Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([OH:11])[CH3:10].[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1.ClCCl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([O:11][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH3:10])[N:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1ccccc1C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccccc1C(C)Oc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
K-t-BuO (0.67 g, 5.97 mmol) was added to a stirred solution of 1-(2-methoxyphenyl)ethanol (0.96 g, 6.28 mmol) in dioxane (15 mL) at 0° C. (ice-bath). After 5 min of stirring at room temperature, the reaction mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (0.78 g, 5.23 mmol) was added whereupon the reaction mixture turned yellow. After being stirrred for 35 min, dichloromethane and K2CO3 were added and the mixture was filtered. Concentration in vacuo furnished a yellow oil that was purified by silica gel chromatography (15×4 cm) using n-hexane ethyl acetate (8:2) as eluent. This gave 1.21 g (92%) of the title compound as a colorless oil. HRMS m/z calcd for C13H13ClN2O2 (M)+ 264.0666, found 264.0677. Anal. (C13H13ClN2O2) C, H, N.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[N:5][C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH:28]([N:31]([CH:34]([CH3:36])C)CC)([CH3:30])C.N1CCCC1.O>C(#N)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]2[C:3]([CH2:2][N:31]3[CH2:28][CH2:30][CH2:36][CH2:34]3)=[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:5]=[C:6]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CBr
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCNC1
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Yield: 32.3 %

Procedure:
Part B: To a magnetically stirred solution of ethyl 5-bromomethyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole4-carboxylate (11.69 g, 23.9 mmol) in acetonitrile (40 ml) is added diisopropylethylamine (DIPEA) (5.2 ml, 30 mmol) and pyrrolidine (1.7 g, 23.9 mmol) and the resulting solution is reacted at room temperature for 2 hours. Water (250 ml) is added and the resulting mixture is extracted three times with dichloromethane. The collected dichloromethane layers are dried over Na2SO4, filtered and concentrated in vacuo. Subsequent purification with flash chromatography (petroleum ether/EtOAC=20/80 (v/v)) gives ethyl 1-(4-chlorophenyl)-2-(2,4-dichloro-phenyl)-5(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxylate (3.7 gram, 32% yield). 1H-NMR (200 MHz, CDCl3): δ 1.42 (t, J=7 Hz, 3H), 1.62-1.72 (m, 4H), 2.42-2.50 (m, 4H), 3.83 (s, 2H), 4.43 (q, J=7 Hz, 2H), 7.17-7.40 (m, 7H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](=O)(OC)OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:9][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: COC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(O)cc1
Yield: 97 %

Procedure:
22 parts of hydroquinone, 18 parts of dimethyl carbonate and one part of triphenylphosphine are kept for 15 hours at 190° C. Working up takes place as described in Example 23. 3 parts (97% of theory, based on converted hydroquinone) of hydroquinone monomethyl ether of boiling point 57° C. are obtained. The conversion is 12 percent.
Reaction SMILES: [CH:1]([N:3]1[CH2:6][CH2:5][C:4]1([CH3:8])[CH3:7])=[O:2].[CH:9](N1CCC1(OC)OC)=[O:10]>F[B-](F)(F)F.C[N+](C)(C)C.CO>[CH:1]([N:3]1[CH:6]([O:10][CH3:9])[CH2:5][C:4]1([CH3:8])[CH3:7])=[O:2]
Reactant: COC1(OC)CCN1C=O
Reactant: CC1(C)CCN1C=O
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Solvent: CO
Product: COC1CC(C)(C)N1C=O

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 19.3 g of 1-formyl-2,2-dimethylazetidine and 54.7 g of methanol in the presence of 0.27 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of 1-formyl-2,2-dimethoxyazetidine the current is switched off. The calculated mean cell voltage is 32.6 volts. Work-up of the electrolysis solution gives 12.2 g of 1-formyl-4-methoxy-2,2-dimethylazetidine (boiling point 52° C./0.26 mbar; nD25 = 1.4496), which corresponds to a product yield of 49.9% and a current efficiency of 39.9%.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.S[CH2:18][CH2:19][CH2:20][C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])=[O:22].[SH:31]CCC(N1CCC[C@H]1C(O)=O)=O>>[O:7]([C:8]([S:31][CH:19]([CH3:18])[CH2:20][C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])=[O:22])=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCCS
Agent: CCOC(=O)Cl
Product: CC(CC(=O)N1CCC[C@H]1C(=O)O)SC(=O)Oc1ccccc1

Procedure:
By substituting phenylchloroformate for the ethyl chloroformate and 4-mercaptobutanoyl-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 58, 1-[3-[[(phenoxy)carbonyl]thio]butanoyl]-L-proline is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].F[B-](F)(F)F.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]#[N:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O.C(O)(=O)C>[Br:1][C:2]1[C:7]([N:26]=[N:25][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)=[N:6][CH:5]=[C:4]([OH:8])[CH:3]=1
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Reactant: Oc1cncc(Br)c1
Agent: F[B-](F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(N=Nc2ncc(O)cc2Br)cc1
Reaction time: 1 h
Yield: 33735.4 %

Procedure:
5-Bromo-3-pyridinol from Example 12b (8.7 g, 0.050 mmol) and KOH (1.1 g, 19.6 mmol) were dissolved in water (200 mL). A suspension of p-nitrobenzenediazonium tetrafluoroborate (11.8 g, 0.50 mol, prepared as described in J. Org. Chem., 44: 1572-15783 (1979)) was added. The reaction was stirred for 1 hour, diluted with acetic acid (50 mL) and filtered. The crude product was allowed to air dry, then chromatographed (silica gel; chloroform/methanol, 95:5-90:10) to provide the title compound (5.45 g, 34% yield): MS (CI/NH3) m/z 323, 325 (M+H)+ ; NMR (DMSO-d6, 300 MHz) δ 8.48-8.43 (m, 2H), 8.21 (d, J=2.4 Hz, 1H), 8.09-8.06 (m, 2H), 7.72 (d, J=2.4 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH2:22])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:22][C@H:11]([C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Cl)c1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 22, (0.41 g, 1 mmol) 3-chlorophenylacetic acid (0.170 g, 1 mmol) and 1-hydroxybenzotriazole (HOBt) (0.070 g, 0.50 mmol) in DMF (5 mL) at 00, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.190 g, 1 mmol) followed by triethylamine (0.42 mL, 3 mmol). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.290 g (60% yield) of the desired product which is used without further purification. ESI− MS 482 (M−1).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][S:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([C:35]2[CH:34]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:38]=[CH:37][N:36]=2)[CH:40]=1)(=[O:46])=[O:47])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 62.9 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of 2-amino-2-methyl-1-propanol (0.097 g, 1.09 mmol), triethylamine (0.11 ml, 0.76 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.21 g, 0.36 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.135 g, 63%). MS (ISP) 597.3 [(M+H)+]; mp 221° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:34])([F:33])[S:8]([O:11][C:12]1[C:13]([NH2:32])=[CH:14][C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=2[CH:31]=1)(=[O:10])=[O:9].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[F:34][C:7]([F:6])([F:33])[S:8]([O:11][C:12]1[C:13]([N:32]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:15]2[O:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=2[CH:31]=1)(=[O:10])=[O:9]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(OS(=O)(=O)C(F)(F)F)cc12
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Methanesulfonyl chloride (146 μL, 1.873 mmol) was added to a stirring solution of 6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (270 mg, 0.624 mmol) and DIEA (500 μL, 2.86 mmol) in DCM (6.3 mL) at 25° C. It was allowed to stir for 1 hour and then diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. It was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (300 mg, 82%). LC-MS retention time: 1.49 min; m/z (MH+): 589. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 mM where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[I:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NCC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[I:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1I
Agent: O=C1CC(=O)N(c2ccc(CNC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3I)cc2)c2ccc3ccccc3c2N1
Yield: 30.8 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-iodobenzoyl chloride (0.143 mmol), the title compound (16 mg, yield 31%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1OS(C(F)(F)F)(=O)=O)([O:3][CH3:4])=[O:2].Cl[P:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.Cl[Ni]Cl.[Zn]>[C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[P:24]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: Cl[Ni]Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 108 °C

Procedure:
To a solution of 66.6 g (0.195 mol) of 1-carbomethoxy-2-(trifluoromethylsulfonyloxy)naphthalene in 450 ml DMF were added, under a nitrogen atmosphere, 3.65 g NiCl2 (dppe) (6.9 mmol) and 35 ml ClPPh2 (0.195 mol). The reaction mixture was cooled in an ice-water bath and 15 g zinc (20% excess) was added portionwise at 8°-15° C. The mixture was then heated to 108° C. for 2 hours, cooled to 50° C., filtered through silica and washed with three 20 ml portions of methanol. The filtrate was concentrated under vacuum to half of its original volume and allowed to crystallize at 0°-4° C. The product was collected and washed with methanol. Further concentration of the filtrate caused additional material to crystallize. The total yield of the title compound was 66.3 g (92%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH2:31]([CH:33]1[O:35][CH2:34]1)Cl.[CH3:36][NH2:37]>CN(C=O)C.C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:31][CH:33]([OH:35])[CH2:34][NH:37][CH3:36])[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: ClCC1CO1
Reactant: CN
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNCC(O)Cn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in a mixture composed of anhydrous DMF (0.5 mL) and anhydrous THF (5 mL) under N2. NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After 30 min of stirring, the reaction mixture was cooled to −15° C. before a solution of epichlorohydrin (79 μL, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for 15 min at −15° C., then for 8 h at room temperature. MeNH2 (2.0 M in MeOH, 1.0 mL) was added and the mixture was heated for 10 min at 105° C. in the microwave oven. The mixture was cooled, filtered and purified by preparative HPLC to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-hydroxy-3-(methylamino)propyl)-1H-indol-5-yl)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.60-7.59 (m, 1H), 7.35 (dd, J=14.3, 8.9 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 1H), 6.94 (dd, J=8.0, 1.6 Hz, 1H), 6.91 (d, J=7.9 Hz, 1H), 6.20 (d, J=2.3 Hz, 1H), 6.03 (s, 2H), 2.82 (d, J=4.7 Hz, 1H), 2.72 (d, J=4.7 Hz, 1H), 2.55 (dd, J=5.2, 5.2 Hz, 1H), 2.50 (s, 3H), 1.43 (s, 9H), 1.39 (dd, J=6.4, 3.7 Hz, 2H), 1.04 (dd, J=6.5, 3.9 Hz, 2H). MS (ESI) m/e (M+H+) 464.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][NH:34][CH2:35][CH2:36][CH3:37]>O1CCCC1>[OH2:19].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:34]([CH3:33])[CH2:35][CH2:36][CH3:37])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCCNC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2.5 hours with a stream of nitrogen bubbling through it. A solution of methylpropylamine (3.81 g, 0.0522 mole) in tetrahydrofuran (4 ml) was added, and the reaction mixture was heated at 45° C. for 15 hours, then stirred at room temperature. The solvents were evaporated under reduced pressure, and the resulting oil was triturated in water (100 ml) which caused a solid to form. The solid was collected by filtration and washed with water, twice with a 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered, and cooled to room temperature. Addition of water to the cloud point caused crystals to form. The solid was collected by filtration, rinsed with water, and dried at high vacuum to give 3.60 g (60%) of title compound, mp 130°-133° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:25][CH2:26][CH2:27][N:28]3[C:32](=[O:33])[C:31]4=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]4[C:29]3=[O:38])[C:15]2=[O:23])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCn1c(=O)n(C2CCNCC2)c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
A mixture of Compound 9 (42.2 g, 0.13M), prepared in Example 9, and N-(3-bromopropyl)phthalimide (35 g, 0.13M) were dissolved in DMF (300 ml). Cesium carbonate (100 g, 0.3M) was added in one portion and the resulting heterogenous mixture heated in an 80° C. oil bath for 16 hours. The mixture was cooled to room temperature and the DMF removed under reduced pressure. The residue was poured into ice water (800 ml) and stirred at room temperature overnight. The white solid precipitates were collected and dried to give the desired product (60 g, 92%). The BOC group was removed by treatment of a solution of the compound in methylene chloride (500 ml) with excess trifluoroacetic acid (46 ml, 0.6M). The mixture was stirred at room temperature overnight and evaporated to dryness under reduced pressure. The resulting white solids were washed with diethyl ether and dried to give the desired TFA salt. m.p. 173-175° C. 1H NMR (300 MHz, DMSO-d6) δ8.79 (m, 1H; 8.54 (m, 1H); 7.82 (s, 4H); 7.35 (m, 1H); 7.25 (m, 1H); 7.07-6.90 (m, 2H); 4.55 (m, 1H); 3.90 (t, J=7 Hz, 2H); 3.63 (t, J=7 Hz, 2H); 3.42 (m, 2H); 3.15 (m, 2H); 2.60(m, 2H); 2.07 (m, 2H); 1.90 (m, 2H). MS: m/z (MH+) 405
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[C:9]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:21][C:15]=4[N:14]=3)=[N:10][NH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[C:29]([OH:34])(=[O:33])[C@H:30]([CH3:32])[OH:31]>CCOC(C)=O.CO>[C:29]([OH:34])(=[O:33])[CH:30]([CH3:32])[OH:31].[CH:1]1([NH:4][C:5]([NH:7][C:8]2[C:9]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH2:22][N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:21][C:15]=4[N:14]=3)=[N:10][NH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: C[C@H](O)C(=O)O
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea (0.7 g, 1.83 mmol) in EtOAc-MeOH was added L-lactic acid (166 mg, 1.85 mmol). The mixture was stirred at ambient temperature then reduced in vacuo. This solid was purified by recrystallisation from boiling EtOH (20 mL) to give after drying 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea, L-lactate salt (0.48 g).
Reaction SMILES: C1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[O:14])[S:11][CH:12]=1.[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.O>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[S:11][CH:12]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: Brc1csc(C2OCCO2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
A benzene (55 mL) solution of 4-bromo-2-thiophene carboxaldehyde (9.76 g 51.09 mmol), ethylene glycol (8.55 mL, 153.26 mmol) and p-toluenesulfonic acid monohydrate (0.972 g, 5.11 mmol) was refluxed with azeotropic removal of H2O for 6 h and then cooled to ambient temperature. The reaction mixture was diluted with Et2O and the organics washed with sat'd NaHCO3, brine and then dried (MgSO4), filtered and concentrated. Chromatography on silica gel using 95:5 Hexanes:EtOAc eluted the product to provide the title compound upon concentration as a yellow oil (10.76 g 90% yield): 1H NMR (CDCl3, 400 MHz) δ 7.22 (s, 1H), 7.08 (s, 1H), 6.07 (s, 1H), 4.14–4.00 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].F[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20].CCOC(C)=O>O>[CH3:18][NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([O:6][CH:3]([CH3:5])[CH3:4])=[C:9]([N+:19]([O-:21])=[O:20])[CH:10]=1)(=[O:16])=[O:15]
Reactant: CC(C)O
Reactant: CNS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1ccc(OC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
NaH (0.440 g, 11 mmol) was added to 20 mL of isopropanol and the resulting mixture stirred at room temperature. After 30 minutes, 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (2.34 g, 10 mmol) was added. The reaction mixture was then stirred at room temperature overnight. The mixture was poured into EtOAc and water. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo to give the crude product. Purification via column chromatography (1:1 petroleum ether/ethyl acetate) afforded N-methyl-4-[(1-methylethyl)oxy]-3-nitrobenzenesulfonamide (1.6 g, 58% yield) as a yellow solid. MS (m/z) 274.7 (M+H+)