,2,3,3-hexafluoro-4,4-dimethylpentane (CH3)3C. CF2. CHF. CF3 (1.39g., 6.7 mmole; 84% based on C3F6 consumed) (Found: C, 40.6; H, 4.7%; M, 209. C7H10F6 required C, 40.4; H, 4.8%; M, 208), b.p. 101° C. Similar reactions carried out at 210° C, 260° C and 330° C gave respectively 2% 43% and 51% conversions to 1,1,1,2,3,3-hexafluoro-4,4-dimethylpentane (100%, 80% 52% yields based on C3F6 consumed).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20](F)=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.N1([CH2:38][C:39]2[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=2)[NH2:42])CCCC1>>[NH2:3][CH:4]1[CH2:38][C:39]2[CH:40]=[C:41]([NH:42][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:22]=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:20]=[CH:19][CH:18]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:43]=[CH:44][C:45]=2[CH2:6][CH2:5]1
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: O=C(Cc1cccs1)Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F
Product: NC1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 55.7 %

Procedure:
N-{5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mmol) and 3-(1-pyrrolidinylmethyl)aniline (78 mg, 0.44 mmol) were coupled according to the procedure of Example 56, Step H to give of the title compound (35 mg, 26%). 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 9.49 (s, 1H), 8.80 (d, J=6.8 Hz, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.26-8.22 (m, 2H), 7.64 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.37-7.32 (m, 3H), 7.16-7.07 (m, 2H), 6.95-6.93 (m, 2H), 6.85 (d, J=7.2 Hz, 1H), 6.49 (d, J=4.8 Hz, 1H), 3.96 (s, 2H), 3.48 (br s, 2H), 2.38 (m, 4H), 1.64 (m, 4H) ppm. ES-LC/MS m/z=604 [M+H]+.