Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][C@@H:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][C:34]([OH:36])=[O:35].C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCCC1.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][C@@H:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][C:34]([OH:36])=[O:35])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[C@H](N)CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CC(=O)O)C(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Temperature: 135 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.100 g, 0.215 mmol: prepared in a similar manner as described below for Compound 25a in scheme 4) and (R)-3-amino-4,4-dimethylpentanoic acid, 2a, (0.031 g, 0.215 mmol) in tetrahydrofuran (1.66 mL) was added freshly ground Na2CO3 (0.068 g, 0.645 mmol) followed by acetonitrile (0.331 mL). The reaction mixture was heated to 135° C. for 30 minutes in a microwave reactor. The reaction mixture was slowly poured into 75 mL of 1N HCl. The pH of final solution was adjusted to 1. The aqueous was extracted with EtOAc (3×5 mL), washed with brine, dried over Na2SO4 and filtered to obtain a crude solid residue. The crude residue was purified via silica gel chromatography (0-10% MeOH—CH2Cl2 gradient) afforded 78 mg of the desired product 3a: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.9 minutes (M+H) 546.22.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH3:23])=[N:6][CH:7]=1.N1C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34](Cl)=[O:35].Cl>ClCCl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH3:23])=[N:6][CH:7]=1)=[O:35]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N)cn2)c(OC)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)c(OC)c1
Reaction time: 1 h

Procedure:
Under ice cooling, to a solution of ethyl 3-(4-(5-aminopyridin-2-yloxy)-3-methoxyphenyl)propionate (1.43 g, 4.5 mmol) in dichloromethane (30 mL) was added pyridine (0.44 mL, 5.4 mmol), and then 3,4-dichlorobenzoyl chloride (0.99 g, 4.7 mmol). The resulting solution was stirred for 1 hour under ice cooling, and then for 10 hours at room temperature. To the resulting reaction solution was added 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. To the residue was added diethyl ether, and stirred. The precipitates were collected by filtration. After washing with water and diethyl ether, the precipitates were air dried at 60° C., to thereby yield 0.52 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22](OC)=[O:23])[CH:18]=3)[CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:29][OH:30].[OH-].[K+].C(O)=O>CO.CS(C)=O>[OH:30][NH:29][C:22]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:27])[F:26])[CH:4]=1)=[O:11])[CH2:21][CH2:20]2)=[O:23]
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)Nc1cccc(C(F)(F)F)c1)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Solvent: CS(C)=O
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)Nc1cccc(C(F)(F)F)c1)C2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(3-(trifluoromethyl)phenylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (obtained in step 1) in methanol (1 mL) was added hydroxylamine hydrochloride (40 mg, 0.5 mmol) and potassium hydroxide (100 mg, 2 mmol). The reactions were left to stir for 2 hours at 80° C. Upon cooling to room temperature, the reaction was quenched with the addition of formic acid (75 μL, 2 mmol) and the solvents were evaporated to dryness. The residue obtained was dissolved in DMSO (1 mL), the residual solids removed by filtration and the solution purified via Gilson prep-HPLC to afford a white solid (4.2 mg, 11% over 2 steps). LCMS (FA) ES+380.
Reaction SMILES: CI.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[OH:13])=O.[C:14](=O)([O-])[O-].[K+].[K+].NN.[OH-].[K+]>CC(C)=O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:4][CH3:3])=[C:7]([O:13][CH3:14])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(Br)cc1O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)=O
Product: CCc1ccc(Br)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.4 %

Procedure:
Methyl iodide (3 mL, 47.3 mmol) was added to a solution of 4-bromo-2-hydroxyacetophenone (9.25 g, 43 mmol) and potassium carbonate (6.54 g, 47.3 mmol) in acetone (20 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to low volume and diluted with water. The aqueous mixture was extracted with dichloromethane (3×50 mL) and the combined organic solution was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 1,2-ethanediol (10 mL), hydrazine (19.47 mL, 400 mmol) and potassium hydroxide (7.86 g, 140 mmol) were added and the reaction mixture was heated at 150° C. for 60 hours. The reaction mixture was then quenched with 1M hydrochloric acid and extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by Kugel Rohr fractional distillation (150° C./0.05 mbar) to provide the title compound as a yellow oil (128 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH:15]([CH3:20])[CH2:16][C:17](O)=[O:18])=[CH:10][CH:9]=2)[CH:2]=1.O.[NH2:23][NH2:24].[ClH:25]>COCCO>[ClH:25].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]([CH3:20])[CH2:16][C:17](=[O:18])[NH:23][N:24]=3)=[CH:10][CH:9]=2)[CH:2]=1
Reactant: CC(CC(=O)O)C(=O)c1ccc(Cc2cccnc2)cc1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: COCCO
Product: CC1CC(=O)NN=C1c1ccc(Cc2cccnc2)cc1

Procedure:
7.1 g (0.025 mole) of 4-(4-(3-pyridylmethyl)-phenyl)-4-oxo-3-methyl-butyric acid and 1.5 ml (0.03 mole) of hydrazine hydrate are stirred in 30 ml of ethylene glycol monomethyl ether at 100° C. for 1 hour. After addition of ethanolic hydrochloric acid, the product is filtered off with suction and recrystallised from 96% strength ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:14]/[CH:15]=[CH:16]/Cl)[CH3:13])[C:4]=2[S:5][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[C:42]([C:46]#[CH:47])([CH3:45])([CH3:44])[CH3:43]>O1CCCC1.[Pd](Cl)Cl.[Cu]I.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:14]/[CH:15]=[CH:16]/[C:47]#[C:46][C:42]([CH3:45])([CH3:44])[CH3:43])[CH3:13])[C:4]=2[S:5][CH:6]=1
Reactant: C#CC(C)(C)C
Reactant: CN(C/C=C/Cl)Cc1cccc2c(Cl)csc12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2c(Cl)csc12
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 0.86 g (3.0 mmol) of (E)-3-chloro-N-(3-chloro-2-propenyl)-N-methylbenzo[b]thiophene-7-methanamine in 5 ml of tetrahydrofuran were added 42.6 mg (0.16 mmol) of triphenylphosphine, 20.1 mg (0.11 mmol) of palladium chloride, 34.0 mg (0.18 mmol) of copper (I) iodide, 0.6 ml (6.1 mmol) of n-butylamine and 0.5 ml (4.1 mmol) of tert-butylacetylene. The mixture was stirred for 24 hours at room temperature, poured into 40 ml of ethyl acetate. The organic layer was separated, washed with 20 ml×2 of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-heptane→n-heptane/ethyl acetate=5/1). The desired fractions were put together and concentrated under reduced pressure. The residue was treated with 3 ml of 23% hydrogen chloride methanol solution and the solution was concentrated. The resulting crystals were suspended in isopropylalcohol, filtered, washed with isopropylalcohol and dried to obtain 0.77 g (yield: 70%) of the above identified compound as white crystalline powder.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18]S(C)(=O)=O)[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Na+].[I-].[C:36]([O-])(O)=[O:37].[Na+].CCOC(C)=O>CN(C=O)C>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18][CH:36]=[O:37])[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOC=O
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-6-methyl-8-(2(methylsulfonyloxy)ethyl)-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (510 mg, 1.03 mmol) in DMF (3 mL) at room temperature (about 22° C.) was added NaI (1 g, 6.7 mmol). The resulting reaction mixture was heated to 80° C. and stirred for 48 h. After cooling to room temperature, saturated NaHCO3 solution (30 mL) and EtOAc (25 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (228 mg, 50%) as a white solid (228 mg, 50%): mp 103-104; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 5.43-5.15 (m, 2H), 5.06 (t, J=9.9 Hz, 1H), 4.93-4.77 (m, 2H), 4.19 (dt, J=11.1, 5.5 Hz, 1H), 4.05 (ddd, J=11.4, 8.9, 4.8 Hz, 1H), 3.60 (s, 1H), 2.71 (td, J=11.4, 2.8 Hz, 1H), 2.67-2.53 (m, 1H), 2.17-2.02 (m, 1H), 1.73 (dt, J=14.7, 7.4 Hz, 1H), 1.45 (s, J=15.6 Hz, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 0.5 Hz, 6H); ESIMS m/z 468 ([M+Na]+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N:1]([CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: OCC1(CBr)COC1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCC1(CO)COC1
Yield: 47.9 %

Procedure:
A solution of sodium azide (2.07 g, 0.0317 mol), 3-bromomethyl-3-hydroxymethyloxetane (5.0 g, 0.028 mol) and tetra-n-butylammonium bromide (0.0978 g, 0.3 mmol) in water (14 mL) was heated for 3 h at 104°-107° C. The solution was cooled and was extracted with ethyl ether (5×20 mL). The combined extracts were evaporated to give 1.92 g (49%) of 3-azidomethyl-3-hydroxymethyloxetane, essentially pure by glc analysis, as an oil. NMR: 1H NMR: 3.70 (s, 2H), 3.84 (d, J=4.9 Hz, 2H), 4.44 (s, 4H); 13C NMR: 44.283, 53.852, 64.073, 76.227.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=O.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F:24][C:25]1[C:30]([F:31])=C(O)[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:13])([F:12])[F:1])=[C:4]2[CH2:8][O:10][C:11]2[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([F:24])[C:30]=2[F:31])=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Product: O=C(O)CCc1ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(Br)cc2)c(F)c1F

Procedure:
The title compound was prepared by (a) reacting the product prepared in Step B of Example 1 and 4-bromophenylboronic acid according to the procedure described in Example 1, Step C, (b) then reacting the resulting product according to the procedure in Example 1, Step D, and (c) then reacting the resulting product with ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate according to the procedure described in Example 1, Steps E and F.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.Cl.C(OCC)(=O)C>CS(C)=O>[CH:2]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:1]
Reactant: Cc1cccc(CCC(=O)OC(C)(C)C)c1CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cccc(CCC(=O)OC(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
To a solution of 770 mg of tert-butyl 3-[2-(hydroxymethyl)-3-methylphenyl]propanoate in 16 ml of dimethylsulfoxide were added 4 ml of triethylamine and 1.22 g of a sulfur trioxide pyridine complex, followed by stirring at room temperature for 5 hours. To the reaction mixture were added diluted hydrochloric acid and ethyl acetate to carry out a layer separation operation. The organic layer was sequentially washed with water, saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 707 mg of tert-butyl 3-(2-formyl-3-methylphenyl)propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH3:20].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[CH3:28][O:27][C:25](=[O:26])[CH2:24][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[C:11]([CH3:20])[N:10]2[CH2:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cc2c(O)cccc2n1Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1c(Cl)cccc1Cl
Yield: 38.8 %

Procedure:
Using the procedure described in Example 1, Part E, 1-[(2,6-dichlorophenyl)methyl]-4-hydroxy-2-methyl-1H-indole (862 mg, 2.8 mmol) was treated with 112 mg (2.8 mmol) of 60% NaH/mineral oil and then 0.27 mL (2.8 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 411 mg (39% yield) of [[1-[(2,6-dichlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, mp, 168-169° C.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37](O)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37]([NH:21][CH:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: NC(CC1CCCCC1)c1ccccc1N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCCCC2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
To a solution of α-cyclohexylmethyl-2-piperidino-benzylamine (1.13 g, 3.96 mmol) in acetonitrile (11 ml) are added, successively, 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid (1 g, 3.96 mmol), of triphenylphosphine (1.25 g, 4.76 mmol), triethylamine (1.11 ml, 7.92 mmol) and carbon tetrachloride (0.38 ml, 3.96 mmol) and the mixture is stirred for 15 hours at ambient temperature. It is then concentrated by evaporation in vacuo and partitioned between ethyl acetate and water. The organic extract is dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=10/1).
Reaction SMILES: CN[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].C(N)CCC.C(NCCCC)CCC.C(NCC1N=CNC=1C)CCC.C(N(CC1N=CNC=1C)CCCC)CCC.[NH2:52][CH2:53][CH2:54][SH:55].[ClH:56]>>[ClH:56].[ClH:56].[NH2:52][CH2:53][CH2:54][S:55][CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9]
Reactant: NCCS
Reactant: CNCc1nc[nH]c1C
Agent: CCCCN(CCCC)Cc1nc[nH]c1C
Agent: CCCCNCc1nc[nH]c1C
Agent: Cl
Solvent: CCCCN
Solvent: CCCCNCCCC
Product: Cc1[nH]cnc1CSCCN

Procedure:
By the same procedure, using methylene in place of dimethylamine, 4-(N-methylaminomethyl)-5-methylimidazole is prepared. In the same way, using butylamine and dibutylamine, 4-(N-butylaminomethyl)-5-methylimidazole and 4-(N,N-dibutylaminomethyl)-5-methylimidazole are prepared. Refluxing these intermediates with cysteamine by the above procedure and treating with hydrochloric acid gives 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35][NH2:36])([CH3:29])([CH3:28])[CH3:27]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:36][CH2:35][CH2:34][CH2:33][NH:32][C:31](=[O:37])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[N:3][CH:4]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 27 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (300 mg, 0.48 mmol) obtained in Example 54 and t-butyl(3-aminopropyl)carbamate (400 μl) was stirred at 120° C. for 2 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (71 mg, 27%) as an oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][CH:3]=1.[SH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[S:6][C:5]([CH2:7][S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][CH:3]=1
Reactant: COC(=O)CCS
Reactant: BrCc1ncc(Br)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCSCc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
5-Bromo-2-(bromomethyl)-1,3-thiazole (1.34 g, 5.22 mmol) was dissolved in DMF (15 mL). Methyl 3-mercaptopropionate (0.689 g, 5.74 mmol) and DIEA (0.876 g, 6.78 mmol) were added, and the reaction was stirred at room temperature for 3 h. The reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (0-30% ethyl acetate in hexanes) afforded methyl 3-{[(5-bromo-1,3-thiazol-2-yl)methyl]sulfanyl}propanoate (1.45 g, 94%) as a pale yellow oil. MS BSI: [M+H]+ m/z 295.9/297.9.
Reaction SMILES: ClC(OCC)=O.[CH:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:21])=[O:20])([CH3:9])[CH3:8].C(N(CC)CC)C>C1COCC1>[CH:7]([C:10]1[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:20])=[O:21])([CH3:9])[CH3:8]
Reactant: CC(C)c1ccc(C(=O)O)cc1S(C)(=O)=O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CO)cc1S(C)(=O)=O
Reaction time: 1 h
Yield: 68.5 %

Procedure:
2.3 g of ethyl chloroformate dissolved in 5 ml of THF were added dropwise at -10° C. to a solution of 4.8 g of 4-isopropyl-3-methylsulfonylbenzoic acid and 2.1 g of triethylamine in 40 ml of THF. After stirring for 1 hour, the precipitate which was deposited was filtered off with suction, and the filtrate was added dropwise to a solution of 2.3 g of sodium borohydride in 25 ml of water. The reaction mixture was subsequently stirred for 5 h, acidified with hydrochloric acid and extracted with ether, and the organic phase was washed with 10 percent sodium hydroxide solution. After concentrating, 3.1 g of 4-isopropyl-3-methylsulfonylbenzyl alcohol were obtained.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>O1CCCC1>[CH3:4][C:3]1[CH2:11][C:10]2[C:1]([CH:2]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CCCCCC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=Cc2ccccc2C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
The ligand (1.0 g) obtained from the previous procedure was dissolved in anhydrous tetrahydofuran (40 ml) and a solution of n-butyllithium in hexane (1.6M, 4.4 ml) was and stirred for 3 hours. The solvents were removed under vacuum to obtain a off-white solid which was washed with dry hexane under nitrogen atmosphere. The solid was cooled to −78° C. and methylene chloride prechilled to −78° C. was added followed by a slurry of zirconium tetrachloride in methylene chloride which was also prechilled to −78° C. The reaction mixture was allowed to gradually come to room temperature and stirred overnight. The solution was filtered and the solid was washed with hexane. The hexane washings were added to the filtrate at which time a off-white solid precipitated. Upon filtration the filtrate was concentrated and cooled to −78° C. for several hours to obtain a yellow solid. This yellow solid (0.30 g) was isolated by filtration and was found to be a mixture (65:35) of rac- and meso-isomers by NMR spectroscopy. 1HNMR (CD2Cl2) (in ppm), 7.67(2d), 7.45(d), 7.08(t), 6.99(t), 6.76(s), 6.74(s), 6.64(s), 2.44(s), 2.20(s), 1.42(s), 1.29(s), 1.22(s). The solid was used as such in polymerizations.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:33])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C)C.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.O>[Cl-].[Na+].O>[CH:38]1([NH:41][C:2]2[C:3]3[C:10]([C:11]([C:13]4[C:14]([F:33])=[C:15]([NH:20][S:21]([C:24]5[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH3:32])=[CH:28][CH:29]=5)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=4[F:19])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:40][CH2:39]1
Reactant: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(Cl)c34)c2F)cc1
Reactant: NC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(NC5CC5)c34)c2F)cc1
Temperature: 80 °C
Yield: 101.7 %

Procedure:
To N-[3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide (P-1034, 50 mg, 0.10 mmol), 0.702 mL of isopropyl alcohol is added, followed by cyclopropylamine (79, 0.0357 mL, 70% aqueous solution, 0.509 mmol). The reaction is heated at 80° C. in an oil bath for 17 hours, then poured into water and brine and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (P-1040, 52 mg). MS (ESI) [M+H+]+=512.0.