Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[CH3:20][O:19][C:17](=[O:18])[NH:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCCOc1ccc2nc(N)sc2c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCOc1ccc2nc(NC(=O)OC)sc2c1
Temperature: 25 °C

Procedure:
To a stirring solution of 24.45 g. of 2-amino-6-n-propyloxybenzothiazole-hydrochloride in 100 ml of pyridine maintained at 0° C by an ice bath, is slowly added 9.45 g. of methyl chloroformate. After the addition is completed the mixture is allowed to warm up to room temperature. It is then poured on 300 g. of ice water. A solid is formed which is isolated by filtration and crystallized from ethanol to yield 20 g., m.p. 178°-180° C.
Reaction SMILES: C[O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH3:15].Cl>C1COCC1.CO.[OH-].[Na+]>[CH3:15][C:11]1[C:10]2[C:14](=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:16])=[O:2])[CH:7]=[CH:8][CH:9]=2)[NH:13][CH:12]=1
Reactant: COC(=O)/C=C/c1cccc2c(C)c[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(/C=C/C(=O)O)cccc12
Temperature: 25 °C

Procedure:
(I-7). To a solution of (E)-3-(3-methyl-1H-indol-7-yl)-acrylic acid methyl ester (2, 180 mg, 0.84 mmol) in THF (5 ml) and methanol (4 ml), NaOH aq. (4 ml) was added at rt. The reaction mixture was stirred at rt over night and then the pH was adjusted to acidic by adding aqueous 2N HCl. The reaction mixture was extracted with EtOAc (2×30 ml). The combined organic phases were washed with water, brine and dried over sodium sulfate. After removal of solvent, 170 mg of I-7 was obtained. 1H-NMR (500 MHz, DMSO-d6).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][OH:11].C(Cl)Cl.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][O:11][S:23]([CH3:22])(=[O:25])=[O:24])(=[O:25])=[O:24]
Reactant: OCCc1ccoc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccoc1CCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of 2,3-di(2-hydroxyethyl)furan (23 mmol) in methylene chloride (114 mmol) is cooled to 0° C. and treated with triethylamine (69 mmol) followed by dropwise addition of methanesulfonyl chloride (50.4 mmol) over 10 minutes. After 1 hour the reaction mixture is transferred to a reparatory funnel and extracted with cold water, 10% citric acid, saturated aqueous NaHCO3, and brine. The organic layer is dried and concentrated twice with the aid of dioxane to produce 2,3-di(2-methanesulfonyloxy-ethyl)furan, which is used crude without further purification.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2Cl)ccn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccccc2Cl)ccn1)NO
Reaction time: 22 h
Yield: 44 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (19 mg, 0.043 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a pale blue oil (8 mg, 44%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:5][CH2:4][CH:3]=[CH2:2])=[CH:9][CH:8]=1
Reactant: Oc1ccc(F)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1ccc(F)cc1
Yield: 36 %

Procedure:
A solution of 4-bromo-1-butene (4.0 g), 4-fluorophenol (3.0 g), potassium carbonate (3.8 g) and acetone (75 ml) was heated at reflux over 16 hours. The mixture was then concentrated in vacuo, dluted with ether, washed with water followed by 1N sodium hydroxide, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on a silica gel column eluting with 25% ethyl acetate-hexane afforded 1.6 g of a colorless oil.
Reaction SMILES: [ClH:1].CCO.[Cl:5][C:6]1[CH:7]=[C:8](/[CH:23]=[C:24](\[F:35])/[C:25]([NH:27][O:28]C2CCCCO2)=[O:26])[CH:9]=[N:10][C:11]=1[NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14]1>CCO>[ClH:5].[ClH:1].[Cl:5][C:6]1[CH:7]=[C:8](/[CH:23]=[C:24](\[F:35])/[C:25]([NH:27][OH:28])=[O:26])[CH:9]=[N:10][C:11]=1[NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:14]1
Reactant: O=C(NOC1CCCCO1)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: O=C(NO)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A solution of 2N HCl-EtOH solution (3.4 ml) was added to a mixture of (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (620 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours. IPE (20 ml) was added to a reaction mixture and the resultant mixture was stirred at ambient temperature for 20 minutes. The precipitate was collected by filtration to give (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride (500 mg).
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([C:9]([O:11]CC)=[O:10])=[CH:7][N:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>CO.O>[CH:1]([C:4]1[S:5][C:6]([C:9]([OH:11])=[O:10])=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(C(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ncc(C(=O)O)s1

Procedure:
A solution of ethyl 2-isopropylthiazole-5-carboxylate (example 55, step a) (0.33 g) in methanol (6 mL) was treated with a solution of lithium hydroxide (0.079 g) in water (3 mL) and the resultant mixture stirred for 2 hours at 20° C. The methanol was evaporated off under reduced pressure and the residue partitioned between ether and brine. The aqueous layer was acidified by dropwise addition of dilute hydrochloric acid and the mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.185 g.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:30])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:17]=[C:16]4[CH:28]=O)[CH:10]=[N:9][CH:8]=2)[CH2:3][CH2:2]1.[N:31]1[CH:36]=[C:35]([NH2:37])[C:34]([NH2:38])=[C:33]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:32]=1.[S]>CN(C=O)C>[CH:1]1([CH2:4][NH:5][C:6](=[O:30])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:17]=[C:16]4[C:28]3[NH:37][C:35]4[CH:36]=[N:31][CH:32]=[C:33]([C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)[C:34]=4[N:38]=3)[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: Nc1cncc(-c2cccnc2)c1N
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(-c3cncc(C(=O)NCC4CC4)c3)cc12
Agent: [S]
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1cncc(-c2ccc3c(c2)c(-c2nc4c(-c5cccnc5)cncc4[nH]2)nn3C2CCCCO2)c1
Temperature: 4 °C
Yield: 23 %

Procedure:
A solution of N-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXI) (0.404 g, 1.0 mmol), 3,3′-bipyridine-4,5-diamine (XV) (186 mg, 1.0 mmol) and sulfur (35 mg, 1.1 mmol) in dry DMF (10 mL) was heated at 140° C. overnight. The reaction was cooled and evaporated under vacuum. The residue was suspended in water, sonicated and filtered. The solid was washed with cold water and dried under vacuum. The crude product was dissolved in DCM and cooled to 4° C. overnight to get N-(cyclopropylmethyl)-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXII) as a brown solid (130 mg, 0.23 mmol, 23% yield). 1H NMR (DMSO-d6) δ ppm 0.19-0.37 (m, 2H), 0.36-0.58 (m, 2H), 0.97-1.115 (m, 1H), 1.67 (br, 2H), 2.14 (d, J=9.98 Hz, 2H), 2.40-2.46 (m, 1H), 3.20-3.33 (m, 3H), 3.75-4.14 (m, 2H), 6.13 (d, J=8.29 Hz, 1H), 7.60 (dd, J=7.82, 4.80 Hz, 1H), 7.92-8.12 (m, 3H), 8.20 (d, J=8.67 Hz, 1H), 8.55-8.67 (m, 2H), 8.94 (br s, 3H), 9.06 (d, J=1.88 Hz, 1H), 9.19 (d, J=1.87 Hz, 1H); ESIMS found C33H30N8O2 m/z 571 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]=[C:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH:11]=[CH:10]1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:11]2[CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:9](=[O:8])[CH2:10]2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C1C=CCCc2ccccc21
Solvent: CCO
Product: CN1CCN(C2CCc3ccccc3C(=O)C2)CC1
Temperature: 20 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A solution of 8 g of N-methylpiperazine in 80 ml of ethanol was added over 5 minutes to a solution of 6.32 g of 5-oxo-8,9-dihydro [5H] benzocycloheptene in 40 ml of ethanol and the mixture was stirred for 4 hours at 20° C and was then evaporated to dryness. The residue was taken up in 0.5 N hydrochloric acid and the solution was washed with ethyl acetate and made alkaline with concentrated ammonium hydroxide. The mixture was extracted with methylene chloride and the extracts were dried and evaporated to dryness to obtain 8.8 g of 7-(4-methylpiperazin-1-yl)-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: [C:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:6]2=[N:5][CH:4]=1)=[CH:12][C:11]([C:27]([F:30])([F:29])[F:28])=[CH:10][CH:9]=3)#[CH:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:50]1([C:56](Cl)=[O:57])[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C(N(CC)CC)C.[Cu](I)I>[N:50]1([C:56](=[O:57])[C:2]#[C:1][C:3]2[N:7]3[C:8]4[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]5[CH2:26][CH2:25][CH2:24][CH2:23][O:22]5)[C:6]3=[N:5][CH:4]=2)=[CH:12][C:11]([C:27]([F:28])([F:29])[F:30])=[CH:10][CH:9]=4)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: C#Cc1cnc2c(NCCCOC3CCCCO3)nc3cc(C(F)(F)F)ccc3n12
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(C#Cc1cnc2c(NCCCOC3CCCCO3)nc3cc(C(F)(F)F)ccc3n12)N1CCOCC1
Temperature: 80 °C
Reaction time: 40 h
Yield: 29.1 %

Procedure:
To a solution of 1-ethynyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-7-(trifluoromethyl)imidazo [1,2-a]quinoxalin-4-amine (46 mg, 0.11 mmol), copper iodide (1 mg, 0.0055 mmol), triphenylphosphine (3 mg, 0.11 mmol) and Pd(PPh3)Cl2 (1.5 mg, 0.0022 mmol) in anhydrous triethylamine (0.5 mL) was added morpholine-4-carbonyl chloride (17 μL, 0.16 mmol) under an argon atmosphere. The mixture was stirred at 80° C. for 40 h, poured onto water and extracted four times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 20/1) to afford the title compound (17 mg, 30%) as a yellow gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:23])[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([O:23][CH3:24])[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CC(C)O1
Product: COC1(c2cccc(OCc3ccccc3)c2)CC(C)OC(C)C1

Procedure:
Using the procedure described in Example 3, the more polar isomer of 4-(3-benzyloxyphenyl)-4-hydroxy-2,6-dimethyltetrahydropyran (described in the portion of Example 52 which is concerned with the preparation of starting materials) was reacted with methyl iodide to give 4-(3-benzyloxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran, (77%, more polar isomer), as an oil.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.Cl.Cl.[NH2:33][CH2:34][CH2:35][NH:36][C:37]([NH2:39])=[NH:38].CC(N(C)C)=O.C(N(CC)C(C)C)(C)C>>[OH:25][C:24]1[C:4]2[O:3][C:2]([NH:33][CH2:34][CH2:35][NH:36][C:37]([NH2:39])=[NH:38])=[C:6]([C:7](=[O:20])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)[C:5]=2[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: N=C(N)NCCN
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)c2c(NCCNC(=N)N)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 30 h
Yield: 28.5 %

Procedure:
To a mixture of 0.02 g (0.046 mmol) of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran and 0.02 g (0.11 mmol) of N-(2-aminoethyl)guanidine dihydrochloride (prepared by Fontand & Pignatti, J. Label. Compd. Radiopharm., 2002, 45, 899-909) in 0.5 ml of anhydrous dimethylacetamide 0.032 ml (0.184 mmol) of N,N-diisopropylethylamine was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 30 h at room temperature, then evaporated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, acetonitrile/water 9:1) to give the title compound as a yellowish solid (0.006 g, 28%); 1H NMR (CD3OD) δ 3.55 (tr, 2H, CH2, J=6 Hz); 3.7-3.86 (m, 14H, OMe×4, CH2); 4.82 (s, H2O); 6.32 (d, 1H, CH aromatic, J=8.47 Hz); 6.69 (d, 1H, CH aromatic, J=8.47 Hz); 6.94 (s, 2H, CH aromatic). MS (m/z) 458.9; 459.9, 460.9.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH:19]([F:21])[F:20])[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[C].[Pd]>[F:21][CH:19]([F:20])[O:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][C:9]=1[OH:8]
Reactant: FC(F)Oc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1cc2cc[nH]c2cc1OC(F)F
Reaction time: 1.25 h

Procedure:
5-(Benzyloxy)-6-(difluoromethoxy)-1H-indole described in Production Example 19-4 (245 mg, 0.847 mmol) was dissolved in ethanol (8.0 mL), then 10% palladium-carbon (water content, 50%) (90 mg) was added at room temperature, and the mixture was stirred under hydrogen atmosphere for 75 minutes. The reaction mixture was diluted with ethyl acetate and the catalyst was filtered off with celite. The filtrate was concentrated under vacuum and then filtered with silica gel (ethyl acetate). The target fraction was concentrated under vacuum to quantitatively obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>>[O:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:13]([NH:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=4)[CH:3]=3)[N:8]=2)[CH2:14]1
Reactant: Cc1cccc(N)n1
Reactant: Brc1ccc2nc(NC3COc4ccccc43)ccc2c1
Product: Cc1cccc(Nc2ccc3nc(NC4COc5ccccc54)ccc3c2)n1

Procedure:
The title compound, light yellow foam, MS: m/e=369.2 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(2,3-dihydro-benzofuran-3-yl)-amine (see example 96, step A) and commercially available 2-amino-6-methyl-pyridine.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:15])[CH:6]=1)C.[ClH:17]>>[ClH:17].[CH3:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:8]=1)[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)c1cc(C)nc(CC(C)C)c1
Agent: Cl
Product: Cc1cc(C(=O)O)cc(CC(C)C)n1

Procedure:
A solution of 2-methyl-6-(2-methyl-propyl)-isonicotinic acid ethyl ester (9.78 g, 45.1 mmol) in 6 N aq. HCl (20 mL) is stirred at 95° C. for 20 h before the solvent is evaporated. The residue is dried under HV to give 2-methyl-6-(2-methyl-propyl)-isonicotinic acid hydrochloride (9.56 g) as a colourless solid, LC-MS: tR=0.52 min.
Reaction SMILES: [CH2:1]([CH:3]1[CH:8]([CH3:9])[C:7](=[O:10])[C:6]2[CH:11]=[C:12]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])[CH:13]=[CH:14][C:5]=2[O:4]1)[CH3:2].C(=O)(O)[O-].[Na+].O>C(O)C>[CH2:1]([CH:3]1[CH:8]([CH3:9])[C:7](=[O:10])[C:6]2[CH:11]=[C:12]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])[CH:13]=[CH:14][C:5]=2[O:4]1)[CH3:2]
Reactant: CCC1Oc2ccc(C(C)C(=O)OC)cc2C(=O)C1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC1Oc2ccc(C(C)C(=O)O)cc2C(=O)C1C

Procedure:
Methyl 2-[2,3-dihydro-2-ethyl-3-methyl-4-oxo-4H-1-benzopyran-6-yl]propionate (6 g) was dissolved in ethanol (200 ml) and heated to reflux with dilute aqueous sodium bicarbonate solution (50 ml) for eight hours. The reaction mixture was poured into water, acidified and extracted with ether. The combined etheral extracts were washed with water and dried (MgSO4) and concentrated in vacuo affording a mixture of the desired product and starting material which were separated by chromatography on silica gel using dichloromethane/ether mixtures as eluant. The title compound was recrystallised from petroleum ether (bp 40°-60° C.) as a white solid: 1.4 g, mp 114°-115° C.
Reaction SMILES: [C:1]([C:5]1[CH:46]=[CH:45][C:8]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:48][CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:48][CH2:49][CH:50]5[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]5)=[CH:40][CH:39]=4)=[CH:36][N:37]=3)=[CH:28][CH:27]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[O:10])=[CH:45][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCC1CCCCC1
Reactant: CC(C)(C)OC(=O)CCNC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Product: CC(C)(C)OC(=O)CCNC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(OCCC4CCCCC4)cc3)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1

Procedure:
Prepared using General Procedure 12 from tert-butyl (S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate and (2-bromoethyl)cyclohexane. LCMS-ESI (m/z) calculated for C45H56N4O5: 732.9. found 733.5 [M+H]+, tR=5.59 min. (Method 16).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:3]1.C(N(CC)CC)C.[C:30]([CH2:34][CH2:35][C:36](Cl)=[O:37])([O:32]C)=[O:31].O.[OH-].[Li+].Cl>C(Cl)Cl.O>[OH:22][C@@H:20]([C:9]1[N:8]([C@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:36](=[O:37])[CH2:35][CH2:34][C:30]([OH:32])=[O:31])[CH2:3]2)[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=1)[CH3:21]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCNC1
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCC(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R)-1-{1-[(3S)-piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (30.0 mg, 0.0885 mmol) (Example 50, step 4) and triethylamine (37.0 μL, 0.266 mmol) in methylene chloride (0. 5 mL) was added 3-(carbomethoxy)propionyl chloride (12.0 μL, 0.0974 mmol). The resulting mixture was stirred at room temperature for 2 h. Water and dichloromethane were added and the layers separated. The organic was concentrated. The crude residue was taken up in methanol (0.5 mL), tetrahydrofuran (50 μL), and water (40 μL). Lithium hydroxide, monohydrate (18 mg, 0.44 mmol) was added and the mixture stirred at room temperature for 3 h. The mixture was made slightly acidic by adding 1N HCl then concentrated. The mixture was dissolved in dichloromethane, stirred, filtered and concentrated to give 37 mg of clean, crude acid. LCMS calculated for C19H23N4O4S (M+H)+: m/z=403.1. Found: 403.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:14]=2[CH:33]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:43])[N:15]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:14]=2[CH:33]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccc(C)cc3)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCCCCOc1ccc2nc(S(=O)Cc3ccccc3)n(-c3ccc(C)cc3)c2c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
500 mg of 6-[[2-benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 9 ml of dichloromethane, mixed with 303 mg of m-chloroperbenzoic acid (about 60%), and the mixture was stirred for 2 hours at 20° C. It was mixed with sodium disulfite solution, extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 232 mg of 6-[[1-(4-methylphenyl)-2-(phenylmethanesulfinyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was obtained.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2[S:14][C:8]3[C:7]([OH:25])=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)=[CH:16][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(C(C)(C)C)cc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(-c2nc3cnc(C(=O)NCC(=O)O)c(O)c3s2)cc1
Yield: 58.4 %

Procedure:
2-(4-tert-Butyl-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (100 mg, 0.28 mmol) and glycine (442 mg, 5.89 mmol) were suspended in 11.2 mL of 0.5 N sodium methoxide in methanol. The reaction was heated at reflux temperature overnight, cooled, and concentrated. The residue was dissolved in water (30 mL), and the solution was acidified to pH 1˜2 with 2 N HCl, extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated to produce 63 mg of a yellow solid. MS: (+) m/z 386.0 (M+1).