Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C@@H:2]([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[Br:1][C@@H:2]([CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:3][O:4][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: OCC[C@H](Br)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC[C@H](Br)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A solution of 70 g (0.414 mol) (S)-2-bromo-1,4-butanediol in 1.5 liters methylene chloride was cooled in ice and 173 ml (1.24 mol) triethylamine (dried over potassium hydroxide) was added to give a clear solution. To this was added dropwise over 80 minutes at 5° to 15° C., 96 ml (1.24 mol) methanesulfonyl chloride. The mixture was then stirred at room temperature for 2.5 hours, washed 2×750 ml with water and 1×750 ml brine, dried (MgSO4), and the solvent evaporated to give an amber oil which was purified by chromatography on a 140 mm×25 cm silica gel column, eluting with 9:1 chloroform:ethyl acetate. The product fractions were combined and solvent evaporated to give 105 g (97%) of the title compound as a waxy white solid; [alpha]D =-34.49° (c=5 in CHCl3).
Reaction SMILES: OO.[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[Cl:10].C(=O)([O-])[O-].[Na+].[Na+].[ClH:18]>O>[NH2:3][C:4]1[C:5]([Cl:18])=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[Cl:10]
Reactant: Nc1cncc(Cl)c1Cl
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(Cl)ncc(Cl)c1Cl
Temperature: 25 °C

Procedure:
Thirty percent aqueous hydrogen peroxide (3.0 g, 26 mmol) was added dropwise with stirring at 15° C. to a solution of 8.0 g (49 mmol) of 3-amino-4,5-dichloropyridine in 450 mL of 37 percent aqueous hydrochloric acid. After 30 min another 2.6 g (23 mmol) of 30 percent aqueous hydrogen peroxide was added and the solution was allowed to slowly warm to room temperature. The resulting mixture was diluted with water, neutralized with sodium carbonate, and extracted with ether. The ethereal extract was dried over magnesium sulfate and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a viscous oil. This oil was partially purified by chromatography to obtain 2.5 g (26 percent of theory) of the title compound, a white solid melting at 88°-90° C., and 5.3 g of a mixture of the title compound and 3-amino-2,4,5,6-tetrachloropyridine.
Reaction SMILES: CSCCC(Cl)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.[CH3:30][S:31][CH2:32][CH2:33][C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1.C(O)C>[CH3:30][S:31][CH2:32][CH2:33][C:34]([N:36]=[C:37]=[S:38])=[O:35].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:37]([NH:36][C:34](=[O:35])[CH2:33][CH2:32][S:31][CH3:30])=[S:38])=[CH:25][CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CSCCC(=O)Cl
Agent: CSCCC(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCSC)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
3-(Methylsulphenyl)propanoyl isothiocyanate was prepared using commercially available 3-(methylsulphenyl)propanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(methylsulphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 56%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH:8]=O)=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.[CH3:16]N(C=O)C.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][SH:26])[CH3:22]>C(O)C.O>[CH2:21]([O:23][C:24]([C:25]1[S:26][CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:16]=1)=[O:27])[CH3:22]
Reactant: Cc1ccc(CC=O)cc1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CS
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(C)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 10° C., p-tolyl-acetaldehyde (11.0 g, 82 mmol) is added to a mixture of POCl3 (20 mL, 230 mmol) and DMF (20 mL). The mixture is stirred at rt for 2 h before the reaction is quenched by adding water/ice and NaOAc and extracted with DCM (2×200 mL). The solvent of the organic extract is evaporated and the product is purified by CC on silica gel eluting with heptane:EA 9:1. The resulting oil (1.95 g) is dissolved in ethanol (5 mL) and then added dropwise to a freshly prepared solution of Na (370 mg, 16.2 mmol) and ethyl-2-mercaptoacetate (1.95 g, 16.2 mmol) in ethanol (20 mL). The reaction mixture is stirred at it for 72 h, diluted with water (100 mL) and extracted with EA (2×150 mL). The organic extracts are dried over MgSO4 and evaporated. CC on silica gel eluting with heptane:EA 5:1 gives 4-p-tolyl-thiopene-2-carboxylic acid ethyl ester (850 mg). This ester is dissolved in ethanol (10 mL) and 3 M aq. NaOH (5 mL) and the mixture is refluxed for 2 h. The reaction mixture is acidified and extracted with DCM. The organic extract is dried over MgSO4 and the solvent is evaporated to give 4-p-tolyl-thiophene-2-carboxylic acid (580 mg) as a solid; LC-MS: tR=0.91 min, [M+1+CH3CN]+=260.16, 1H NMR (CDCl3): δ 8.14 (s, 1H), 7.70 (s, 1H), 7.50 (d, J=7.6 Hz, 2H), 7.24 (d, J=7.6 Hz, 2H), 7.05 (s br, 1H), 2.39 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(NCC2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(NCC2CCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethylamino]benzoate (2.17 g, 6.490 mmol) in CH2Cl2 (44 mL) was added TFA (8.7 mL) at 0° C., and the resulting mixture was stirred overnight at room temp. The solvent was removed under a reduced pressure and the residue was treated with 1N NaOH. The mixture was extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, and the solvent was concentrated under a reduced pressure to afford 1.34 g (88%) methyl 4-(2-pyrrolidinylmethylamino)benzoate as a brown oil, which is used to the subsequent reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[N:3]=1.Cl[CH2:13][CH:14]=O>C(O)C.O>[Br:1][C:2]1[N:3]=[C:4]([NH:8][C:9]2[S:10][CH:13]=[CH:14][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1cccc(Br)n1
Reactant: O=CCCl
Solvent: O
Solvent: CCO
Product: Brc1cccc(Nc2nccs2)n1
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
A suspension of 2-bromo-6-thioureidopyridine (3 g, 12.92 mmol) and chloroacetaldehyde (3.28 mL, 25.85 mmol) in ethanol (27 mL) and water (7 mL) was heated at reflux for 4.75 h. The solution was concentrated in vacuo and the residue was diluted with 1 N aqueous NaOH solution at 0° C., stirred for 10 min, and the pH was then adjusted to 8.5 by addition of 6 N aqueous HCl solution. The precipitate was collected by filtration, washed several times with water and dried in vacuo over P2O5 to obtain the titled compound (3.17 g, 96%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([I:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][Br:26])=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CC(C)=O>S1(CCCC1)(=O)=O>[Br-:26].[OH:1][C:2]1[C:3]([I:8])=[N+:4]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCc1ccc(CBr)cc1
Reactant: Oc1cccnc1I
Solvent: O=S1(=O)CCCC1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCc1ccc(C[n+]2cccc(O)c2I)cc1
Product: [Br-]
Yield: 80.3 %

Procedure:
A mixture of 3-hydroxy-2-iodopyridine (22.1 g, 0.1M) and 4-dodecylbenzyl bromide (37.2 g, 0.101M) was stirred in sulpholane (100 ml) at 90° C. for 8 hours. Acetone was added and the precipitated product filtered and washed with acetone to yield a white solid (45 g). The product was recrystallised from a mixture of methanol and water, collected and dried at 60° C. (35 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[NH2:10][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][C:16]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:17])[CH:8]=[C:7]([NH2:9])[N:6]=1
Reactant: NCc1cc(N)nc(N)c1
Reactant: O=C(Cl)C1CCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Nc1cc(CNC(=O)C2CCCC2)cc(N)n1
Yield: 26.6 %

Procedure:
A solution of 205.6 mg (1.49 mmol) 4-aminomethyl-pyridine-2,6-diamine in 5 ml pyridine was treated with 198 mg (1.49 mmol) cyclopentane carboxylic acid chloride and a catalytic amount 4-dimethylaminopyridine and stirred for 2.5 h at room temperature. The mixture was evaporated to dryness and the residue was purified by column chromatography on silica eluting with dichloromethane/methanol 9/1 to yield 93 mg (26%) of the title compound.
Reaction SMILES: CO.Cl.Cl.Cl.[CH2:6]([NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[NH:18])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH3:35][C:36]([CH3:38])=O>>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH3:35][C:36]1([CH3:38])[N:15]=[C:14]([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[N:18]1
Reactant: CC(C)=O
Reactant: CCCCCCCCCNC(=N)NC(=N)NCc1ccccc1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccccc2)N1

Procedure:
140 ml of methanol, 100 ml of acetone and 0.5 ml of concentrated hydrochloric acid were added to 8.0 g (19.1 mmol) of N1-benzyl-N5-nonyl-biguanide dihydrochloride. The mixture was refluxed for 20 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of ethanol, and to the solution were added 60 ml of water and 8.4 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of 70% aqueous acetonitrile, and to the solution was added 4.8 g (38.2 mmol) of oxalic acid dehydrate. The mixture was dissolved under heating, and then cooled. The resulting crystals were recrystallized from 70% aqueous acetonitrile to obtain 8.1 g of colorless crystals having a melting point of 105 to 107° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:9][CH:8]=1>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:1]=[N+:2]=[N-:3])=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCCCN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
Sodium azide (3.07 g, 0.047 mol) was added to a solution of 1 (12.9 g, 0.04 mol) in anhydrous DMF (70 mL) and the reaction mixture was stirred 12 h at 80° C. (oil bath). Then solvent was removed at reduced pressure and the residual oil was treated with a mixture of CH2Cl2/ether 3:1 (100 mL). The resulting solution was washed with water (2×100 mL), brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and 7.6 g (95%) of 2 was obtained. The purity of 2 (99%) was determined by GC and TLC (eluent: hexane/ethyl acetate 1:1), Rf0.84.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Br:26][C:23]1[CH:24]=[CH:25][C:16]([NH:15][C:10](=[O:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-(trifluoromethyl)phenyl)acetyl chloride (23.4 mmol assuming quantitative yield in previous step, Intermediate 5: step a) in DCM (50 mL) in an ice bath was added methyl 2-amino-5-bromobenzoate (4.90 g, 21.3 mmol) followed by triethylamine (6.51 mL, 46.8 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl then water. The organic phase was dried (Na2SO4), filtered, and concentrated and the residue was purified by flash column chromatography (50-70% DCM-heptanes). Some of the title compound was obtained in pure form from the column, along with mixed fractions containing the title compound and the starting aniline. The mixed fractions were left to stand in DCM:heptanes (1:1) overnight, forming crystalline needles of the title compound, which were collected by vacuum filtration and combined with clean fractions from the column.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(OC(=O)C)C>CS(C)=O>[N:14]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(C(F)(F)F)c(N2CCCCC2)c1
Temperature: 55 °C
Reaction time: 43 h
Yield: 87.3 %

Procedure:
To a solution of 3-fluoro-4-(trifluoromethyl)benzonitrile (300 mg, 1.59 mmol) in DMSO (5.0 mL) was added piperidine (675 mg, 7.93 mmol), and the mixture was stirred for 43 hours at 55° C. After the mixture was cooled to room temperature, ethylacetate was added and washed with water then brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane:ethylacetate=10:1) to afford 3-piperidin-1-yl-4-(trifluoromethyl)benzonitrile (353 mg, 88% yield).
Reaction SMILES: Cl.Cl.C(S[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]=1)C.Cl.[F:49][C:50]([F:54])([F:53])[CH2:51][NH2:52].C([O-])(=O)C.[Na+].C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:15]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:52][CH2:51][C:50]([F:54])([F:53])[F:49])=[NH:47])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)SCC)c1
Reactant: NCC(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)NCC(F)(F)F)c1
Reaction time: 12 h
Yield: 86 %

Procedure:
Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride (1.074 g., 1.5 mmoles) was added to a slurry of 2,2,2-trifluoroethylamine hydrochloride (406 mg., 3.0 mmoles) and anhydrous sodium acetate (246 mg., 3.0 mmoles) in chloroform (10 ml.) and glacial acetic acid (0.3 ml., 5.3 mmoles). The mixture was held for 12 hours at room temperature. It was then diluted to 300 ml. with chloroform, washed with saturated aqueous sodium bicarbonate solution (2 × 50 ml.), washed with saturated aqueous sodium chloride solution (2 × 50 ml.), dried (Na2 SO4) and filtered. The filtrate was acidified with a 10% solution of anhydrous hydrogen chloride in dioxane (5ml.) and then evaporated in vacuo to a foam. The foam was crystallized from 1,2-dimethoxyethane [974 mg., 86% yield, Rf .39 (4:1, benzene: ethanol on silicic acid), m.p.-forms a gel at 125°-127° C.].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][NH2:20].C1COCC1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]([NH:20][CH3:19])=[O:12]
Reactant: CN
Reactant: Cc1cc(Cl)c(C(=O)O)c(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1c(Cl)cc(C)nc1C
Temperature: 0 °C
Yield: 62 %

Procedure:
4-Chloro-2,6-dimethyl-pyridine-3-carboxylic acid (925 mg, 5 mmol) was suspended in anhydrous dichloromethane (15 ml), the mixture was cooled to 0° C. and oxalyl chloride (560 μl, 6.5 mmol) was added dropwise with stirring followed by two drops of DMF. The mixture was stirred at room temperature for 90 minutes, the solvent was removed under reduced pressure, the residue was dissolved in anhydrous dichloromethane (15 ml), the solution was evaporated to dryness again, and the residue was dissolved in anhydrous dichloromethane (15 ml) and cooled to 0° C. TEA (2.1 ml, 15 mmol) was added dropwise followed by dropwise addition of a 2M solution of methylamine in THF (5 ml, 10 mmol). The mixture was stirred at 0° C. for 30 minutes, the solvent was removed under reduced pressure and the residue taken up in saturated sodium bicarbonate solution (40 ml). The mixture was extracted with dichloromethane (3×), the combined extracts were dried over sodium sulfate, the solvent was evaporated under reduced pressure and the residue was triturated with diethylether to yield 610 mg of a crystalline solid (3.1 mmol, 62%). MS (APCI): m/z=198.8 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:42])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)(=O)C.O>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:42][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)Nc4ccccc4)c3)ccc2O1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1)Nc1cccc(COCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Temperature: 25 °C
Yield: 216.7 %

Procedure:
A solution of N-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]-N′-phenylurea (0.025 g) in acetic acid (1 ml) and water (0.5 ml) were stirred under nitrogen at 70° C. for 75 min. The reaction mixture was cooled to room temperature before concentrating under vacuum and azeotroping with MeOH (2×10 ml) to give the title compound (0.028 g). LCMS RT=2.50 min, ES+ve 552 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:26])[O:19][C:20]=3[C:21]([C:23](O)=[O:24])=[CH:22][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[CH:32]1([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:26])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([NH:39][C:38]3[CH:40]=[CH:41][C:35]([CH:32]4[CH2:34][CH2:33]4)=[CH:36][CH:37]=3)=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Reactant: Nc1ccc(C2CC2)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C4CC4)cc3)c3c(c21)CC(C)(C)O3
Yield: 13.2 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-49, 0.100 g, 0.256 mmol), thionyl chloride (2.0 mL), 4-cyclopropyl aniline (0.102 g, 0.769 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.017 g of the desired product. 1HNMR (DMSO-d6): δ 0.62 (d, J=3.9 Hz, 2H), 0.91 (d, J=6.3 Hz, 2H), 1.60 (s, 6H), 1.88 (m, 1H), 3.45 (s, 2H), 3.55 (s, 3H), 6.98-7.16 (m, 3H), 7.19-7.36 (m, 3H), 7.53 (d, J=8.1 Hz, 2H), 9.60 (s, 1H), 10.48 (s, 1H); MS [M+H]+: 505.26.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O)=[CH:9][C:8]([I:23])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24].Cl.CO.C(OC(C)C)(C)C>CO>[ClH:1].[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:9][C:8]([I:23])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Agent: Cl
Solvent: CO
Solvent: CC(C)OC(C)C
Product: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 193 %

Procedure:
4-Chloro-5-[3-(tert-butoxycarbonylamino)propoxy]-7-iodoisoindolinone (101 mg, 0.216 mmol) was suspended in methanol (1.5 mL), and the suspension was added with 10% hydrogen chloride-methanol solution (1.5 mL), followed by stirring at 60° C. for 1.0 hour. The reaction mixture was added with diisopropylether. The obtained solid was collected by filtration and washed with diisopropylether, followed by drying under reduced pressure to obtain 4-chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (84.0 mg, yield 96%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([CH:11]2[C@H:16]([O:17]CC3C=CC=CC=3)[C@@H:15]([O:25]CC3C=CC=CC=3)[C@H:14]([O:33]CC3C=CC=CC=3)[C@@H:13]([CH2:41][O:42]CC3C=CC=CC=3)[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][CH3:58])=[CH:53][CH:52]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C@H:11]2[C@H:16]([OH:17])[C@@H:15]([OH:25])[C@H:14]([OH:33])[C@@H:13]([CH2:41][OH:42])[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:57][CH3:58])=[CH:55][CH:56]=1
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCO3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of compound 35 (1.03 g, 1.30 mmol) in THF/MeOH (30 mL/30 mL) was added Pd/C (10% Pd, 154 mg). The mixture was stirred at rt under hydrogen atmosphere for 15 h. The catalyst removed by filtration, and then the filtrate was concentrated in vacuo. The residue was purified by prep HPLC (reverse phase) to provide the compound E010 (0.28 g, 0.64 mmol, 49%).