Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[CH2:7]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:33])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C>CO>[CH3:3][N:14]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:33])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(Cc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
0.7 ml of a 37% aqueous formaldehyde solution and 0.21 g of sodium cyanoborohydride were added to 30 ml of a solution of 0.82 g of 4-benzylamino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine in methanol, under ice-cooling. To the mixture was dropwise added 0.7 ml of acetic acid. The mixture was stirred at room temperature for 1 hour and then subjected to distillation to remove the solvent. The residue was extracted with methylene chloride. The extract was washed with a 1 N aqueous sodium hydroxide solution and water, dried with anhydrous magnesium sulfate, and then concentrated. The residue was purified by a silica gel column chromatography (eluant: methylene chloride/methanol=50/1), followed by recrystallization from methylene chloridediethyl ether to obtain 0.28 g of 4-(N-methyl-N-benzylamino)-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=4)[NH:12][C@H:11]3[CH2:34][C:35]([CH3:42])([CH3:41])[CH2:36][O:37]C(=O)C)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].CO>O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:23]([CH:13]2[NH:12][CH:11]([CH2:34][C:35]([CH3:42])([CH3:41])[CH2:36][OH:37])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:43])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:33])=[CH:30][CH:29]=1)#[N:32]
Reactant: CC(=O)OCC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CO)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of acetic acid rac-3-[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-5′-(4-cyano-phenylcarbamoyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidin]-2′-yl]-2,2-dimethyl-propyl ester (17 mg, 0.027 mmol) in tetrahydrofuran (2 mL) was added an aqueous solution (1N) of NaOH (0.5 mL, 0.5 mmol) and methanol (0.2 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a off white solid (14 mg, 88%).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([Cl:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/CCC#Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/CCC#Cc1ccccc1

Procedure:
7-Phenylhept-2E-en-6-ynoic acid (2 g) was dissolved in benzene (20 ml), thionyl chloride (2.5 ml) was added, and the mixture was refluxed under a nitrogen atmosphere for 45 minutes. Benzene and excess thionyl chloride were removed under reduced pressure and the residue was treated with benzene (2×4 ml), followed by evaporation, to leave a residue of 7-phenylhept-2E-en-6-ynoyl chloride. The acid chloride was dissolved in ether (20 ml), and triethylamine (1.5 ml) and isobutylamine (3 ml) were added. The mixture stirred at room temperature for 2 hours then cooled to 0° C. The mixture was filtered and the filtrate was subjected to chromatography on silica (60 g), eluting with 100% hexane grading to 100% ether, to yield N-isobutyl-7-phenylhept-2E-en-6-ynamide mp 86°-8° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33])=[O:10])C1C=CC=CC=1.C(O)=O>CN(C)C=O.[Pd]>[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33])([OH:10])=[O:8]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Agent: [Pd]
Solvent: O=CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)O)cc23)c(OC)c1
Reaction time: 24 h
Yield: 88.5 %

Procedure:
A solution of methyl 4-(5-benzyloxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate (41.0 g) and formic acid (40 mL) in N,N-dimethylformamide (600 mL) was treated with 10% (w/w) palladium on carbon (10 g) and shaken under hydrogen (3.45 bar) for 24 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate evaporated to give an amber solid. The solid was triturated with warm diethyl ether and filtered to afford methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate as a light gray solid (28.9 g, 88%); mp 249°-251° C.; partial NMR (250 MHz, DMSO-d6): 3.78 (s, 3H, NCH3), 3.64 (s, 3H, CO2CH3), 3.93 (s, 3H, OCH3), 4.09 (s, 2H, CH2), 7.12 (s, 1H, indole-H(2)), 8.16 (s, 1H, indole-H(4)), 12.44 (br, 1H, CO2H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11](O)=O)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCCC1.C=O>CCO>[CH:1]1([CH2:6][C:7](=[CH2:11])[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C(CC1CCCC1)C(=O)O
Yield: 85.6 %

Procedure:
A mixture of 2-cyclopentylmethyl-malonic acid (24.90 g, 133.7 mmol), piperidine (15.9 mL, 160.8 mmol), 37% aqueous formaldehyde (51.0 mL, 647.2 mmol), and EtOH (250 mL) is stirred at reflux for 16 hours. The reaction is quenched with 1N HCl to a pH=1, and the mixture is extracted with EtOAc. The EtOAc layers are combined, dried over Na2SO4, and concentrated. The crude product is purified by flash chromatography (SiO2, 10% acetone in DCM), which gives 2-cyclopentylmethyl-acrylic acid (17.65 g, 86% yield) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:8][CH2:9][OH:10])=[CH:5][S:6][CH:7]=1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:8][CH2:9][O:10][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[CH:5][S:6][CH:7]=1
Reactant: COc1cscc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cscc1CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
Into a 500 ml three-necked flask (reaction container) with thermometer and dropping funnel, 7.72 g (48.8 mmol) of 2-(4-methoxythiophene-3-yl)ethane-1-ol represented by the formula (VI-A) shown below, 11.58 g (146 mmol) of pyridine, and 135 ml of methylene chloride were transferred. The reaction container (flask) was cooled in an ice bath, then 50 ml of methylene chloride containing 18.6 g (97.6 mmol) of p-toluene sulfonic chloride was added dropwise over a period of 10 minutes, then the ice bath was removed from the flask. The reaction solution was stirred at room temperature for a period of 1.5 hours. After the reaction was completed, 100 ml of water was added to separate the organic layer from the water layer. The organic layer was washed twice each with 100 ml of water, then washed twice with saturated aqueous sodium hydrogen carbonate and then dried over anhydrous sodium sulfate. Then it was condensed under a reduced pressure, thereby obtaining a crude product. This crude product was purified using silica gel column chromatography to obtain p-toluene sulfonic acid-2-(4-methoxythiophene-3-yl)ethyl ester (10.5 g, 33.6 mmol, yield 68.9%), a thiophene derivative represented by the formula (IV-A) having properties described below. The chemical equation (X-A) is shown below.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[OH:12][CH2:13][C:14]([CH2:19][OH:20])([CH2:17][CH3:18])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:2][C:1]1([CH3:6])[O:16][CH2:15][C:14]([CH2:17][CH3:18])([CH2:19][OH:20])[CH2:13][O:12]1
Reactant: CCC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(CO)COC(C)(C)OC1
Reaction time: 4 h
Yield: 8050.3 %

Procedure:
2.75 g of p-toluenesulfonic acid are added to 275 g (2.05 mol) of 2,2-bis(hydroxymethyl)-1-butanol in 1.4 1 of acetone, and the mixture is heated to reflux. After 4 hours, the solution is neutralized while still hot by adding 8.25 g of potassium carbonate, and the mixture is stirred for a further 30 minutes and subsequently allowed to stand overnight at room temperature. The turbid mixture is filtered through kieselguhr, and the solvent is removed by distillation in vacuo, leaving 400 ml of a turbid, oily residue, which is purified by distillation in a high vacuum, giving 224 g of the alcohol 1 as a colorless oil.
Reaction SMILES: NC(N)=O.[C:5]1([C:11]2[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][N:20]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH3:21]>>[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][C:24]1([CH3:25])[C:13]2[S:12][C:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:15][C:14]=2[CH2:16][CH2:17][O:18]1
Reactant: CC(=O)CCN(C)C
Reactant: OCCc1csc(-c2ccccc2)n1
Agent: NC(N)=O
Product: CN(C)CCC1(C)OCCc2nc(-c3ccccc3)sc21

Procedure:
By following the procedure of Example 2(a) but using as starting material in Example 2(a) an appropriate starting material of formula II, for example, those described in Examples 2 to 14 and an appropriate aminoketone of formula III in which R2 and n are as described above and A is CH2NR4R5 wherein R4 and R5 are as described above, the amino compounds of formula I listed in Examples 31 to 46 are obtained. For example, according to the present procedure 2-phenyl-4-(β-hydroxyethyl)thiazole condenses with 1-(N,N-dimethylamino)-3-butanone to give the title compound, identical to the amine described in Example 31.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:12][CH:11]=[C:10]([NH:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)[N:9]=1)(C)(C)C.[ClH:30]>O1CCOCC1.C(OCC)C>[ClH:30].[NH2:7][C:8]1[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:12][CH:11]=[C:10]([NH:18][CH2:19][CH2:20][NH2:21])[N:9]=1
Reactant: CCC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)nc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCC(=O)c1ccc(NCCN)nc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
530 mg (1.30 mmol) of tert-butyl[6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-3-propanoylpyridin-2-yl]carbamate (Example 24A) were dissolved in 15 ml of a solution of hydrochloric acid in dioxane (4 M), and the mixture was stirred at RT for 20 h. After the reaction had gone to completion, the reaction mixture was diluted with diethyl ether (100 ml), and the precipitate was filtered off, washed with diethyl ether (100 ml) and dried. This gave 290 mg (91% of theory) of the product as a solid.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1C=O.Cl>N1C=CC=CC=1>[CH:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:15]=1[CH:1]=[CH:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 82 %

Procedure:
Malonic acid (7.5 g, 72.1 mmole) and 2-naphthaldehyde (5.0 g, 32.0 mmole) were dissolved in pyridine (20 mL) and refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into 2N HCl solution (200 mL). The product precipitated immediately. It was collected by filtration and recrystallized from aqueous ethanol (200 mL ethanol/50 mL water) to give colorless needles (5.2 g, 82%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[N:12][C:6]2[S:7][CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1>[O-2].[O-2].[Mn+4]>[O:11]=[C:9]1[CH2:8][S:7][C:6]2[N:12]=[CH:13][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[NH:10]1
Reactant: O=C1CSc2ncc(CO)cc2N1
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1cnc2c(c1)NC(=O)CS2
Yield: 58 %

Procedure:
7-Hydroxymethyl-1H-pyrido[2,3-b][1,4]thiazin-2-one (1.22 g) was oxidized with manganese dioxide by the method of Preparation (14c) to afford a solid (0.7 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].[NH2:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]2[C:21]=1[CH2:22][O:23][C:24]2=[O:30]>C(#N)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[N:19]/[C:20]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]3[C:21]=2[CH2:22][O:23][C:24]3=[O:30])=[CH:7][CH:6]=1)[CH3:3]
Reactant: Nc1cc(F)cc2c1COC2=O
Reactant: CN(C)Cc1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CN(C)Cc1ccc(/C=N/c2cc(F)cc3c2COC3=O)cc1
Yield: 53.1 %

Procedure:
To a stirred mixture of 4-((dimethylamino)methyl)benzaldehyde (4 g, 24.5 mmol) and anhydrous magnesium sulfate (15.8 g, 111.5 mmol) in anhydrous acetonitrile (100 mL) was added 4-amino-6-fluoroisobenzofuran-1(3H)-one (4 g, 22.3 mmol) at 0° C. After the addition, the mixture was stirred at reflux for 3 days. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product, which was re-crystallized with isopropanol to give the title compound (3.7 g, yield 55%). LC-MS (ESI) m/z: 314 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9](=[CH:12]N(C)C)[C:10](=O)[C:4]=2[CH:3]=1.[NH2:19][C:20]([NH2:22])=[NH:21]>>[NH2:21][C:20]1[N:22]=[CH:12][C:9]2[CH2:8][C:7](=[O:16])[NH:6][C:5]3[CH:17]=[CH:18][C:2]([I:1])=[CH:3][C:4]=3[C:10]=2[N:19]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(I)cc2C1=O
Reactant: N=C(N)N
Product: Nc1ncc2c(n1)-c1cc(I)ccc1NC(=O)C2

Procedure:
In a manner similar to that described in method H, 7-iodo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-a) and guanidine were converted to I-51 (79%): HRMS Calcd. for C12H9N4O: 352.9899, Found 352.9900.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:28])[CH2:26][CH3:27])=[C:21]([OH:29])[C:20]=3[CH3:30])[CH:12]=2)=[N:6][CH:5]=1.[OH-].[Li+].O.Cl>O1CCCC1>[OH:29][C:21]1[C:20]([CH3:30])=[C:19]([CH:24]=[CH:23][C:22]=1[C:25](=[O:28])[CH2:26][CH3:27])[O:18][CH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][N:6]=1
Reactant: CCC(=O)c1ccc(OCc2cccc(Oc3ccc(C(=O)OC)cn3)c2)c(C)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1ccc(OCc2cccc(Oc3ccc(C(=O)O)cn3)c2)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
Dissolve 6-[3-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenoxy]-nicotinic acid methyl ester (0.10 g, 0.24 mmol) in tetrahydrofuran (2 mL). Add lithium hydroxide (0.007 g, 0.29 mmol) and water (0.5 mL). Stir at ambient temperature for 2 hrs. Add 1 N hydrochloric acid (5 mL) and extract with ethyl acetate (3×10 mL). Combine the organic extracts, dry over magnesium sulfate, filter and concentrate under reduced pressure to obtain a residue. Purification using 5% isopropyl alcohol/chloroformchloroform to 10% isopropyl alcohol/chloroform as gradient eluent gives the title compound (0.06 g, 58%): MS (m/z): 406.1 (M−1). 1H NMR (acetone-d6) 13.00 (s, 1H), 8.76 (s, 1H), 8.40 (dd, J=1.7 Hz, 8.4 Hz, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.38 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.76 (d, J=9.2 Hz, 1H), 5.36 (s, 2H), 3.09 (q, J=7.2 Hz, 2H), 2.14 (s, 3H), 1.20 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:32])[CH2:19][CH2:18][C:17]([CH2:30][NH2:31])([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:31][CH2:30][C:17]1([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][CH2:19][C:14]([F:13])([F:32])[CH2:15][CH2:16]1)=[O:6]
Reactant: COc1cccc(C(=O)O)c1Cl
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: COc1cccc(C(=O)NCC2(c3cnc(C(F)(F)F)nc3)CCC(F)(F)CC2)c1Cl

Procedure:
From 2-chloro-3-methoxybenzoic acid and [4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine. LCMS (MH+): m/z=464.1, tR (minutes, Method F)=3.02
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:24])=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:24])=[C:19]([F:23])[CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:25])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(Br)c3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(-c4ccccc4C)c3O2)cc1
Yield: 84.1 %

Procedure:
Treatment of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.59 mmol) with 2-methylphenyl boronic acid (0.732 g, 5.38 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.293 g, 0.359 mmol), and potassium carbonate (0.993 g, 7.18 mmol) generally according to the procedure described for Intermediate 118 afforded 1.3 g (84%) of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.72 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) δH 7.67 (d, 2H); 7.38 (d, 2H); 7.20 (m, 3H); 7.05 (m, 2H); 5.05 (m, 1H); 4.22 (dd, 2H); 4.13 (dd, 1H); 3.40 (dd, 1H); 3.02 (dd, 1H); 2.05 (s, 3H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:37])[CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[NH:27])[CH:23]=3)[C:18]2=[O:36])=[CH:11][CH:10]=1)C.CC(O)=O>CO>[C:32]([O:31][C:29]([NH:28][C:26](=[NH:27])[C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:36])[N:17]([CH2:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:38])=[O:5])=[CH:14][CH:13]=1)=[O:37])[CH2:25]2)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)COc1ccc(C(=O)CN2Cc3cc(C(=N)NC(=O)OC(C)(C)C)ccc3C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(=N)c1ccc2c(c1)CN(CC(=O)c1ccc(OCC(=O)O)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aqueous 0.1N NaOH (11.4 ml; 1.14 mmol) was added to a solution of the compound of example 17a (0.375 g; 0.756 mmol) in MeOH (10 ml), The reaction mixture was stirred at room temperature for 30 min., acidified with AcOH and concentrated. The crude title compound obtained was filtered, washed with cold water and dried under vacuum. Yield, 140 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C[O-].[Na+].[CH2:13](Cl)[C:14]#[CH:15]>CO.C(Cl)Cl>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])[C:14]#[CH:13]
Reactant: C#CCCl
Reactant: OCc1cccc(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C#CCOc1cccc(CO)c1
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A 20.0 L flange flask was charged with 3-hydroxybenzyl alcohol (97%, ex. Aldrich, 903 g, 7.28 mol, 1 eq.) in methanol (MeOH)(9.1 L, dried over 3 A molecular sieves) to give a clear solution, into which sodium methoxide (25% in methanol, ex. Aldrich, 1.746 L, 7.63 mol, 1.05 eq.) was slowly added with vigorous stirring. After stirring for 10 min. the propargyl chloride (70 wt % in toluene, ex. Aldrich, 542.6 g, 805 ml, 7.29 mol, 1 eq) was added slowly with vigorous stirring over a period of 30 minutes. The reaction mixture was heated under reflux for 40 h (isomantle set to 76° C. with an internal temp. of 64° C.). TLC-examination (10% MeOH in DCM) showed that the reaction was not complete. The reaction was nevertheless worked-up at this stage. The MeOH was removed by rotary evaporation, and the residue dissolved in DCM (10.2 L) to give a clear solution, which was washed with water (5.82 L×3), and dried over sodium sulfate. The solvent was removed in vacuo, to give the title compound (706 g, 60%) as an orange gum.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:19]1([CH:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:26][N:13]2[CH2:14][CH2:15][CH2:16][N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:18][CH:17]=3)[CH2:11][CH2:12]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(CN2CCCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CN2CCCN(CC(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The resulting 1-[4-(methylsulfonyl)benzyl]homopiperazine was dissolved in 5 mL of dichloromethane, followed by adding 223 mg of diphenylacetaldehyde and 217 mg of sodium triacetoxyborohydride. After the mixture was stirred at room temperature for 16 hours, it was mixed with 30 mL of aqueous saturated sodium hydrogencarbonate, and extracted with 30 mL×2 of ethyl acetate. The organic layers were combined, washed with 30 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to obtain 173 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure, the residue was dried to give the hydrochloride salt of the titled compound.