Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[OH:14])=[CH:7][CH:6]=1.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-].O>C1(C)C=CC=CC=1.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[O:14][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][CH:6]=1
Reactant: OC1CCc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)COC1CCc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Reaction time: 8 h

Procedure:
Rhodium (II) acetate dimer (approximately 10mg) was suspended in a solution of the indanol (Example 3, step B, 0.5g) in dry toluene (10 cm3). A solution of ethyl diazoacetate (0.18g) in a small volume of dry toluene was slowly added dropwise to the reaction mixture. Effervescence was observed, the solid dissolved and the solution turned a blue green colour. The mixture was allowed to stand at room temperature overnight then poured into water. The aqueous mixture was extracted with diethyl ether, washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Preparative thin layer chromatography (silica/hexane-ether, 7:3) gave compound 3, ethyl (RS)-6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)indan-1-yloxyacetate, as a colourless oil (0.17g,27%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Br[CH2:9][CH2:10][C:11]#[N:12]>C(O)C.[OH-].[Na+]>[C:11]([CH2:10][CH2:9][S:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)#[N:12]
Reactant: Sc1nnc(S)s1
Reactant: N#CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CCCSc1nnc(S)s1

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole (7.50 g) was dissolved in a mixture of 50 ml of ethanol and 50 ml of 1N-sodium hydroxide solution to which 4.15 ml of 3-bromopropionitrile was added under stirring. After stirring for 48 hours at room temperature, the mixture was concentrated under reduced pressure. The concentrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and distilled off to remove the solvent. The residue was washed with ethyl ether to give 7.74 g of 2-(2-cyanoethylthio)-5-mercapto-1,3,4-thiadiazole as yellow crystals.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36].C(N(CC)CC)C.[C:45]([C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>C(OCC)(=O)C.CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:53][C:52]2[CH:54]=[CH:55][C:49]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:50][CH:51]=2)=[O:32])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To DMF (10 mL) was added HATU (3.61 g, 9.50 mmol), 4-amino-3-nitrobenzoic acid (1.15 g, 6.32 mmol), triethylamine (1.32 mL, 958 mg, 9.47 mmol), and 4-tert-butylaniline (1.0 mL, 945 mg, 6.33 mmol). The mixture was stirred at ambient temperature for 18 h then was poured into ethyl acetate and extracted once with water and five times with brine. The organic phase was dried, filtered, and the solvent removed under reduced pressure. The residue was purified by chromatography using gradient of a 30-70% heptane/ethyl acetate to afford 4-amino-N-(4-tert-butylphenyl)-3-nitrobenzamide. MS (ESI) m/z 314.1 (M+H); retention time 1.50 min (Method 10), which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:36][C:35]1=[O:48]>>[Si:41]([O:40][CH2:39][C@@H:38]1[CH2:37][CH2:36][C:35](=[O:48])[N:34]1[C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:20])[CH3:21])=[O:23])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1c1cc(F)ccc1CN
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one, derived from reduction of intermediate 121, (R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile. 1HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.52–7.33 (7H, m), 7.02 (1H, broad s), 5.60 (2H, s), 4.60–4.20 (2H, m), 4.02 (3H, t, J=5.0 Hz), 3.89 (3H, t, 5.0 Hz), 3.53 (2H, broad s), 2.51 (2H, s), 2.44–2.26 (2H, m), 1.94 (1H, broad s), 1.57 (3H, s), 1.55 (3H, s), 0.82 (9H, broad s), −0.02 (6H, s). LCMS (M+H)+ m/z 665.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[OH-].C(O)(=O)C>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Reaction time: 18 h

Procedure:
To a solution of 1.3 g (2.7 mmol) of ethyl 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]octanoate in 8.1 ml acetonitrile is added 2.7 ml (5.4 mmol) 2 M LiOH solution in water. After 18 hours at room temperature, the reaction mixture is diluted with 9.5 ml water and filtered to remove a small amount of insoluble solid. The filtrate is acidified with 0.36 g (5.94 mmol) acetic acid and stirred in an ice bath. After 2 hours the solid is filtered, washed with water and dried. Recrystallization from acetonitrile gives pure compound of example 31, namely 8-(p-chlorophenyl-sulfonamido)-4-[2-(3-pyridyloxy)ethyl]octanoic acid, m.p. 86-88°; further recrystallization gives m.p. 89-91°. Compound forms potassium salt as hydrate (containing 1.5 moles water).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][Cl:26])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1ccc(Cc2ccccc2OCc2ccccc2)cc1

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzyl alcohol (0.67 g) in dichloromethane (30 mL) was added thionyl chloride (0.48 mL), and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 4-(2-benzyloxybenzyl)benzyl chloride (0.68 g).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CO[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[C@:26]3([C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:35])[CH2:25]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C@H:24]2[C@:26]3([C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([C:11]4[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=4)[C:8]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:16])[C:27]3=[O:35])[CH2:25]2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1cccc(I)c1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@H]2c1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cccc(N2C(=O)[C@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 85 starting from methanesulfonamide, methyl-3-iodobenzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H19ClN2O4S: 466, observed (M+H)+: 467.2 1H NMR (400 MHz, DMSO-d6) δppm 2.31-2.41 (m, 2 H) 3.37 (s, 3 H) 3.43 (t, J=8.72 Hz, 1 H) 6.90 (d, J=7.83 Hz, 1 H) 7.16 (t, J=7.33 Hz, 1 H) 7.25 (dd, J=7.83, 1.01 Hz, 1 H) 7.27-7.35 (m, 3 H) 7.35-7.43 (m, 2H) 7.62-7.70 (m, 2 H) 7.94-7.99 (m, 2 H) 12.24 (br. s., 1 H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:30]1([C:36]2[N:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]4[N:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37]=4)[CH2:31][CH2:32]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ncc2c1
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3ncc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-piperazin-1-yl-quinazoline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)=[CH:23][CH:22]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-(trifluoromethyl) pyridine (3000 mg, 13.274 mmol), [2-(4-hydroxy-phenyl)ethyl]-carbamic acid tert-butyl ester (3150 mg, 13.274 mmol) and potassium carbonate anhydrous (2752 mg, 19.911 mmol) were dissolved in DMF (150 ml) and reaction was stirred at 60° C. overnight. The reaction mixture was washed with EtOAc and water (3×). Organic layers were combined and dried over phase separator filter tube affording the crude product which was purified on Biotage SP-1 system using 50 g Si SNAP column. The column containing sample was eluted with EtOAc/CyHex gradient (0-30% of EtOAc/30 CV). Fractions with desired product were gathered and solvent was evaporated to give the required product {2-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester as a white solid (2200 mg, yield=42.9%, purity 99%). [M+H]+=383.39
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[C:7]([Cl:20])[CH:6]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([Cl:20])[CH:6]=1
Reactant: COC(=O)Cc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1cc(Cl)c(Oc2ccc(NCc3ccccc3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 88.1 %

Procedure:
A stirred mixture consisting of methyl[3,5-dichloro-4-(4-aminophenoxy)phenyl]acetate (0.32 g), benzaldehyde (0.20 g), sodium cyanoborohydride (0.03 g), methanol (15 mL) and one drop of acetic acid was stirred at room temperature for 5 days. The reaction mixture was concentrated and the residue partionated between ethyl acetate and sodium hydrogen-carbonate (saturated aqueous solution). The aqueous phase was further extracted with ethyl acetate. The collected organic phases were purified on column (silica gel, n-heptane/ethyl acetate, 9:1) to give 0.36 g of methyl[3,5-dichloro-4-(4-benzylaminophenoxy)phenyl]acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14]C)=[O:12])[CH3:2].[H-].[Na+].[CH:28](OCC)=[O:29]>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:28][OH:29])=[O:25])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CO)c1c(C(=O)OC)ccn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 2-[2-(ethyloxy)-2-oxoethyl]-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrole-3-carboxylate (18.51 g) in dry tetrahydrofuran (300 ml) was stirred at room temperature under argon. Sodium hydride (60% dispersion in mineral oil, 70.0 g) was added portionwise and stirring continued for 15 minutes after complete addition. Ethyl formate (9.12 ml) was added to the reaction mixture and stirred for 30 minutes after which time an exotherm was observed and controlled by cooling the reaction mixture to room temperature with an ice bath. The reaction mixture was stirred for a further 3.5 h. The reaction mixture was cooled in an ice bath and quenched by addition of the minimum amount of methanol then evaporated. The residue was partitioned between ethyl acetate and saturated ammonium chloride, the aqueous layer was removed and acidified to pH 1 with a 2M solution of aqueous hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated to afford an oil consisting of two layers. The top layer was discarded and the lower layer isolated to afford the title compound as a brown oil (17.6 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=4)(O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CO>C1(C)C=CC=CC=1>[CH2:24]([C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH2:15][CH2:16][CH:11]([CH:8]3[CH2:7][CH2:6][C:5]4([O:1][CH2:2][CH2:3][O:4]4)[CH2:10][CH2:9]3)[CH2:12][CH:13]=2)=[CH:23][CH:22]=1)[CH2:25][CH3:26]
Reactant: CCCc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)cc1

Procedure:
250 g (about 0.7 mol) of crude 4-(1,4-dioxaspiro[4.5]dec-8-yl)-1-(4-propylphenyl)cyclohexanol are heated on a water separator together with 13.2 g (69 mmol) of p-toluenesulfonic acid monohydrate and 40.7 ml (0.73 mol) of ethylene glycol in 800 ml of toluene. The solution is washed a number of times with water and dried using sodium sulfate. The crude product remaining after removal of the solvent is purified by chromatography (SiO2, n-heptane:MTBE=5:1). 8-[4-(4-Propylphenyl)cyclohex-3-enyl]-1,4-dioxaspiro[4.5]decane is obtained as a colourless solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[C:14]1([S:20]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:36][CH:35]=3)[CH:26]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([S:20]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[C:27]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)[CH:26]=2)(=[O:21])=[O:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Reactant: CCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
Triethylamine (0.060 g) and 0.084 g of butyryl chloride were added to a solution of 0.300 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 2 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was directly purified through silica-gel column chromatography to obtain 0.250 g of N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-butyrylaminobenzamide. To this compound were added 5 ml of methanol and 0.50 g of 35% hydrochloric acid, and the mixture was stirred at 60° C. for 3 hours. Then, 20% potassium hydrogencarbonate was added thereto to stop the reaction, and the reaction solution was extracted with ethyl acetate and with water. The organic layer was concentrated, and the product was dissolved in a small amount of chloroform. Ether was added thereto for crystallization. The crystals precipitated were separated through filtration, and were dried to give 0.157 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylbenzimidazole potassium salt (232).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)[CH3:2].[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:31]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:32])[CH2:23][CH2:24]2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)[CH3:2]
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)N2CCOCC2)CC1
Yield: 61.3 %

Procedure:
Using the general method of Example 11 Part H, 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine (0.304 g, 0.917 mmol) was reacted with 4-morpholinecarbonyl chloride (0.107 mL, 0.917 mmol) to provide 0.250 g of 2-(ethoxymethyl)-6,7-dimethyl-1-{2-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine as an yellow orange solid, m.p. 158.1-160.5° C. Analysis: Calculated for C23H36N6O3: %C, 62.14; %H, 8.16; %N, 18.90; Found: %C, 62.02; %H, 7.94; %N, 18.99. 1H NMR (300 MHz, DMSO-d6) δ5.82 (s, 2 H), 4.64 (s, 2 H), 4.34-4.29 (m, 2 H), 3.62-3.54(m, 6 H), 3.50 (q, J=7.0 Hz, 2 H), 3.1 (t, J=4.4 Hz, 4 H), 2.74 (t, J=11.8 Hz, 2 H 2.38 (s, 3 H), 2.31 (s, 3 H), 1.67-1.55 (m, 5 H), 1.27-1.1 (m, 2H), 1.14 (t, J=7.0 Hz, 3 H); MS (CI) m/e 445.2935 (445.2927 calcd for C23H36N6O3, M+H).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5]N.Cl.[CH2:8]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C([N:37](CC)CC)C>CN(C)C1C=CN=CC=1.C(COC)OC>[Br:2][CH2:3][CH2:4][CH2:5][CH:31]([C:28]1[CH:29]=[CH:30][C:25]([NH:24][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:26][CH:27]=1)[C:32]([NH2:37])=[O:33]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)Cl)cc1
Reactant: NCCCBr
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(CCCBr)C(N)=O)cc1

Procedure:
To a slurry of 21.80 g. of 3-bromopropylamine hydrobromide in 200 ml. of glyme at 3° C. is added a solution of 23.96 g. of 4-(hexadecylamino)phenylacetyl chloride hydrochloride in 65 ml. of glyme, concurrently with 26 ml. of triethylamine diluted to 39 ml. with glyme. The solution is warmed to reflux and 0.2 g. of 4-dimethylaminopyridine is added. The solution is heated for four hours and cooled overnight. The solid is removed and the mother liquor diluted with 200 ml. of water giving 12.94 g. The solid is recrystallized from cyclohexane and is then chromatographed on silica gel by elution with chloroform. The largest component is recrystallized from acetronitrile.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](Cl)=O)[O:4][N:3]=1.OC[CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:21][CH2:20]1.[C:32](=[O:35])(O)[O-:33].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:31][S:28]([NH:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([O:33][C:32](=[O:35])[N:13]([CH3:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:5]2[O:4][N:3]=[C:2]([CH3:1])[N:6]=2)[CH2:24][CH2:23]1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)NCCN1CCC(CO)CC1
Reactant: O=C([O-])O
Reactant: Cc1noc(-c2ccccc2NC(=O)Cl)n1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1noc(-c2ccccc2N(C)C(=O)OC2CCN(CCNS(C)(=O)=O)CC2)n1
Reaction time: 0.17 h

Procedure:
[2-(3-Methyl-1,2,4-oxadiazol-5-yl)phenyl]carbamoyl chloride (7.5 g) was placed in a flask equipped with an air stirrer and ground to a powder N-[2-[4-(Hydroxymethyl)-1-piperidinyl]ethyl]methanesulphonamide (9.33 g) was added and the solids intimately mixed under nitrogen for 10 min at room temperature. The mixture was stirred under a stream of nitrogen at 150° for 10 min. The mixture was allowed to cool then toluene/ethanol (10:1; 110 ml) was cautiously added followed by 8% sodium bicarbonate solution. The mixture was vigorously stirred, the layers were separated and the aqueous phase extracted with 10% ethanol in dichloromethane (4×100 ml). The organic solutions were combined and dried and concentrated in vacuo to give a beige solid. This was purified by FCC eluting with System A (100:8:1) to give the title compound (11.83 g) as fluffy off-white needles.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:10]2)=[CH:5][CH:4]=1.O1CCCC1.O.[Li+].[OH-]>CO>[CH3:28][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)=[CH:26][CH:27]=1
Reactant: CN(C)c1ccc(CCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(CCN2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-(4-dimethylaminophenethyl)-3-(4-nitrobenzoyloxy) pyrrolidine (1.00 g, 2.70 mmol) was dissolved in methanol (20 ml), tetrahydrofuran (20 ml) and water (10 ml). 4M-LiOH (3 ml) was added dropwise in the obtained solution, and they were stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was distributed in water and ether. The organic layer was dried and the solvent was evaporated under reduced pressure to obtain (S)-1-(4-dimethylaminophenethyl)-3-hydroxypyrrolidine in the form of a light yellow solid (320 mg, 62%).