Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([N+:31]([O-])=O)[CH:30]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[O:8])([O-])=O>C(OCC)(=O)C.[C].[Pd]>[NH2:31][C:29]1[CH:28]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:30]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[O:8]
Reactant: CC[C@H]1CC[C@H](c2ccc(OCCCOC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@H]1CC[C@H](c2ccc(OCCCOC(=O)c3cc(N)cc(N)c3)cc2)CC1

Procedure:
In 300 ml of ethyl acetate was dissolved 15.0 g (0.033 mol) of [4-(trans-4-ethyl-cyclohexyl)phenoxypropyl] 3,5-dinitrobenzoate, and 1.50 g of 5% palladium-carbon was then added thereto and catalytic reduction was carried out at ordinary temperature under atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration and the solvent was distilled off under reduced pressure to obtain a crystal. The thus obtained crystal was recrystallized from n-heptane/ethyl acetate twice to obtain 11.1 g (0.028 mol) of [4-(trans-4-ethyl-cyclohexyl)phenoxypropyl] 3,5-diaminobenzoate. The melting point of this compound was in the range of 91.5° to 92.4° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([OH:28])=O)=[CH:25][C:19]=3[N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:32][CH:31]=3)[C:17](=[O:43])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.Cl.[CH3:47][NH:48][CH3:49].C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:47][N:48]([CH3:49])[C:26]([C:24]1[CH:23]=[CH:22][C:20]2[CH2:21][N:15]([C:13](=[O:14])[C:12]3[CH:44]=[CH:45][C:9]([Cl:8])=[CH:10][CH:11]=3)[CH2:16][C:17](=[O:43])[N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)=[CH:32][CH:31]=3)[C:19]=2[CH:25]=1)=[O:28]
Reactant: O=C(O)c1ccc2c(c1)N(Cc1ccc(OC3CCNCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc2c(c1)N(Cc1ccc(OC3CCNCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
5 mg (0.008 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(4-piperidyloxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid trifluoroacetate was dissolved in 5 ml of dichloromethane. 2 mg (0.018 mmol) of dimethylamine hydrochloride, 3 mg (0.018 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 ml (0.036 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([N:23]2[C:27](=[O:28])[CH:26]=[CH:25][C:24]2=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:17]1([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([O:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:24]2=[O:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: O=C1C=CC(=O)N1c1ccccc1
Solvent: C1CCOC1
Product: O=C1CC(ON(Cc2ccccc2)Cc2ccccc2)C(=O)N1c1ccccc1
Yield: 56.4 %

Procedure:
A suspension of 6.0 g (28 mmole) of N,N-dibenzylhydroxylamine and 4.87 g (28 mmole) of N-phenylmaleimide in 50 ml of dry tetrahydrofuran is heated at reflux for 40 hours. The solvent is removed in vacuo and the residue is recrystallized from toluene to give 6.1 g (56%) of a white solid, mp 91°-93° C.:
Reaction SMILES: [CH2:1]([P:7](=[O:24])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][CH:22]=O)[CH:14]=1)[O:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([NH:32][NH2:33])=[S:31])=[CH:28][CH:27]=1>CO.C(Cl)Cl>[CH2:1]([P:7](=[O:24])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][CH:22]=[N:33][NH:32][C:30](=[S:31])[C:29]2[CH:34]=[CH:35][C:26]([CH3:25])=[CH:27][CH:28]=2)[CH:14]=1)[O:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCP(=O)(OCCC)Oc1cccc(CCCC=O)c1
Reactant: Cc1ccc(C(=S)NN)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCCCP(=O)(OCCC)Oc1cccc(CCCC=NNC(=S)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O-propyl O-[3-(3-formylpropyl)phenyl] hexylphosphonate (0.02 mole) in methanol (50 ml) and 4-methylthiobenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product O-propyl O-{3-[4(4-methylthiobenzoylhydrazono)butyl]phenyl} hexylphosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:19](Br)[CH2:20]Br.C1(C)C=CC=CC=1.[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:16]#[N:17])[CH2:20][CH2:19]3)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(-c2ccc(Cl)c(Cl)c2)c(F)c1
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Temperature: 2.5 °C
Reaction time: 6 h

Procedure:
3′,4′-dichloro-2-fluoro-4-cyanomethyl-biphenyl (9.0 g, 0.032 mol), 1,2-dibromomethane (9.0 g, 0.048 mol), 1.2 tetrabutylammonium chloride (1.2 g, 0.043 mol), toluene (60 ml), and water (9 ml) were loaded in a reactor. Sodium hydroxide 30% aq. (60 g, 0.45 mol) was added drop-wise over 30 minutes at 20 to 25° C. and the reaction mixture was stirred for 6 hours. The organic phase was separated, washed with water (12 ml), with hydrogen chloride 3 M aq. (36 ml) and finally with water (12 ml). The solution was concentrated, then n-heptane (18 ml) was added at 80° C. The solution was cooled to 0 to 5° C. and stirred for 30 minutes. The product crystallized from solution, it was filtered, washed with cold n-heptane (5 ml) and dried at 40° C. under vacuum. The compound 1-(3′,4′-dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanenitrile was obtained as a yellow powder (6.4 g, 65% yield).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:27][NH:26][CH2:25]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2].[CH:29]([CH:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:25][N:26]([CH:35]3[CH2:36][CH2:37][CH:32]([CH:29]([CH3:31])[CH3:30])[CH2:33][CH2:34]3)[CH2:27]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C1CCC(=O)CC1
Reactant: CC(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Product: CC(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(C(C)C)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid isopropylamide (as prepared in Example 90, Step A) and 4-iso-propyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[CH3:1][O:2][C@H:3]([CH3:13])[CH2:4][N:5]([CH3:16])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CO[C@H](C)CNC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H](C)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(2R)-2-methoxypropyl]carbamate (2.72 g) in DMF (41 ml) was added NaH (862 mg; 60% oil suspension) under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. MeI (1.79 ml) was added to the mixture, and the whole was stirred for 3 hours at the same temperature. Water was added, and the whole was extracted with EtOAc and the extract was washed with water and brine and dried over MgSO4. Concentration under reduced pressure gave a residual oil, which was purified with silica gel column eluting with EtOAc:n-hexane=1:5 to give tert-butyl [(2R)-2-methoxypropyl]methylcarbamate (1.94 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][S:30]([C:33]4[C:34]([CH3:39])=[N:35][O:36][C:37]=4[CH3:38])(=[O:32])=[O:31])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH:19]2[CH2:20][C:21]3[CH:22]=[C:23]([O:29][S:30]([C:33]4[C:34]([CH3:39])=[N:35][O:36][C:37]=4[CH3:38])(=[O:32])=[O:31])[CH:24]=[CH:25][C:26]=3[CH2:27][CH2:28]2)[CH2:10][CH2:9]1
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 4-({[7-(3,5-dimethyl-isoxazole-4-sulfonyloxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propyl-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (1.16 g, 2.1 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min. and concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford 3,5-dimethyl-isoxazole-4-sulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (847 mg).
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[N:32][CH:33]=2)[CH2:24][CH2:23]1>>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:31]=[N:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:5]
Reactant: CC(C)C(=O)Nc1cncc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cncc(C2CCN(CCCNC(=O)C(O)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 176 was prepared from hydroxy(diphenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-3-pyridinyl}-2-methylpropanamide according procedures described in Scheme 12; ESMS m/e: 515.4 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1.C(OC1C(=O)C=CN(CCO)C=1C(C1C=CC=CC=1)OC1CCCCO1)C1C=CC=CC=1>C(O)C.Cl>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccn(CCO)c(C(O)c2ccccc2)c1OCc1ccccc1
Agent: Cl
Agent: O=c1ccn(CCO)c(C(OC2CCCCO2)c2ccccc2)c1OCc1ccccc1
Solvent: CCO
Product: O=c1ccn(CCO)c(C(O)c2ccccc2)c1O

Procedure:
3-Benzyloxy-1-(2-hydroxy-ethyl)-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one: 3.39 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[phenyl-(tetrahydropyran-2-yloxy)-methyl]-1H-pyridin-4-one are boiled under reflux for 3 hours in 40 ml of ethanol and 10 ml of 2N HCl. For working-up, the ethanol is removed using a rotary evaporator. The residue is diluted with 50 ml of water and covered with 10 ml of ethyl acetate. Then, with stirring, 25 ml of saturated aqueous sodium hydrogen carbonate solution are added. The resulting product is filtered off and washed with water and ethyl acetate. After drying, 3-benzyloxy-1-(2-hydroxy-ethyl)-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one remains, in the form of colourless crystals. M.p.: 191.5°-192.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.II.C(N(CC)CC)C.[F:21]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:21][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: FF
Reactant: Clc1ccc2ncccc2c1
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1ccc2cc(Cl)ccc2n1
Yield: 74 %

Procedure:
A solution containing 6-chloroquinoline (1.0 g, 6.1 mmol), iodine (1.55 g, 6.1 mmol) and triethylamine (0.62 g, 6.2 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown solid (1.03 g). GC/MS analysis showed a 79% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2-fluoro-6-chloroquinoline (0.82 g, 93%), RF 0.78 (CH2Cl2); δH (400 MHz CDCl3, Me4Si) 7.12 ppm (1H, d d, JH3,H4 8.8, JH3,F 2.8, H-3), 7.67 (1H, d d, JH7,H8 9.2, JH5,H7 2.4, H-7), 7.82 (1H, d, JH5,H7 2.4, H-5), 7.87 (1H, d, JH7,H8 9.0, H-8), 8.16 (1H, d d, JH3,H4 =JH4,F 8.8, H-4);δC (100 MHz, CDCl3, Me4Si) 111.1 ppm (d, 2J 42.3, C-3), 126.3 (s, C-5), 127.3 (s, C-4a), 129.6 (s, C-8), 131.4 (s, C-7), 131.9 (s, C-6) 141.0 (d,3J 9.9, C-4), 144.1 (d 3J 16.8, C-8a), 161.2 (d, 1J 243.8, C-2); δF (235 MHz, CDC13, CFCl3) -61.5 ppm (s); m/z (E1+) 181 (M+, 100%), 183 (M+, 32), 146 (34), 126 (11).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
NaOH 4N (20 mL) was added to a solution of (trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (Intermediate I, 4 g, 0.0149 mol), in Methanol (40 mL) and stirred at rt for 2 h. After completion of reaction, checked by TLC, the solvent was evaporated and the residue was diluted with water (50 mL), acidified with HCl 4 N solution, the solid formed was filtered and dried to get (trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid (2.59 g, 72%), as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:17][C:16]=1[CH2:31][OH:32].O>C1COCC1>[CH3:1][S:2]([O:32][CH2:31][C:16]1[CH:17]=[C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:15]=1[C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[F:6])(=[O:4])=[O:3]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CO)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(COS(C)(=O)=O)c2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Methanesulfonyl chloride (0.164 mL) was added to a solution of (2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)methanol (390 mg) in THF (10 mL) at 0° C., and the mixture was stirred at 0° C. for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)methyl methanesulfonate. To solution (10 mL) of the obtained compound and TBAI (117 mg) in DMF was added sodium hydride (60%, 85 mg) at 0° C., and the mixture was stirred at 0° C. for 5 min, then at 80° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (326 mg) as a colorless oil.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[S:34]1[C:38]([C:39](=[O:41])[CH3:40])=[CH:37][C:36]2[CH:42]=[CH:43][CH:44]=[CH:45][C:35]1=2>O1CCCC1>[S:34]1[C:38]([C:39](=[O:41])[CH2:40][Br:1])=[CH:37][C:36]2[CH:42]=[CH:43][CH:44]=[CH:45][C:35]1=2
Reactant: [Br-]
Reactant: CC(=O)c1cc2ccccc2s1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 193.5 %

Procedure:
Phenyltrimethylammonium tribromide (32.04 g) was added in portions under nitrogen at 0° C. over 10 minutes to a stirred solution of 1-(benzo[b]thiophen-2-yl]ethan-1-one (15.0 g) in tetrahydrofuran (400 ml), the mixture was stirred at ambient temperature for 5 hours, then it was filtered and the solvent was removed in vacuo. The residue was triturated with a 9:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate (50 ml) and the resulting solid was collected by filtration and dried in vacuo to give 1-(benzo[b]thiophen-2-yl)-2-bromoethan-1-one (24.40 g) as a brown solid which was used without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15]CC)=[O:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(OCCN2CCOCC2)c1
Agent: Cl
Product: O=C(O)c1cccc(OCCN2CCOCC2)c1
Reaction time: 2.5 h

Procedure:
To the material of ethyl 3-{[2-(4-morpholinyl)ethyl]oxy}benzoate D47 (98 mg) was added HCl (0.5 mL, 16.46 mmol) at room temperature. The reaction was stirred at 100° for 2.5 hours. The mixture was concentrated in vacuo. To the residue was added 2 ml of ether and stirred for 0.5 hours, filtered. The filtrate was evaporated in vacuo to give the expected product D51 in 90 mg, as a white solid. LCMS Retention time=0.84 mins, [M+H]+ 252 (5 min run)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])([C:10]([OH:13])([CH3:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:22][O:23][C:24](OC)(OC)OC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:9])[C:10]([CH3:11])([CH3:12])[O:13][C:22]([O:23][CH3:24])=[N:17][S:14]2(=[O:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(C)(c1ccc(Br)cc1)S(N)(=O)=O
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(C)(c2ccc(Br)cc2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2.01 g of 2-(4-bromophenyl)-3-hydroxy-3-methylbutane-2-sulfonamide in 15 ml of tetramethoxymethane was admixed with 3 ml of acetic acid and stirred at 100° C. for 1.5 hours. After the removal of the solvent under reduced pressure, the crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined, concentrated by rotary evaporation and dried under high vacuum. This gave the product (0.21 g) with a molecular weight of 362.2 g/mol (C13H16BrNO4S).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1.[CH2:15]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl.C(Cl)(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:37](=[O:38])[CH2:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: NCc1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)NCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a 0° C. solution of 4.64 g of 2-(aminomethyl)pyridine, 13.2 ml of pyridine and 50 ml of methylene chloride is added, dropwise, 15 g of product from Example 53 in 150 ml of methylene chloride. The reaction is stirred at 0° C. for 1 hour followed by 18 hours at room temperature. The reaction is diluted with chloroform, washed with sodium bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica ge1:75-100% ethyl acetate/hexane) to give 11.0 g of the desired product as colorless prisms.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([CH3:19])([C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:11].C([O-])(=O)C.[NH4+].O>CC(C)(C)C#N>[Br:1][CH:13]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12](=[O:18])[C:10]([CH3:19])([CH3:9])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)CC(=O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: CC(C)(C)C#N
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)C(=O)C(Br)C(C)(C)C

Procedure:
24 g of N-bromosuccinimide (0.1344 mol) was added to 10 g of 2,2,5,5-Tetramethyl-3-hexanone (0.064 mol) in 50 mL of trimethylacetonitrile. To this mixture, 10 g of ammonium acetate (0.1344 mol) was added within 5 minutes. This mixture was refluxed overnight then filtered. To the filtrate, 24 g of N-bromosuccinimide (0.1344 mol) and 10 g of ammonium acetate (0.1344 mol) was added, then refluxed for 5 hours. The reaction mixture was then cooled, 600 mL of water added, and the resulting mixture then filtered. The aqueous layer was washed three times with 50 ml of hexanes. The hexane fractions were then combined, washed three times with 50 ml of with water, then dried with anhydrous magnesium sulfate. Product was collected by distilling off the hexane at atmospheric pressure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:27]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 55 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.=155-158° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.89 (m, 2H), 7.69 (t, 1H), 7.52 (m, 4H), 7.40 (m, 1H), 4.40 (m, 1H), 3.50 (brm, 2H), 3.24 (m, 1H), 3.11 (s, 2H), 2.08 (m, 1H), 1.90 (m, 3H); LCMS: 440 [M+H].