Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([S:26]([O-:28])=[O:27])[CH:20]=[CH:19]3)=[CH:12][CH:11]=1.[Na+]>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([S:26]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH2:7][OH:8])(=[O:28])=[O:27])[CH:20]=[CH:19]3)=[CH:12][CH:11]=1
Reactant: OCc1ccsc1Br
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1sccc1CO

Procedure:
Prepared according to the method of Example 6 Step 4 using (2-bromo-3-thienyl)methanol (itself prepared according to WO2004/065384A1) and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate. 1H NMR (400 MHz, d6-DMSO): δ 8.72 (1H, s), 8.36 (2H, d, J=7.9 Hz), 8.21 (1H, d, J=8.8 Hz), 8.04 (2H, dd, J=3.2, 8.4 Hz), 7.93-7.87 (3H, m), 7.38 (2H, t, J=8.9 Hz), 7.26 (1H, d, J=5.1 Hz), 5.47 (1H, t, J=5.9 Hz), 4.70 (2H, d, J=5.9 Hz). m/z (ES+) 384 [(M-OH)+].
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:9][O: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][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O.[CH:46]1[C:58]2[CH:57]([CH2:59][O:60][C:61]([NH:63][C@@H:64]([CH2:72][SH:73])[C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])=[O:62])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50]=2[CH:49]=[CH:48][CH:47]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[CH:55]1[C:56]2[CH:57]([CH2:59][O:60][C:61](=[O:62])[NH:63][C@H:64]([C:65]([O:67][C:68]([CH3:70])([CH3:69])[CH3:71])=[O:66])[CH2:72][S:73][CH2:7][C@H:8]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:9][O: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][CH2:23][CH2:24][CH2:25][CH3:26])[C:58]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]=2[CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)OCCCCCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2,3-bis(hexadecyloxy)propyl trifluoromethanesulfonate (1 eq), (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 2 eq) and K2CO3 (1 eq) in EtOH (0.1 M) was stirred for 30 minutes at 60° C. The reaction mixture was filtered and washed with DCM. The filtrate was concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% EtOAc/Hex to give (5R,9R)-tert-butyl 1-(9H-fluoren-9-yl)-9-(hexadecyloxy)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29]([O:31]C)=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2([C:29]([OH:31])=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3cccnc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccnc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidinecarboxylate (430 mg, 0.94 mmol) in 8 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 235 mg (57%) of the acid. HR—MS: m/z Calculated for C22H22N2O6S 443.1271; Found 443.1270.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1ccccc1CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1ccccc1Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 1-(bromomethyl)-2-methylbenzene using DBU as a base in DMF at 80° C., Mass: 514.11 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:3]=1.[CH2:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH:22]=[CH2:23]>CS(C)=O.O>[CH2:21]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:3]=2)[CH2:26][CH2:25]1)[CH:22]=[CH2:23]
Reactant: C=CCN1CCNCC1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ncn2)cc1
Solvent: CS(C)=O
Solvent: O
Product: C=CCN1CCN(c2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ncn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
430 mg (1.38 mmol) of N-(6-chloropyrimidin-4-yl)-4-isopropylbenzenesulfonamide from Example 18.1 were dissolved in 3 ml of dimethyl sulfoxide, after which 1.74 g (13.79 mmol) of N-allylpiperazine were added and the mixture was stirred overnight. Subsequently, the reaction mixture was stirred at 100° C., in a microwave oven, for 45 minutes. After the reaction mixture had cooled down to room temperature, it was diluted with 50 ml of water. After that, the aqueous reaction mixture was extracted with 50 ml of ethyl acetate and the precipitate was filtered off with suction, with 190 mg (34% of theory) of the title compound being obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[N:20]#[C:21]Br>O1CCOCC1.O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]2[O:8][C:21]([NH2:20])=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a solution of 4-(trifluoromethyl)benzohydrazide (0.5 g, 2.449 mmol) in dioxane (10 mL) and water (2 mL) was added sodium bicarbonate (0.617 g, 7.35 mmol) and cyanic bromide (0.519 g, 4.90 mmol). The reaction was stirred at room temperature for 15 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc, dried over sodium sulfate, and evaporated to yield 5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine (0.28, 50%). 1H NMR: 400 MHz, DMSO-d6: δ 7.43 (s, 2H), 7.91 (d, J=8.40 Hz, 2H), 8.00 (d, J=8.40 Hz, 2H). LCMS: RT 1.55 min. LCMS (ES-API), m/z 230.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])([O:19][CH2:20][CH3:21])[CH2:15][CH:14]=1)=O)([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([O:8][CH2:9][CH2:10][NH:12][C:13]2[CH:14]=[CH:15][C:16]([N+:22]([O-:24])=[O:23])([O:19][CH2:20][CH3:21])[CH2:17][CH:18]=2)[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1([N+](=O)[O-])C=CC(NC(=O)COc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=CC1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC1([N+](=O)[O-])C=CC(NCCOc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=CC1

Procedure:
1.92 g (4.5 mmole) of 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]-N-(4-nitrophenetyl)acetamide (synthesis intermediate of compound 47) is introduced into 80 ml of anhydrous THF in a flask, under an argon atmosphere. A solution of 13.45 ml (13.45 mmole) of BH3 in THF is added to the reaction mixture and the mixture is agitated while heating at reflux for 4 hours 30 minutes. At the end of the reaction, 10 ml of MeOH is added and heating is maintained for a further 30 minutes. The reaction mixture is then concentrated under vacuum, the residue is taken up in 30 ml of a MeOH/HCl 3N mixture (2/1) and the mixture is taken to reflux for another hour. The reaction mixture is returned to 22° C., diluted with 50 ml of CH2Cl2 and 2M aqueous soda is added until a basic pH is obtained. After decantation, the organic phase is washed successively with 20 ml of water and 20 ml of brine, dried over sodium sulphate, filtered and concentrated under vacuum. The expected product is purified by chromatography on a silica column (eluent: CH2Cl2/EtOH: 25/1). Pale yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])=[CH:25][CH:24]=3)=[O:20])[CH:10]=1)=[O:8])(=[NH:3])[NH2:2].Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1>>[C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:42]([NH2:43])=[NH:37])=[CH:25][CH:24]=3)=[O:20])[CH:10]=1)=[O:8])(=[NH:2])[NH2:3]
Reactant: CC(C)Cn1cc(NC(=O)c2cc3cc(NC(=O)CCN)ccc3[nH]2)cc1C(=O)NCCC(=N)N
Reactant: N=C(N)n1cccn1
Agent: Cl
Product: CC(C)Cn1cc(NC(=O)c2cc3cc(NC(=O)CCNC(=N)N)ccc3[nH]2)cc1C(=O)NCCC(=N)N
Yield: 26 %

Procedure:
Compound 114 was treated with 1H-pyrazole-1-carboxamidine hydrochloride according to the procedure for 47 to give compound 115. Yield: 26%. MS: 262.17 (M/2+H+). 1H-NMR (DMSO-d6): 11.51 (s, 1H), 10.25 (s, 1H), 9.93 (s, 1H), 8.89 & 8.60 (2br s, 3H), 8.25 (t, 1H), 7.99 (s, 1H), 7.51 (t, 1H), 7.37 (d, 1H), 7.26 (d, 1H), 7.25 (s, 1H), 7.19 (d, 1H), 6.92 (d, 1H), 4.11 (d, 2H), 2.59 (t, 2H), 1.98 (m, 1H), 0.80 (d, 6H).
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)C.[BrH:20].O>C(OCC)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][Br:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccccc1Oc1ccc(Br)cc1
Reactant: Br
Solvent: O
Solvent: CCOCC
Product: BrCc1ccccc1Oc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 413.0 g of the 2-(4-bromophenoxy)benzyl alcohol and 1290 ml of 48% hydrobromic acid is boiled under reflux for 4 hours, then cooled and poured onto 2000 ml of ice and water. The greenish oil that separates out is dissolved in 2000 ml of diethyl ether. The organic phase is washed twice with 400 ml of water and with 400 ml of a 1N aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation at 40° under 11 mm Hg. The 2-(4-bromophenoxy)benzyl bromide, obtained in the form of an oily residue, is used without purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([S:13]([CH2:16][CH2:17][CH2:18][C:19]2[N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[N:22]=[C:21]([C:28]([OH:30])=O)[CH:20]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+:32]>ClCCl.CN(C=O)C>[C:7]1([S:13]([CH2:16][CH2:17][CH2:18][C:19]2[N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[N:22]=[C:21]([C:28]([NH2:32])=[O:30])[CH:20]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCn1nc(C(=O)O)cc1CCCS(=O)(=O)c1ccccc1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCn1nc(C(N)=O)cc1CCCS(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Oxalyl chloride (7.8 mL, 90.0 mmol) was added slowly via syringe to a solution of 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxylic acid (10.5 g, 30.0 mmol) in 100 mL of dichloromethane containing one drop of DMF. After 2 hours of stirring, saturated ammonium chloride (100 mL) was added to the reaction mixture and the reaction was maintained for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane and washed with water. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 10.4 g of 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxamide.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: Cc1oc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(F)c(-c2cc(C=O)c(C)o2)c1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.3 g), 2-fluoro-5-methoxyphenylboronic acid (1.4 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.5 g, 93%) as a white crystal.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.[CH2:20]([O:22]C=O)C>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]([CH:20]=[O:22])=[CH:7][N:6]=1
Reactant: CC(C)(C)CNc1nc(Cl)ncc1Br
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)CNc1nc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (5-bromo-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine (30 g, 108 mmol) in THF (500 ml) is added n-butyllithium (1.6 mol/l in n-hexane, 148 ml, 237 mmol) dropwise at −78° C. and the mixture is stirred for 10 min. Ethylformate (19 ml, 230 mol) is added dropwise to the mixture at −78° C., and the reaction mixture is allowed to warm to ambient temperature. After being stirred for 1 hour, the reaction mixture is quenched with saturated NH4Cl at −78° C. and then extracted with AcOEt. The combined extracts are washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent:n-hexane:AcOEt=4:1) give 2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carbaldehyde. Rf=0.56 (n-hexane:AcOEt=1:1). 1H NMR (400 MHz, DMSO-d6) δ 1.00 (s, 9H), 3.41 (d, 2H), 8.40 (s, 1H), 8.88 (brs, 1H), 9.84 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[O:7][N:6]=1)[CH3:4].[CH2:19]([CH:21]1[O:23][CH2:22]1)Br.[Cl-].[Na+]>>[CH2:3]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:21]2[O:23][CH2:22]2)[O:7][N:6]=1)[CH3:4]
Reactant: BrCC1CO1
Reactant: CCc1cc(C=Cc2ccccc2O)on1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: CCc1cc(C=Cc2ccccc2OCC2CO2)on1

Procedure:
This compound is prepared by the method described for Example V, from 5.1 g of 55% strength sodium hydride (0.116 mole), 25.0 g (0.116 mole) of 3-ethyl-5-(2-hydroxystyryl)-isoxazole and 15.9 g (0.116 mole) of epibromohydrin. The reaction mixture is poured into sodium chloride solution and extracted by shaking with diethyl ether. The ether solution is dried over anhydrous sodium sulfate, and concentrated. 29.2 g (93% of theory) of a colorless oil are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O>[CH2:15]([O:14][C:12]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Piperidine-4-carboxylic acid (64.8 g, 0.5 mol) in H2O (50 mL) was treated with NaOH (44.0 g, 1.1 mol). The reaction mixture was cooled to 0° C. and treated with CbzCl (93.8 g, 0.55 mol). The reaction mixture was stirred at ambient temperature for 4 hours and the mixture was extracted with Et2O (3 150 mL). The aqueous phase was acidified with 6 N HCl (140 mL) and extracted with EtOAc (3 200 mL). The solution was dried over MgSO4, filtered, and concentrated to afford crude piperidine-1,4-dicarboxylic acid monobenzyl ester (120 g), which was used without further purification: MS (ESI) m/z 262 [M−H]+.
Reaction SMILES: COP([CH2:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH:11]=[CH2:12])(OC)=O.[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[CH:26][C:25]=1[N+:35]([O-:37])=[O:36])=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCO>[C:16]([O:15][C:14]([NH:13][C@@H:9]([CH2:10][CH:11]=[CH2:12])[C:8](=[O:21])/[CH:7]=[CH:22]/[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[CH:26][C:25]=1[N+:35]([O-:37])=[O:36])=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: COC(=O)Nc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)CP(=O)(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)/C=C/c1ccc(NC(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90 %

Procedure:
To a vigorously stirred solution of 5E (4.47 g, 13.92 mmol) and 5D (2.6 g, 11.60 mmol) in THF (anhydrous) (115 mL) and EtOH (absolute) (1.148 mL) under nitrogen was added portion wise K2CO3 (anhydrous) (2.56 g, 18.56 mmol) at 0° C. The reaction mixture was allowed to raise to rt and then the mixture was heated at 55° C. The reaction mixture was then filtered with the aid of EtOAc and the filtrate evaporated to a residue which was dissolved in a small amount of methylene chloride and purified by normal phase chromatography to give 5F (4.38 g, 90%) as yellow solid. MS (ESI) m/z: 420.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.83-7.73 (m, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.02 (d, J=15.9 Hz, 1H), 5.77 (ddt, J=17.0, 10.2, 6.7 Hz, 1H), 5.16-5.01 (m, 2H), 4.32 (td, J=8.5, 4.9 Hz, 1H), 3.71 (s, 3H), 2.34-2.23 (m, 1H), 1.36 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:14](I)=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:14]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1nc2cc(Cl)c(I)cc2[nH]1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Compound number 130 (i.e., 6-chloro-5-(4-chlorophenyl)-2-trifluoromethylbenzimidazole was prepared as follows. A 250-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. 5-chloro-6-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole (400 mg, 1.15 mmol, 1.00 equiv), (4-chlorophenyl)boronic acid (359 mg, 2.30 mmol, 1.99 equiv), sodium carbonate (380 mg), dioxane (40 mL), Pd(PPh3)4 (67 mg), and water (10 mL) was placed in the flask. The resulting solution was stirred for 4 h at 100° C. in an oil bath. The mixture was cooled. The resulting solution was diluted with 100 mL of H2O. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×100 mL of brine (sat.). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 34.9 mg (9%) of 6-chloro-5-(4-chlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[O:5][C:6]=1[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C([Li])(C)(C)C.CON(C)[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33].O>CCOCC>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C:6]1[O:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=2[C:2]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[CH3:10]
Reactant: CON(C)C(=O)c1ccccc1F
Reactant: CCOC(OCC)c1oc2ccccc2c1Br
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CCOC(OCC)c1oc2ccccc2c1C(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
To a solution of 3 g of 3-bromo-2-(diethoxymethyl)-benzo[b]furan in 80 ml of dry ether under nitrogen at -100° C was added 17.4 ml of a 1.7 M solution of tert-butyllithium in hexanes. The solution was stirred at the low temperature for 2 h then a solution of 2.76 g of N-methoxy-N-methyl-2-fluorobenzamide in 20 ml of dry ether was added and the solution stirred at the low tempertature for 10 min. The solution was then allowed to slowly warm to 0° C., water was added and the organic layer was separated, washed with water and dried over sodium sulfate and evaporated. Gravity chromatography eluting 0 to 50% toluene in heptane afforded 0.91 g of 2-(diethoxymethyl)-3-(2-fluorobenzoyl)-benzo[b]furan as an oil, 1H-NMR (200 MHz, CDCl3) d 5.76 (CHOEt).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].[OH-].[Na+]>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CN(c1ccccc1)S(=O)(=O)c1ccccc1Cl
Yield: 87 %

Procedure:
To 0.97 g (˜0.01 mole) of freshly prepared N-methyl-aniline (b.p. 196° C.) is added 1.94 g (˜0.01 mole) of 2-chlorobenzenesulfonyl chloride (98 w/w %). The mixture is stirred until it becomes hot, and then ten percent sodium hydroxide is added dropwise with stirring until the solution is slightly alkaline. 2-chloro-N-methylbenzenesulfonanilide is formed as a viscous yellow liquid. It is washed with water several times until the wash water is neutral to litmus paper, and the viscous yellow liquid extracted with ether. The ether layer is dried over magnesium sulfate, filtered and the solvent removed by evaporation. The yield of a yellow oil is 2.2 g (87% yield).