Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:45])[NH:31][C@@H:32]4[CH2:35][C@H:34]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:44])[CH3:43])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:49])[CH3:48])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH3:43][C:33]1([CH3:44])[C@@H:34]([C:36]([N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:37])[CH2:35][C@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:46])([CH2:12][CH2:13]2)[C@@:10]2([CH3:47])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:48])([CH3:49])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-2,2-dimethyl-3-(pyrrolidine-1-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 43, 0.350 g, 0.517 mmol) in MeOH:THF (2:1) (30 ml) 2N NaOH (10 ml) was added at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried over Na2SO4 then the solvent was evaporated and the resulting crude was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum to afford the title compound. Wt: 0.220 g: Yield: 67%; 1H NMR (300 MHz, CDCl3): δ 6.27 (d, 1H, J=8.1 Hz), 4.72 (s, 1H), 4.57 (s, 1H), 4.17-4.07 (m, 1H), 3.56-3.11 (m, 4H), 3.19-3.09 (m, 2H), 2.82-2.76 (m, 1H), 2.57-2.43 (m, 1H), 2.39-2.18 (m, 2H), 2.01-1.72 (m, 7H), 1.67 (s, 3H), 1.61-1.11 (m, 22H), 0.96, 0.93, 0.87, 0.81, 0.74 (s, 18H); Mass: [M+1]+ 635 (5%), [M+Na]+ 657 (100%); IR (KBr, cm−1): 3390, 3071, 2947, 2869, 1617, 1455, 1369, 1341, 1250, 1194, 1168, 1108, 1034, 921, 880; M.R: 176.3° C.-180.9° C.; HPLC: 98.9%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][C@@H:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Br:17][CH2:18][CH2:19][CH2:20]Br>O1CCCC1>[Br:17][CH2:18][CH2:19][CH2:20][C@@:11]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][C@H:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:9]=[CH:10]1
Reactant: BrCCCBr
Reactant: COC(=O)[C@H]1C=C[C@@H](n2c(C)ccc2C)C1
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(CCCBr)C=C[C@@H](n2c(C)ccc2C)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of Example 1B (16.5 g, 74.4 mmol) in tetrahydrofuran (200 ml) was added dropwise lithium hexamethyl bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 119 mL) at −50° C. The reaction mixture was stirred for 1 hour at the same temperature. 1,3-Dibromopropane (150 g, 744 mmol) was added dropwise over 1 hour. The reaction mixture was allowed to warm to −20° C. and stirred at the same temperature for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was quenched with an aqueous ammonium chloride solution (6%, 600 mL), and extracted with ethyl acetate. The organic fraction was washed with aqueous ammonium chloride (6%), brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:1) to give Example 1C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:36]([O:35][C:33](=[O:34])[CH2:32][O:23][C:19]1[C:18]([CH3:24])=[CH:17][C:16]([C:14]2[O:13][C:11]3[N:12]=[C:7]([CH2:6][C:5]4[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[C:10]=3[N:15]=2)=[CH:21][C:20]=1[CH3:22])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 60 °C

Procedure:
A mixture of 1.5 g of 4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol (example 17), 690 mg of tert-butyl bromoacetate and 1.96 g of potassium carbonate in 50 ml of dimethylformamide was heated to 60° C. for 1 h. After cooling to room temperature, the solids were removed by filtration. The solvent was distilled off in vacuo and the residue was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][C@@H:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34][N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1
Reactant: Cc1cnc(CN[C@H]2CCCc3cccnc32)c(C)c1
Reactant: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(C(=O)OC)c1

Procedure:
Using General Procedure A: Reaction of (S)-(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 4-bromomethyl-isophthalic acid dimethyl ester (Egbertson, M. S. et al. Bioorg. Med. Chem. Lett. 1996, 6, 2519-2524), DIPEA and KI in CH3CN gave 4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-isophthalic acid dimethyl ester as a tan oily foam. 1H NMR (CDCl3) δ 1.64 (m, 1H), 2.01 (m, 2H), 2.14 (s+m, 4H), 2.27 (s, 3H), 2.68 (m, 1H), 2.79 (m, 1H), 3.89 (s, 6H), 3.92 (s, 2H), 4.09 (t, 1H, J=6.0 Hz), 4.26 (m, 2H), 6.97 (s, 1H), 7.03 (m, 1H), 7.30 (d, 1H, J=9.0 Hz), 7.89 (dd, 2H, J=7.5, 4.5 Hz), 8.02 (s, 1H), 8.25 (s, 1H), 8.50 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.1, 18.7, 22.2, 26.8, 29.7, 52.5, 54.7, 57.1, 63.3, 121.9, 128.0, 130.7, 131.4, 131.9, 133.3, 134.5, 136.7, 138.8, 146.3, 148.5, 166.8, 168.1. HPLC: 96%. ES-MS m/z 474 [M+H]+, 496 [M+Na]+. Anal. Calcd. for C28H31N3O4.1.1H2O: C, 68.30; H, 6.59; N, 8.53. Found: C, 68.23; H, 6.41; N, 8.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:11]1[N:12]=[C:13]([NH:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[S:14][CH:15]=1
Reactant: COc1cc(Cl)c(-c2csc(N)n2)c(Cl)c1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2csc(NC(=O)c3ccncc3)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a solution of 4-(2,6-dichloro-4-methoxyphenyl)thiazol-2-ylamine (10-5, 0.10 g, 0.36 mmol) in CH2Cl2 (10 mL) was added DMAP (88 mg, 0.72 mmol) followed by isonicotinoyl chloride hydrochloride (83 mg, 0.47 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was collected and recrystallized in toluene to give N-(4-(2,6-dichloro-4-methoxyphenyl)thiazol-2-yl)isonicotinamide (50 mg, 0.13 mmol) as white solids in 37% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J=5.8 Hz, 2 H), 7.99 (d, J=6.0 Hz, 2 H), 7.31 (d, J=1.7 Hz, 1 H), 7.26 (s, 1 H), 7.22 (d, J=1.7 Hz, 1 H), 3.75 (s, 3 H). ESI-MS: m/z 381.4 (M+H)+.
Reaction SMILES: [C:1]([N:20]1[C:24]([CH2:25]O)=[C:23]([CH3:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:42]([CH2:25][C:24]1[N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[N:22][C:23]=1[CH3:27])=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CO
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CN=[N+]=[N-]
Temperature: 60 °C

Procedure:
To a solution of 1-trityl-4-methyl-5-imidazolemethanol (3.7 g, 10 mmol) and DPPA (3.0 ml, 13 mmol) in THF (100 ml) was added DBU (2.0 ml, 13 mmol). The resulting solution was heated to 60° C. for 2 h. The solvents were removed in vacuo and the residue purified by flash chromatography (2:1 hexane/ethyl acetate) to give of the title compound. 1H NMR (CDCl3) d 1.42 (s, 3 H), 4.22 (s, 2 H), 7.10-7.35 (m, 16 H).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH:15]([C:18]1[S:19][CH:20]=[C:21]([C:23]([N:25]2[CH2:30][C:29]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[O:28][CH2:27][CH2:26]2)=[O:24])[N:22]=1)([CH3:17])[CH3:16].Br[CH2:37][C:38]1[CH:39]=[C:40]([CH2:45][CH2:46][OH:47])[CH:41]=[C:42]([Cl:44])[CH:43]=1>C(#N)C.ClCCl>[Cl:44][C:42]1[CH:43]=[C:38]([CH:39]=[C:40]([CH2:45][CH2:46][OH:47])[CH:41]=1)[CH2:37][N:33]1[CH2:32][CH2:31][C:29]2([O:28][CH2:27][CH2:26][N:25]([C:23]([C:21]3[N:22]=[C:18]([CH:15]([CH3:17])[CH3:16])[S:19][CH:20]=3)=[O:24])[CH2:30]2)[CH2:35][CH2:34]1
Reactant: OCCc1cc(Cl)cc(CBr)c1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(Cl)cc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.18 mL) was added to a suspension of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.217 g) and 2-(3-(bromomethyl)-5-chlorophenyl)ethanol (example 52, step b) (0.160 g) in acetonitrile (5 mL) and the resulting solution was stirred at room temperature overnight. The solution was then purified by flash chromatography on silica eluted with 1:5:94 triethylamine:methanol:dichloromethane to afford a gum. The gum was dissolved in dichloromethane and the solution was washed three times with water, dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the subtitled compound as a pale yellow foam. Yield 0.254 g.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].O(C(C)C)C(C)C>>[CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(N)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: C[C@@H](N)c1ccccc1

Procedure:
A mixture of 1 part of (+)-α-methylbenzylamine salt with R-(+)-1-(α-methylbenzyl)-5-imidazolecarboxylic acid and 6 parts of sodium hydroxide solution 1N is shaken in a closed tube till all solid enters solution (pH = ± 11). The resulting solution is shaken five times for 1 minute, each time after the addition of 1.4 parts of 2,2'-oxybispropane. The organic phases are combined (the alkaline aqueous phase is set aside) and evaporated, yielding R-(+)-α-methylbenzylamine.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2]>[C].[Pd].CO>[CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCOc1ccc(N)cc1
Yield: 98.4 %

Procedure:
N,N-diethyl-2-(4-nitrophenoxy)ethylamine (28.19 g) was dissolved into methanol (300 ml) and subjected to hydration reaction at ambient pressure by adding 10% palladium carbon catalyst (1.5 g). After completion of hydration reaction, catalyst was removed by filtration. Filtrate was concentrated under vacuum to obtain N,N-diethyl-2-(4-aminophenoxy)ethylamine (24.25 g) as color-less oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[CH2:25])[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:25])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: C=C(C(=O)OCc1ccccc1)c1ccc(COCCOC)c(F)c1
Agent: [Pd]
Solvent: CO
Product: COCCOCc1ccc(C(C)C(=O)O)cc1F
Yield: 57.5 %

Procedure:
A suspension of benzyl 2-(3-fluoro-4-((2-methoxyethoxy)methyl)phenyl)acrylate (2.8 g, 8.139 mmol), 10% Pd/C (300 mg) in MeOH (20 mL) was hydrogenated (balloon pressure) at RT for 1 h until complete consumption of benzyl 2-(3-fluoro-4-((2-methoxyethoxy)methyl)phenyl)acrylate, as evidenced by TLC analysis. The reaction mixture was filtered through celite pad, washed with MeOH (2×15 mL). The combined filtrate was concentrated and the obtained crude compound was purified by CC using 30% EtOAc in PE as eluent to afford 2-(3-fluoro-4-((2-methoxyethoxy)methyl)phenyl)propanoic acid (1.2 g, 58%) as a colorless oil (TLC solvent system: 30% EtOAc-PE; Rf: 0.15).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2]>ClCCl.C(O)(C(F)(F)F)=O>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH2:23])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:32]
Reactant: CCN(CC)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCc3ccccc3C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Yield: 97.3 %

Procedure:
(2-(4-Diethylamino-phenylcarbamoyl)-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester from Example 3 (320 mg) was dissolved in dichloromethane (10 mL) and TFA (5.0 mL). The volatiles were removed after 2 h. The amine-TFA salt was then dissolved in ethyl acetate (30 mL) and washed with 1 N NaOH. The organic phase was dried over MgSO4 and purified by column chromatography to provide the titled compound (240 mg, 97%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][N:9]=1.[OH-].[Na+]>ClCCl>[OH:6][CH2:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:11]=[CH:10][N:9]=1
Reactant: COCc1nccc(N2CCOCC2)n1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: OCc1nccc(N2CCOCC2)n1
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A solution of boron tribromide (9.02 ml) in dichloromethane (100 ml) was added dropwise to a stirred solution of 2-methoxymethyl-4-morpholinopyrimidine (4.99 g) in dichloromethane (50 ml) at -25° under nitrogen. After 15 minutes the mixture was allowed to warm to 0°-5°, and left to stand for 2 hours at this temperature. After pouring onto ice, the pH was raised to 14 (NaOH), and the organic phase separated off. The aqueous phase was further extracted with chloroform, and the combined extracts dried (K2CO3) and stripped. The residue was triturated with ether to give 2-hydroxymethyl-4-morpholinopyrimidine (3.16 g) as a crystalline solid, m.p. 76°-8°.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:15])=O.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:15][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: OCCn1cnc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: ClCCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
To a slurry of 30 g (0.185 mole) of 1-(2-hydroxyethyl)benzimidazole in 200 ml of methylene chloride was added dropwise 13.5 ml (0.185 mole) of thionyl chloride in 50 ml of the same solvent. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was added to an equal volume of water and made basic (pH 8-9) by the addition of sodium bicarbonate. The organic phase was separated, dried over magnesium sulfate and evaporated to give 27.3 g of product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.CN1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)CCC1=O.BrC1C=NC=C(Br)C=1.[C:49]([O:53][C:54]([N:56]1[CH2:61][CH:60]=[C:59](B2OC(C)(C)C(C)(C)O2)[CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>>[C:49]([O:53][C:54]([N:56]1[CH2:57][CH:58]=[C:59]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]4)[CH:3]=2)[CH2:60][CH2:61]1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CN1C(=O)CCc2cc(-c3cncc(Br)c3)ccc21
Agent: Brc1cncc(Br)c1
Agent: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(C4=CCN(C(=O)OC(C)(C)C)CC4)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 45, 6-(5-bromo-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (prepared from 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) and 3,5-dibromo pyridine also with a procedure as used for the preparation of example 45) has been coupled to 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester to give the title compound as light yellow amorphous solid. MS: 420.5 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9]Br.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].C(N(C(C)C)CC)(C)C.CCCCCC>C(#N)C.C(OCC)(=O)C>[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:15]1[CH2:2][CH2:3][C:4]2[S:5][CH:6]=[CH:7][C:8]=2[CH2:9]1
Reactant: NCc1ccccc1Cl
Reactant: BrCCc1sccc1CBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccccc1CN1CCc2sccc2C1
Yield: 77.5 %

Procedure:
At below 5° C., 5.0 g of 2-(2-bromoethyl)-3-bromomethylthiophene obtained in Example 7 was dissolved in 50 mL of acetonitrile, and added thereto was a solution obtained by dissolving 2.7 g of 2-chlorobenzylamine and 6.8 g of diisopropylethylamine in 25 mL of acetonitrile. The resulting mixture was refluxed for 5 hours, and concentrated by evaporation under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, and washed twice with 70 mL portions of water. The organic layer was washed with 50 mL of saturated sodium chloride aqueous solution and concentrated under reduced pressure. The dark yellow colored oily residue thus obtained was subjected to a silica gel column chromatography (eluent, n-hexane:ethyl acetate=5:1) to obtain 3.6 g (yield of 78%) of the title compound as a yellowish oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=2)[O:8][N:7]=1)=[O:5])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:40][C:41]1[CH:50]=[CH:49][CH:48]=[C:47](O)[C:42]=1[C:43]([O:45][CH3:46])=[O:44].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[OH:40][C:41]1[C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:47]([CH:48]=[CH:49][CH:50]=1)[O:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2cccc(CCCO)c2)on1
Reactant: COC(=O)c1c(O)cccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cccc1OCCCc1cccc(-c2cc(C(=O)O)no2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
To 5-(3-(3-hydroxy-propyl)-phenyl)-isoxazole-3-carboxylic acid ethyl ester (31 mg, 0.1 mmol) was added triphenylphosphine (29 mg, 0.11 mmol), methyl (2,6-dihydroxy)benzoate (20 mg, 0.12 mmol), then THF (1 mL). After the solids had dissolved, diethylazodicarboxylate (20 μL, 0.13 mmol) was added, and the reaction was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo, and the residue was taken up in aqueous 2M NaOH (1 mL), along with enough methanol to make the solution homogeneous. After stirring for 10 minutes, the solvents were removed in vacuo, glacial acetic acid (4 drops)was added, and the product was purified by reverse phase HPLC, eluting with a acetonitrile/0.1% aq. trifluoroacetic acid gradient to provide the title compound (2.7 mg, 7%). 1H NMR (500 MHz, d6-DMSO) δ 9.94 (s, 1H), 7.79 (s, 1H), 7.76 (d, 1H, J=7.8 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.37 (d, 1H, J=7.5 Hz), 7.34 (s, 1H), 7.15 (t, 1H, J=8.3 Hz), 6.49 (dd, 2H, J=2.8, 8.4 Hz), 3.95 (t, 2H, J=6.2 Hz), 3.79 (s, 3H), 2.78 (t, 2H, J=7.5 Hz), 2.01 (m, 2H); MS (ESI) m/z 398 (M+H), 415 (M+NH4).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:20]([F:28])[CH:21]=1
Reactant: Brc1cccc2[nH]ncc12
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(-n2ncc3c(Br)cccc32)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 60.3 %

Procedure:
To a solution of 4-bromo-1H-indazole (4.32 g, 21.9 mmol) in dichloromethane (100 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (10.8 g, 43.9 mmol), pyridine (3.5 mL, 43.3 mmol), copper acetate (5.9 g, 32.6 mmol) and powdered 4A molecular sieves (5 g). The reaction mixture was stirred at room temperature in the presence of air for 5 days. Celite was added to the reaction mixture and the mixture stirred for 5 minutes. The mixture was then filtered through a pad of celite and washed with dichloromethane and then the filtrate concentrated in vacuo. The residue was diluted in dichloromethane and water. After separation of the layers, the aqueous phase was extracted with dichloromethane (×4). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 10-80% dichloromethane in hexane to yield the title compound (D38) (5.25 g).