Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:53][O:54][C:55](=[O:73])[C@@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[C:65]=2[CH3:71])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:20])[NH:72][C@H:56]([C:55]([O:54][CH3:53])=[O:73])[CH2:57][C:58]2[CH:59]=[CH:60][C:61]([C:64]3[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[C:65]=3[CH3:71])=[CH:62][CH:63]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (150 mg) was taken in 2 mL of anhydrous DCM and EDCI (64 mg), HOBT (47 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (91 mg) and stirred for 5 minutes. Reaction mixture was cooled to 0° C. and DIEA (164 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction is complete, it was purified by silica gel column chromatography (1:3 EtOAc/hexanes to 2% MeOH in 1:1 EtOAc/hexanes) (152 mg). LCMS (m/z): 853.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10]([NH2:13])(=[O:12])=[O:11])[CH2:5][CH2:4]1.[H-].[Na+].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[CH:24][N:25]=2)[N:22]=1>CN(C)C=O>[ClH:16].[S:10]([CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][O:1][C:17]2[CH:18]=[CH:19][C:20]3[N:21]([CH:23]=[CH:24][N:25]=3)[N:22]=2)[CH2:4][CH2:5]1)(=[O:11])(=[O:12])[NH2:13]
Reactant: NS(=O)(=O)CC1CCC(CO)CC1
Reactant: Clc1ccc2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: NS(=O)(=O)CC1CCC(COc2ccc3nccn3n2)CC1
Reaction time: 3 h
Yield: 43.6 %

Procedure:
A mixture of (4-hydroxymethylcyclohexane-1-yl) methanesulfonamide (0.58 g), sodium hydride (0.23 g), 6-chloroimidazo[1,2-b]pyridazine (0.43 g) and dimethylformamide (20 ml) was stirred for 3 hours at 85° -90° C. The reaction solution was concentrated under reduced pressure and the residue was poured into water (20 ml). The mixture was adjusted to pH 7.0 with 1 N-hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from a mixture of ethanol and ethyl ether to afford the above-identified compound (0.44 g).
Reaction SMILES: C(C1C=CC(N2CCC(N[C:16]([O:18]C(C)(C)C)=[O:17])CC2)=CC=1)#N.F[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C(O[CH:37]1[CH2:42][CH2:41][N:40](N=C=O)[CH2:39][CH2:38]1)(C)(C)C>>[C:16]([CH:37]1[CH2:38][CH2:39][N:40]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH2:41][CH2:42]1)([OH:18])=[O:17]
Reactant: CC(C)(C)OC1CCN(N=C=O)CC1
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C#N)cc2)CC1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1

Procedure:
1-(4-cyanophenyl)-4-tert.butyloxycarbonylamino-piperidine By reacting 4-fluorobenzonitrile with 4-tert.butyloxy-carbonylamino-piperidine
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[NH4+]>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h

Procedure:
17.5 g (0.10 mol) of 1-acetyl-2-indolinone are dissolved in 100 ml of conc. sulphuric acid and at −10° C. 8.8 g (0.11 mol) of ammonium nitrate are added batchwise and stirred for 15 minutes. The reaction is poured onto ice water, suction filtered and washed with water. The residue is distributed in ethyl acetate/water, the combined organic extracts are dried and concentrated by evaporation.
Reaction SMILES: CO[C:3]1[C:7]([O:8][CH3:9])=NS(=O)[N:4]=1.N[C:12]1C(CCCCN)=NC=C(Br)C=1.[NH2:24][C:25]1[C:26]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]2[C:41](OC)=[N:40][S:39](=[O:44])[N:38]=2)=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=1.NC1C(C2(OC)NS(=O)N=C2)=NC=C(Br)C=1.N>CO.C(Cl)(Cl)Cl>[CH3:3][CH2:7][O:8][CH2:9][CH3:12].[NH2:24][C:25]1[C:26]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]2[C:41]([NH2:4])=[N:40][S:39](=[O:44])[N:38]=2)=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=1
Reactant: COC1=NS(=O)N=C1NCCCCc1ncc(Br)cc1N
Reactant: NCCCCc1ncc(Br)cc1N
Reactant: COC1=NS(=O)N=C1OC
Agent: COC1(c2ncc(Br)cc2N)C=NS(=O)N1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOCC
Product: NC1=NS(=O)N=C1NCCCCc1ncc(Br)cc1N
Yield: 9.7 %

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.995 g) in methanol (25 ml) was reacted with a solution of 3-amino-5-bromo-(4-aminobutyl)pyridine (1.5 g) in methanol (25 ml) at room temperature for 3 hours. The solvent was removed in vacuo and the residue was chromatographed on silica in ethanol to give an oil which was triturated with ether and recrystallised from ethanol/ether to give 3-[4-(3-amino-5-bromopyrid-2-yl) butylamino]-4-methoxy-1,2,5-thiadiazole-1-oxide (1.7 g) m.p. 118°-120° C. (g) Reaction of 3-[4-(3-amino-5-bromopyrid-2-yl)-4-methoxy-1,2,5-thiadiazole-1-oxide (0.56 g) with methanolic ammonia solution (50 ml) at room temperature overnight gave after chromatography on silica in chloroform and trituration with ether 3-[4-(3-amino-5-bromopyrid-2-yl)butylamino]-4-amino-1,2,5-thiadiazole-1-oxide (0.19 g) m.p. 105°-109° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.CO.[C].[Pd]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)/C=C/c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: O=C(O)CCc1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of 180 mg of (2E)-3-[1-(phenylsulfonyl)-1H-indol-2-yl]acrylic acid in 3 mL of ethanol and 5 mL of methanol, 50 mg of 10% palladium-carbon (wet, water content 53%) was added, and the resulting mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 2 hours. The catalyst was removed from the solution, the solvent was evaporated under reduced pressure, and the residue was washed with ether to obtain 90 mg of 3-[1-(phenylsulfonyl)-1H-indol-2-yl]propanoic acid as a white solid. FAB−: 328
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([OH:30])[CH:13]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][NH:28][CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:15]=1.[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH3:36]>>[Cl:9][C:10]1[CH:11]=[C:12]([OH:30])[CH:13]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][N:28]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:35]([CH2:34][CH2:33][O:32][CH3:31])[CH3:36])[CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:15]=1
Reactant: O=C(O)/C=C/CBr
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Reactant: CNCCOC
Agent: Cl
Product: COCCN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)cc(Cl)c4)c23)C1

Procedure:
In analogy to Example 130, the title compound was prepared from (2E)-4-bromobut-2-enoic acid (84 mg, 0.41 mmol), 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (100 mg, 0.27 mmol) and 2-methoxy-N-methylethanamine (39 mg, 0.43 mmol) to yield 24 mg (18%).
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:16]O.S([O-])(O)(=O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Br:2][CH2:16][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]=1[Cl:5]
Reactant: OCc1cccc(C(F)(F)F)c1Cl
Reactant: BrP(Br)Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(CBr)c1Cl
Reaction time: 1 h
Yield: 57 %

Procedure:
Phosphorus tribromide (11.75 ml, 125 mmol) was added to a solution of crude (2-chloro-3-(trifluoromethyl)phenyl)methanol (9.37 g, 44.5 mmol) in dioxane (200 ml). The reaction mixture was stirred for 1 hour. Another portion of phosphorus tribromide (11.75 ml, 125 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. It was diluted with ethyl acetate (200 ml). A 10% aqueous solution of sodium hydrogensulphate (200 ml) was added, while cooling with a water bath. The phases were separated. The organic phase was washed with a 10% aqueous solution of sodium hydrogensulphate (100 ml). The combined aqueous layers were extracted with ethyl acetate (100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (150 g), using ethyl acetate/heptane (1:3) as eluent, to give 6.94 g of 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:14][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:12])[F:1])=[N:9][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(OC(F)F)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1ccc(CBr)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of (6-(difluoromethoxy)pyridin-3-yl)methanol (246 mg; 1.41 mmol) in anh. DCM (10 ml) was treated at rt with CBr4 (467 mg; 1.41 mmol), and with triphenylphosphine (369 mg; 1.41 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 15 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 5-(bromomethyl)-2-(difluoromethoxy)pyridine as an orange oil which was directly used for the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6]
Reactant: O=C(O)c1ccncc1Br
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(c1ccncc1Br)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of 3-bromoisonicotinic acid (0.250 g, 1.238 mmol) in DMF (1.5 mL) was added pyrrolidine (0.097 g, 1.361 mmol), EDC (0.285 g, 1.485 mmol), and HOBt (0.227 g, 1.485 mmol) resulting in a homogenous solution. After stirring at room temperature 3 hours, the reaction mixture was dissolved in a saturated aqueous solution of sodium bicarbonate (20 mL) and extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide Intermediate 12A as a colorless oil (0.219 g, 0.850 mmol, 68.7% yield). HPLC Ret timea: 1.463 min. MS (ES): m/z=257.0 [M+H]+. 1H NMR (400 MHz, acetone) δ ppm 1.77-2.03 (m, 4 H) 3.20 (t, J=6.40 Hz, 2 H) 3.55 (t, J=6.65 Hz, 2 H) 7.38 (d, J=4.27 Hz, 1 H) 8.63 (d, J=4.77 Hz, 1 H) 8.78 (s, 1 H).
Reaction SMILES: C[CH2:2][C:3](=O)[C:4]([O-:6])=[O:5].Cl.[N+:9]([C:12]1[CH:13]=[C:14]([NH:18][NH2:19])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].[C:20]([O-])(=O)C.[Na+]>O.C(O)C.O.C(O)C>[N+:9]([C:12]1[CH:13]=[C:14]([NH:18][N:19]=[C:3]([CH3:2])[C:4]([O:6][CH3:20])=[O:5])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: CC(=O)[O-]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCC(=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)C(C)=NNc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of methylpyruvate (31.8 g, 0.312 mol) in water-ethanol (10:1, 100 ml) was slowly added to a hot solution of 3-nitrophenylhydrazine hydrochloride (59.2 g, 0.312 mol) and sodium acetate (28.0 g, 0.34 mol) in water and ethanol (5:7, 1200 ml). The mixture was stirred at room temperature for 2 h during which time a heavy yellow precipitate developed. The precipitate was filtered, washed with cold water (2000 ml), and dried to give the product (66 g) as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@H:14]([N:18]2[CH2:21][C:20]4([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:19]2)[CH2:13][CH2:12]3)=[N:7][CH:8]=1)[CH3:2].[ClH:34].CO>O1CCOCC1>[ClH:34].[ClH:34].[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@H:14]([N:18]2[CH2:21][C:20]4([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH2:19]2)[CH2:13][CH2:12]3)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To a flask charged with tert-butyl 2-[(1R)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1b, 583 mg, 1.39 mmol) was added 8.0 mL of 4N HCl in dioxane at room temperature. A yellow precipitate formed immediately after the addition. The mixture was stirred at room temperature for 40 minutes. Anhydrous methanol (4 mL) was added to solublize the reaction. The resulting solution was stirred at room temperature for 4 hours. Solvent and excess HCl were removed and dried in vacuo to afford 630 mg (100%) of a light yellow solid (3-1c). The crude product was taken on to the next step without further purification. MS (ES+) 349.4 (M+H)+. 1H NMR (CD3OD) δ 1.40 (t, 3H) 2.21-2.28 (m, 5H) 2.61 (br s, 1H) 2.93 (q, 2H) 3.16-3.34 (m, 4H), 3.38-3.51 (m, 1H), 4.12-4.29 (m, 4H) 4.52-4.56 (m, 1H) 5.08-5.12 (m, 1H) 7.89-7.93 (m, 1H) 8.29-8.33 (m, 2H), 9.15-9.19 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:17][C:18]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(O)c1ccco1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccco4)cc3)sc2c1
Temperature: 25 °C

Procedure:
First Route: 2-Furoic acid (1.85 g, 16.5 mmole) was dissolved in anhydrous methylene chloride (30 ml), to which solution was added a suspension of 2-(4-amino-phenyl)-6-methyl benzothiazole (4.76 g, 16.5 mmole) and N-methyl morpholine (2.0 g, 16.5 mmole) in methylene chloride (30 ml, at room temperature). Then, 1-hydroxy-benzotriazole hydrate (2.67 g, 16.5 mmole) and 1-(3-dimethyl amino propyl)-3-ethyl carbodiimide hydrochloride (4.75 g, 16.5 mmole) were added at room temperature. More methylene chloride (20 ml.) was added with stirring at room temperature, and the reaction maintained overnight. The initial clear reaction solution changed to a turbid solution. More methylene chloride (10 ml.) was added to the product mixture, which was then extracted with 1N HCl to separate a solid. The solid was filtered and washed with water. The product solid was crystallized from large amount of MeOH to yield 2.19 g (33.1%). mp 238-240° C. 1H and 13C NMR were consistent with the expected product. TLC showed one spot (5% MeOH-CH2Cl2 as developing solvent on silica gel plate).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](OC)=[O:4].C(N(CC)CC)C.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].Cl>CO.C(OCC)(=O)C>[F:8][C:2]([F:1])([F:7])[C:3]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4]
Reactant: COC(=O)C(F)(F)F
Reactant: NCCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CCCCCCCCCCCNC(=O)C(F)(F)F
Reaction time: 18 h
Yield: 97 %

Procedure:
Methyl trifluoroacetate (200 μL, 1.99 mmoles) and triethylamine (184 μL, 1.32 mmoles) were added to a suspension of 12-aminododecanoic acid (300 mg, 1.32 mmoles) in methanol (2 mL). After the mixture was stirred vigorously for 18 h, 1 N HCl was added dropwise until the a pH of 2 was obtained. The reaction was added to ethyl acetate (20 mL) was washed with 1 N HCl (2×5 mL), dried over MgSO4, and concentrated in vacuo to yield the amide as a white solid (398 mg, 1.28 mmoles, 97%). LRMS: not performed. 1H NMR: spectrum is consistent with the predicted structure.
Reaction SMILES: C[O:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1.B(Br)(Br)Br>ClCCl>[N:19]1([S:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][OH:2])[N:9]=3)[CH2:15][CH2:14]2)(=[O:18])=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COCc1nccc(N2CCN(S(=O)(=O)N3CCCC3)CC2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(N1CCCC1)N1CCN(c2ccnc(CO)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxymethyl-4-[4-(pyrrolidine-1-sulfonyl)-piperazin-1-yl]-pyrimidine (prepared according to the method of Example 121, Step A, 3.1 g, 9.4 mmol) in dichloromethane (47 mL) was added boron tribromide (1 M in dichloromethane, 19 mL, 18.7 mmol) at 0° C. then stirred at ambient temperature for 2 h. The mixture was washed twice with saturated aqueous sodium bicarbonate, and the organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give an oil which was crystallized from isopropyl ether to give the title compound as a white solid, 2.43 g (77%). 1H NMR (CDCl3, 300 MHz) δ 1.82 (m, 4H), 3.15 (m, 8H), 3.81 (m, 4H), 4.35 (d, 2H), 4.83 (t, 1H), 6.71 (d, 1H), 8.18 (d, 1H); mp: 128-131° C.; MS (Cl) 328 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:8]2[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:24]1([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:33][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])=[O:17])=[CH:13][CH:12]=2)[C:8]2[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nc2ccccc2n1Cc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
4-[(2-Butyl-1H-benzimidazol-1-yl)methyl]benzoic acid (150 mg) was added to a solution of benzenesulphonamide (79 mg), dimethylaminopyridine (60 mg) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (91 mg) in dry dichloromethane (5 ml). The mixture was stirred overnight and then diluted with dichloromethane (20 ml). The solution was washed successively with 1M hydrochloric acid (20 ml), water (20 ml) and saturated brine (20 ml), and then dried (MgSO4). The solvent was removed by evaporation and the residue triturated with ether to give 4-[(2-butyl-1H-benzimidazol-1-yl)methyl]-N-phenylsulphonylbenzamide as a white solid, m.p. 241°-242° C.; NMR (d6 -DMSO): 0.9(t,3H), 1.35(m,2H), 1.7(m,2H), 2.85(t,2H), 5.6(s,2H), 7.2(m,3H), 7.4(m,1H), 7.6(m,4H). 7.8(d,2H), 8.0(d,2H); mass spectrum (-ve FAB, DMSO/m-nitrobenzyl alcohol): 446(M-H)- ; microanalysis found: C,66.7; H,5.6; N,9.1; C25H25N3O3S requires: C,67.1; H,5.6; N,9.4%.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])[CH3:4].[H][H]>[Pt].C(C(C)=O)C>[CH:3]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[C:5]([CH:3]([O:2][CH3:1])[CH3:4])[CH:6]=1)([CH2:5][CH3:11])[CH3:4]
Reactant: COC(C)c1cccc(N)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCC(C)=O
Product: CCC(C)Nc1cccc(C(C)OC)c1
Temperature: 95 °C
Yield: 572.6 %

Procedure:
A 300-cubic centimeter capacity stirred autoclave equipped with a heating mantle and sample port was charged with 3.02 grams (0.02 mole) of the 3-(1-methoxyeth-1-yl)aniline prepared in paragraph (b) of Example IV and 0.6 gram of 5 percent platinum on carbon hydrogenation catalyst in 200 milliliters of methyl ethyl ketone. The autoclave was then sealed, the air driven stirrer turned on, and the temperature was brought up to and maintained at about 95° C. The autoclave was then charged with hydrogen gas to a pressure of 200 psi (the valve to the hydrogen cylinder being left open). After 5 hours' reaction, the autoclave was cooled, broken open, and the contents were removed and filtered. The filtrate was concentrated on a rotary evaporator at 55° C., leaving 11.87 grams of a light yellow liquid identified by NMR spectroscopy as N-sec-butyl-N-3-(1-methyleth-1-yl)aniline.
Reaction SMILES: CC(C)([O-])C.[K+].FC(F)(S([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.CN(C=O)C.[Cl:36][C:37]1[C:46](O)=[C:45]([S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]>O>[Cl:36][C:37]1[C:46]([O:22][CH2:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])=[C:45]([S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1O
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(F)(F)C(F)F
Temperature: 120 °C

Procedure:
1.200 g (4.3 mmol) of potassium tert-butoxide and 1.917 g (4.3 mmol) of 2,2,3,3-tetrafluoropropyl perfluorobutanesulfonate were introduced into 30 ml of DMF in a vessel. At RT, 1200 g (4.3 mol) of methyl 2-chloro-3-hydroxy-4-ethylsulfonylbenzoate were added and the mixture was then heated at 120° C. for 7 h. It was subsequently introduced into water and subjected to extraction with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Drying under an oil pump vacuum gave methyl 2-chloro-3-(2,2,3,3-tetrafluoropropyloxy)-4-ethylsulfonylbenzoate as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][OH:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.C(OCC)(=O)C.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH:10]=[O:11]
Reactant: COc1cc(C)cc(CO)c1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of (3-methoxy-5-methylphenyl)methanol (2.20 g) in DMSO (15 mL) was added 2-iodoxybenzoic acid (4.00 g), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate (50 ml) and water (10 mL) were added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.00 g) as a yellow oil. This compound was used for the next step without further purification.