Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: COC(=O)Cl
Reactant: CCCN1C(=O)Cc2cc(N3C[C@@H](CN)OC3=O)cc(F)c21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC)OC3=O)cc(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.038 ml, 0.480 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-7-fluoro-1-propyl-1,3-dihydro-indol-2-one (0.135 g, 0.320 mmol) and diisopropylethylamine (0.235 ml, 1.28 mmol) in dichloromethane (3 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as an off white solid. HPLC r.t. 4.40 min; 1H NMR (300 MHz, CDCl3) 7.30 (m, 1H), 7.21 (m, 1H), 5.10 (t, 1H), 4.77 (m, 1H), 4.02 (t, J=9 Hz, 1H), 3.77-3.82 (m, 3H), 3.68 (s, 3H), 3.57 (s, 2H), 3.49-3.63 (m, 2H), 1.69 (m, 2H), 0.95 (t, J=7.5 Hz, 3H); MS for C17H20F2N3O5 m/z 366.1 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][C@H:3]1[C:6]([O:8][CH3:9])=[O:7].[C:10]([N:14]=[C:15]=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[CH3:9][O:8][C:6]([C@@H:3]1[CH2:4][CH2:5][N:2]1[C:15](=[O:16])[NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7]
Reactant: CC(C)(C)N=C=O
Reactant: COC(=O)[C@@H]1CCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCN1C(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 80 %

Procedure:
(2S)-Methyl azetidine-2-carboxylate hydrochloride from Reference Example 1 (185.8 mg, 1.23 mmol, 1.0 eq) was dissolved in dry dichloromethane (10.0 mL) and treated with t-butyl isocyanate (210 μL, 1.84 mmol, 1.5 eq) at about 0° C. under an argon atmosphere. After adding triethylamine (190 μL, 1.36 mmol, 1.1 eq) dropwise, the reaction mixture was warmed to about room temperature and stirred overnight. The solvent was evaporated and the residue was subjected to flash chromatography (1:1 ether:dichloromethane) to give 211.6 mg (80% yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 1.33 (s, 9H); 2.34-2.49 (m, 2H); 3.66-3.76 (m, 1H); 3.80 (s, 3H); 3.90 (q, 1H, J=8.6); 4.61 (t, 1H, J=8.6); 5.07-5.16 (br, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=1[CH3:13]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]([Cl:3])=[O:18])[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: COc1cc(C=CC(=O)O)ccc1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(C=CC(=O)Cl)ccc1C

Procedure:
Toluene (750 ml) and thionyl chloride (11 ml) were subsequently added to 3-(3-methoxy-4-methylphenyl)acrylic acid (20 g, 0.104 mol) at room temperature. The suspension was refluxed for 2 h while vigorously stirring to give a clear slightly yellow solution. The reaction mixture was concentrated in vacuo, then toluene added and the mixture re-concentrated in vacuo to give 3-(3-methoxy-4-methylphenyl)acryloyl chloride for use in the next step.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:52])[C:28]2[C:29]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)=[C:30]3[C:38](=[CH:39][C:40]=2[CH:41]([CH3:43])[CH3:42])[O:37][C:33]2([CH2:36][CH2:35][CH2:34]2)[CH2:32][C:31]3=[O:44])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>CO>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C@H:27]([OH:52])[C:28]2[C:29]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)=[C:30]3[C:38](=[CH:39][C:40]=2[CH:41]([CH3:43])[CH3:42])[O:37][C:33]2([CH2:34][CH2:35][CH2:36]2)[CH2:32][C@@H:31]3[OH:44])=[CH:25][CH:26]=1)([CH3:19])([CH3:20])[CH3:18]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
Under argon, 2.1 mg (0.014 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 3 ml of abs. tetrahydrofuran, 102 μl (0.575 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 70 mg (0.144 mmol) of 6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 55A), dissolved in 3.25 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature for 18 h. 2 ml of methanol are added and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 26 mg (37% of theory, 86% ee) of Example 34 and 29 mg (42% of theory, 89% ee) of Example 35. Subsequent chromatographic separation of 15 mg of Example 34 on a chiral phase [column: Chiralpak AD-H, 250×20 mm; mobile phase: isopropanol/isohexane 5:95; flow rate: 15 ml/min; 24° C.; detection: 260 nm] gives 10.6 mg of Example 34 having an ee of >99%.
Reaction SMILES: C[O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:16][CH2:15][N:14]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].[OH-].[Na+]>>[C:19]1([CH:17]([N:14]2[CH2:15][CH2:16][C:11]3([CH2:10][C:9](=[O:29])[C:8]4[C:26](=[CH:27][CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:30])=[O:2])[CH:7]=4)[O:25]3)[CH2:12][CH2:13]2)[CH3:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(C)c3ccccc3)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: CC(c1ccccc1)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Yield: 87.4 %

Procedure:
(±)-(E)-3-{1′-(1-Phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (526 mg, 1.30 mmol) was treated with 1 M NaOH following the procedure described in Example 71 Step B, giving (±)-(E)-3-{1′-(1-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (445 mg, 88%). The resulting product was treated with NH2OTHP according to the procedure described in Example 71 Step C, giving (±)-(E)-3-{1′-(1-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Finally, removal of the THP protecting group following the procedure described in Example 71 Step C gave (±)-(E)-3-{1′-(1-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (197 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[CH2:33][C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:40][C:37]2[CH:36]=[N:35][C:34]([CH2:33][CH:29]3[O:30][CH2:31][CH2:32][O:28]3)=[CH:39][N:38]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnc(CC2OCCO2)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CC3OCCO3)cn2)cc1Cl
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 47.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 160 mg, 0.48 mmol) in methylene chloride (5 mL) and N,N-dimethylformamide (2 drops) was cooled to 5° C. and then treated with oxalyl chloride (90 μL, 1.03 mmol). After 5 min, the cooling bath was removed, and the stirring was continued for 15 min. The mixture was concentrated in vacuo to dryness, and the residue was further concentrated in vacuo to dryness from benzene (15 mL). The resulting acid chloride was dissolved in methylene chloride (10 mL), cooled to 5° C., and then treated with a solution of the 5-[1,3]dioxolan-2-ylmethylpyrazin-2yl-amine (0.49 mmol) and pyridine (100 μL, 1.23 mmol) in methylene chloride (5 mL). The mixture was stirred at 5° C. for 30 min then at 25° C. for 18 h. The mixture was diluted with methylene chloride (25 mL) and washed with a saturated aqueous sodium bicarbonate solution (20 mL), a 0.5M aqueous hydrochloric acid solution (20 mL), and a saturated aqueous sodium chloride solution (20 mL). Each aqueous layer was back-extracted with a small portion of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3]dioxolan-2-ylmethyl-pyrazin-2-yl)-propionamide (112 mg, 47%) as a colorless foam: (ES)+-HRMS m/e calcd for C23H28ClN3O5S (M+H)+ 494.1511, found 494.1517.
Reaction SMILES: C([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([CH3:16])[CH:6]=1)(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:11][C:9]1[CH:10]=[CH:5][CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1CC(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1CC(=O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
16.52 g [75 mmol] of 4-tert-butyl-2,6-dimethylphenylacetic acid and 100 ml of toluene are initially charged in a 250 ml autoclave. After cooling to 0° C., 40 ml of HF are added and the autoclave is closed. The reaction mixture is then stirred at 38-40° C. for 4 hours. Toluene and HF are then distilled off at 20° C./100 mbar. The residue is diluted with 65 ml of water and, with ice-cooling, made alkaline using 100 ml of 10% strength aqueous sodium hydroxide solution. The solution is extracted once with 65 ml of MTBE and once with 35 ml of MTBE, the aqueous phase is then, with ice-cooling, adjusted to pH 1 using 32% strength hydrochloric acid, then precipitate formed is dissolved in 130 ml of methylene chloride, the organic phase is dried and the solvent is removed under reduced pressure. This gives 11.91 g of a white solid which, according to GC(sil.), comprises 95.8% of 2,6-dimethylphenylacetic acid (92.6% of theory).
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[N:9]=[C:8]([SH:10])[NH:7][C:6]=2[CH:11]=1.Cl.[CH3:19][C:20]1[C:21]([CH2:26]Cl)=[N:22][CH:23]=[CH:24][CH:25]=1.[OH-].[Na+].[K+].[Br-]>C(O)C>[N:12]1([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([CH2:26][S:10][C:8]3[NH:7][C:6]4[CH:11]=[C:2]([F:1])[C:3]([N:12]5[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]5)=[CH:4][C:5]=4[N:9]=3)[C:20]=2[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cccnc1CCl
Reactant: Fc1cc2[nH]c(S)nc2cc1N1CCCCC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(N2CCCCC2)ccnc1CSc1nc2cc(N3CCCCC3)c(F)cc2[nH]1
Yield: 154.4 %

Procedure:
The title compound (0.95 g, 63%) was prepared by the general procedure using, 6-fluoro-5-(piperidin-1-yl)-2-mercapto-1H-benzimidazole (0.70 g, 2.8 mmol) (obtained in preparation 3), 4-(piperidin-1-yl)-3 )-methyl-2-chloromethylpyridine hydrochloride (0.91 g, 3.5 mmol), sodium hydroxide (0.30 g, , 7.7 mmol) and ethanol (15 mL). mp 161-162° C.; IR (KBr) 3430, 1581, 1429 cm-1 ; 1H NMR (CDCl3) δ 1.60 (m, 4H, 2×CH2), 1.74 (m, 8H, 2×(CH2)2), 2.30 (s, 3)H, CH3), 3.00 (m, 8H, 2×N(CH2)2), 4.32 (s, 2H, SCH2), 6.82 (d, J=5.4 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.24 (d, J=12.1 Hz, 1H), 8.28 (d, J=5.5 Hz, 1H); Mass (m/z) 439 (M+).
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[O:17][CH2:18][CH:19]([F:21])[F:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH:41][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=5[O:17][CH2:18][CH:19]([F:21])[F:20])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: FC(F)COc1ccc(Cl)cc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(Cl)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
7-{8-[5-Chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-[5-chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]-triazolo[1,5-a]pyridine (0.215 g, 625 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.245 g, 937 mmol) in a manner analogous to Example 311a and 311b to give product (0.117 g, 33%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.52 (s, 1H), 8.78 (d, 1H), 7.80 (s, 1H), 7.68 (d, 1H), 7.45 (m, 3H), 7.30 (m, 1H), 7.05 (m, 2H), 6.25 (br m, 1H), 4.35 (m, 2H), 3.45 (m, 4H), 2.82 (m, 4H), 1.41 (s, 9H). MS=571 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[N:41]=[C:40]([CH3:52])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[N:41]=[C:40]([CH3:52])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(COC4CCCCO4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (320 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (550 mg, 82%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:26]([C@H:28]1[CH2:30][C@@H:29]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[N:32]=1)=[O:27])[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:13][N:14]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)[C:26]([C@H:28]1[CH2:30][C@@H:29]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[N:32]=1)=[O:27]
Reactant: CCCC#Cc1ccc(N(C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)C(=O)[C@H]2C[C@@H]2c2cccc(F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC#Cc1ccc(N(C[C@@H](N)[C@@H](C)CC)C(=O)[C@H]2C[C@@H]2c2cccc(F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
((1S,2S)-1-{[[(1S,2S)-2-(6-Fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-(4-pent-1-ynyl-phenyl)-amino]-methyl}-2-methyl-butyl)-carbamic acid t-butyl ester (0.0657 g, 0.126 mmol), trifluoroacetic acid (1 mL) and dichloromethane (2 mL) were mixed at 0° C., then stirred at room temperature for 1 hr. The excessive solvent was removed in vacuum. The residue was purified by preparatory HPLC to give a white solid (0.0277 g, 34%): 1H NMR (400 MHz, MeOD) δ ppm 7.66 (m, 1H), 7.24 (m, 4H), 7.07 (td, J=7.1, 2.3 Hz, 1H), 6.66 (m, 1H), 4.16 (m, 1H), 3.58 (m, 1H), 3.21 (dt, J=3.3, 1.6 Hz, 1H), 2.47 (br. s., 1H), 2.29 (td, J=7.0, 3.2 Hz, 2H), 1.81 (dd, J=5.3, 3.5 Hz, 1H), 1.62 (m, 1H), 1.53 (m, 3H), 1.29 (m, 2H), 1.10 (m, 1H), 0.95 (td, J=7.3, 2.5 Hz, 3H), 0.86 (dd, J=7.1, 4.8 Hz, 3H), 0.73 (m, 3H); LCMS (ESI) m/e 422.3 [(M+H)+, calcd for C26H33FN3O 422.6].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26].O>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([CH:13]=[C:25]([C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:26][O:17]2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)C1=Cc2ccc(OCc3ccccc3)cc2OC1
Temperature: 155 °C
Yield: 76.8 %

Procedure:
To a stirred solution of 4-benzyloxy-2-hydroxy benzaldehyde (11.41 g, 50 mmol) in NMP (30 ml) was added K2CO3 (13.0 g, 100 mmol) and heated to 155° C. under N2 atmosphere. t-Butyl acrylate (36.5 ml, 250 mmol) was divided into 4 portions (10, 10, 10 & 6.5 ml). First 10 ml was added to the reaction mixture and heated at 155° C. The rest were added after 2 hr intervals and the reaction mixture was heated for total of 8 hrs. The reaction mixture was cooled to room temperature and water (150 ml) was added. The product was extracted with 150 ml of ether. The ether layer was washed with water twice and dried. Ether layer was diluted with 50% hexanes and passed through a pad of silica (3 inch length and 4 inch diameter). The silica was washed with 50% ether/hexane mixture and the solvent was evaporated to give the product as pale yellow solid (13 g, 77%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=2[F:22])[N:4]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:39](B(OCCCC)OCCCC)=[CH2:40].C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:22][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[N:4]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:3]=[C:2]([CH:39]=[CH2:40])[C:10]=12
Reactant: C=CB(OCCCC)OCCCC
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2nccc(Oc3ccc(NC(C)=O)cc3F)c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
1.00 g (1.93 mmol) of N-[4-({3-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)-3-fluorophenyl]acetamide and 800 mg (5.79 mmol) of potassium carbonate are suspended in DMF (6 ml). The solution is degassed and vented with argon. 79 mg (0.110 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride/methylene dichloride complex and 0.85 ml (3.86 mmol) of di-n-butyl vinylboronate are then added, and the mixture is stirred at 90° C. for 3 hours. After addition of sodium bicarbonate solution, the mixture is extracted three times with dichloromethane. The combined organic phases are concentrated, and the crude product is purified by chromatography on silica gel (mobile phase: dichloromethane/acetone 20:1 to 10:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc2nccnc2c1
Product: CCOC(=O)C(=CNc1ccc2nccnc2c1)C(=O)OCC
Temperature: 110 °C
Yield: 89.9 %

Procedure:
A mixture of 6-aminoquinoxaline(19.2 g) and diethyl ethoxymethylenemalonate(34.8 g) was heated for an hour at 110° C. After filtration, the crystals thus obtained were crystallized from ethanol to give diethyl N-(6-quinoxalyl)aminomethylenemalonate (37.5 g) as pale yellow needles, m.p. 112°-114° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH3:29]>>[CH2:28]([N:27]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1)[CH2:26][CH2:25][O:24][CH3:23])[CH3:29]
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Reactant: CCNCCOC
Product: CCN(CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and N-(2-methoxyethyl)ethylamine were converted to yield Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-amine as colorless oil, MS: 402 (MH+).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH:25][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: C[C@H](Nc1cncc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Agent: Cl
Product: C[C@H](Nc1cncc(-n2cnc3ccc(NC(=O)c4ccncc4)cc32)n1)c1ccccc1
Yield: 23 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-amine (33 mg, 0.10 mmol) and isonicotinoyl chloride hydrochloride (20 mg, 0.11 mmol) furnished the product (10 mg, 23%) after chromatography.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:7]=[C:6]([C:19]2[S:20][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23](=[O:25])[N:24]=2)[N:5]=1)=[O:3].C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[C:6]([C:19]2[S:20][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23](=[O:25])[N:24]=2)[N:5]=1)=[O:3]
Reactant: CS(=O)c1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CS(=O)c1cc(CCC(=O)O)cc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
tert-Butyl 3-[2-(methylsulfinyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.12 g, 0.28 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 0.5 hr. Diisopropyl ether was combined with the reaction mixture to give precipitates, which were recrystallized from ethanol to give the titled compound (0.095 g, 91%) as white crystals.