Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([OH:11])[N:5]=[C:4]([S:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[N:3]=1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(Cl)Cl>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH2:8][CH2:9][O:10][Si:24]([CH3:26])([CH3:25])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:6]([OH:11])[N:5]=[C:4]([S:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nc(SCc2ccc3ccccc3c2)nc(O)c1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1c(N)nc(SCc2ccc3ccccc3c2)nc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(4-amino-6-hydroxy-2-[2-naphthylmethyl]thio-5-pyrimidinyl)-ethanol (Cpd #279; 106 mg, 0.32 mmol) is dissolved in pyridine (0.64 ml) and the solution is cooled to 0° C. then treated with t-butyl dimethylsilyl chloride (0.058 g, 0.39 mmol). The solution is stirred at 0° C. for 2 hours and two new spots developed in the mixture. The reaction mixture is poured into methylene chloride and washed 3× with 1 M HCl, 10% HCl, 3× H2O, 2× 6% NaHCO3, dried with MgSO4, then concentrated in vacuo. The crude product is then purified by chromatography (SiO2 1:1 hexane/ethyl acetate): 60 mg (0.18 mmol, 57%), mp 156-158° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.C([Li])CCC.[CH3:15][N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2.Cl>C(OCC)C.O1CCCC1.O>[Cl:9][C:4]1[CH:3]=[C:2]([C:19]2([OH:24])[CH2:20][CH:21]3[N:16]([CH3:15])[CH:17]([CH2:23][CH2:22]3)[CH2:18]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Clc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CN1C2CCC1CC(O)(c1ccc(Cl)c(Cl)c1)C2
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 1-bromo-3,4-dichlorobenzene (178.6 g, 0.8 mol) in anhydrous diethyl ether (1430 mL) under an argon atmosphere was cooled to -70° C. A solution of n-butyllithium in hexanes (310 mL 2.5 M; 0.78 mol) was added slowly while the temperature was kept below -65° C. (addition time=1 hour). The resulting solution was stirred for another 30 minutes at -70° C. followed by addition of a solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (50 g, 0.36 mol) in anhydrous tetrahydrofuran (360 mL). The temperature was kept below -50° C. during the addition which took approximately one hour. The resulting solution was stirred at -50° C. for two hours followed by a addition of water (215 mL) over 15 minutes and 4M HCl (360 mL) over 25 minutes. The temperature reached -20° C. by the end of the addition. The organic phase was discharged and the aqueous phase was washed once with diethyl ether (500 mL). Concentrated NH4OH (approximately 200 mL) was added to the aqueous phase to pH=10 which resulted in precipitation of the title compound. A crude product was isolated by filtration which was suspended twice in water (2×300 mL) and finally dried under a lamp yielding the title compound as a white solid (88 g, 86%), m.p. 179.3-180.5° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].O[CH2:15][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[OH:22][CH2:21][C:19]1[O:20][C:16]([CH:15]=[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:1](=[O:3])[CH3:2])[C:5]2=[O:13])=[CH:17][CH:18]=1
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: O=Cc1ccc(CO)o1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)N1C(=O)C(=Cc2ccc(CO)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-acetyloxindole (1 equivalent), 5-hydroxymethyl-2-furaldehyde (0.5 equivalent) and piperidine (0.2 equivalent) were dissolved in ethanol such that 1 mL of ethanol was used per 1 μmol of the total amount of the compounds, and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the resulting precipitate was collected by filtration, washed with cooled ethanol several times and dried, whereby 3-((5-(hydroxymethyl)furan-2-yl) methylene)-N-acetyl-2-oxoindoline was obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:12][C:3]1[C:4]([C:5]([N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:33][CH2:34]2)=[O:7])=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([O:15][C:14]([F:26])([F:25])[F:13])[CH:21]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1ccc(Br)c(C)c1C(=O)O
Product: Cc1ccc(-c2cccc(OC(F)(F)F)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for intermediate 1,2,4-dimethyl-3′-trifluoromethoxy-biphenyl-3-carboxylic acid (prepared from 3-bromo-2,6-dimethyl-benzoic acid [Lee, J.; et al. Bioorganic & Medicinal Chemistry Letters (2003), 13(11), 1879-1882] and 3-trifluoromethoxy-phenyl boronic acid in analogy to the procedure described for the preparation of example 1) was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light yellow solid. MS: 447.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].Cl[CH:37]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:38]([O:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=1)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH:37]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:38]([O:40][C:41]3[CH:42]=[C:43]([CH3:48])[CH:44]=[C:45]([CH3:47])[CH:46]=3)=[O:39])[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: Cc1cc(C)cc(OC(=O)C(Cl)c2ccccc2)c1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cc1cc(C)cc(OC(=O)C(c2ccccc2)N2CCN([C@H]3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H](Cc4ccccc4)C3)CC2)c1
Yield: 43.1 %

Procedure:
A mixture of compound 15 (2.5 g), intermediate 5 (1.65 g) and sodium carbonate (0.64 g) in methylisobutylketon (50 ml) was stirred and refluxed for 3 hours. The reaction mixture was washed and the separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0 and 99.5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 1.59 g (43%) of (±)-3,5-dimethylphenyl cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-α-phenyl-1-piperazineacetate compound 43; mp. 88.1° C.).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:7][CH:8]([CH3:12])[C:9](O)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH:1]1([O:6][C:9](=[O:10])[CH:8]([SH:7])[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: CC(S)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CC(S)C(=O)OC1CCCC1

Procedure:
Into a 250 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 86 grams of cyclopentanol; 25 grams of 2-mercaptopropionic acid; and 1 gram of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 8 hours. At the end of the 8 hour reflux period, the reaction mass is cooled and admixed with 200 ml diethylether followed by washing with two 100 ml volumes of 10% aqueous sodium carbonate and one 100 ml volume of water. The reaction mass is dried over anhydrous sodium sulfate and the solvent is recovered on a Buchi apparatus. The reaction mass is then micro distilled yielding the product having the structure: ##STR134##
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:5][N:4]=1)[NH2:2].[CH3:19][C:20](=O)[CH2:21][CH2:22][C:23](=O)[CH3:24]>C(O)(=O)C>[CH3:24][C:23]1[N:2]([NH:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:5][N:4]=2)[C:20]([CH3:19])=[CH:21][CH:22]=1
Reactant: NNc1nnc(N2CCOCC2)c2ccccc12
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1nnc(N2CCOCC2)c2ccccc12
Temperature: 65 °C

Procedure:
To 4.9 grams (20 m moles) of 1-hydrazino-4-morpholino phthalazine (prepared from 1,4-dichlorophthalazine) according to the procedure of U.K. Pat. No. 1.157.642; M.p. 255°-260° C.) dissolved in 30 ml of acetic acid, 2.74 g (24 m moles) of 2,5-hexanedione are added and the mixture is heated at 65° C. for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1B1OC(C)(C)C(C)(C)O1.Br[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:29][OH:30])[CH2:21]2.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:29][OH:30])[CH2:21]2
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1c2ccc(Br)cc2CN1[C@H](CO)Cc1cccc(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1ccc2c(c1)CN([C@H](CO)Cc1cccc(F)c1)C2=O
Yield: 66.6 %

Procedure:
A mixture of 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (177.0 mg, 0.7297 mmol), bis(tri-t-butylphosphine)palladium (31.1 mg, 0.0608 mmol), 5-bromo-2-[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]isoindolin-1-one (220.0 mg, 0.6081 mmol) and N,N-diisopropylethylamine (0.318 mL, 1.82 mmol) in 1,4-dioxane (3 mL, 40 mmol) and water (150 μL, 8.3 mmol) was microwaved at 110° C. for 15 minutes. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluting with EtOAc/hexane (30-100%) to give 0.162 g (67% yield) of the desired product as yellowish solid. LC/MS found: 399.9 (M+1)+.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[OH:20][C:21]([CH3:29])([C:27]#[CH:28])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>>[CH3:25][N:24]([CH3:26])[C:22](=[O:23])[C:21]([OH:20])([CH3:29])[C:27]#[C:28][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)C(=O)N(C)C
Product: CN(C)C(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 13 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-hydroxy-N,N,2-trimethylbut-3-ynamide to give 24.2 mg of the titled compound (13%),
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@H:24]([OH:26])[CH2:25][C@@H:20]4[CH2:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].CC(C)([O-:32])C.[K+].[CH2:35](Br)[C:36]#[CH:37]>C1(C)C=CC=CC=1.CCCCCC.CCOC(C)=O>[CH2:35]([O:26][C@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:27])[CH:20]([CH2:19][CH2:18][C@@H:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH2:8][OH:32])[CH2:25]1)[C:36]#[CH:37]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C#CCBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C#CCO[C@H]1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)CO)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3β-cholestanol (1.23 g, 3.16 mmol) was completely dissolved in anhydrous toluene (7 mL, 0.45 M) at r.t. Powdered potassium t-butoxide (1.06 g, 9.49 mmol, 3 eq) was added in one portion. The mixture was stirred at r.t. for 3 h. A solution of propargyl bromide (80 wt % in toluene, 0.94 g, 6.32 mmol, 2 eq) was added. The mixture was stirred at r.t. for 3 days. The mixture was diluted with hexane (30 mL) and EtOAc (10 mL), washed with water (2×60 mL) and brine (60 mL). The aqueous phase was extracted once with EtOAc (20 mL). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated onto silica gel and purified by column chromatography (silica gel 2.5×24 cm, gradient elution with hexane 250 mL, hexane-EtOAc 125:5) to give the product as a yellow solid. Recrystallization from EtOAc (3 mL) gave off-white crystals (736 mg, 55%). 1H NMR (CDCl3, 400 MHz) δ 4.18 (d, 2H, J=2.2), 3.45 (m, 1H), 2.38 (t, 1H, J=2.2), 1.99-0.57 (m, 31H), 0.89 (d, 3H, J=6.6), 0.86 (d, 3H, J=6.6), 0.86 (d, 3H, J=6.6), 0.79 (s, 3H), 0.64 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=O)[CH:4]=1.O=P(Cl)(Cl)[Cl:12]>>[Cl:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: COc1cc[nH]c(=O)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccnc(Cl)c1
Yield: 63 %

Procedure:
4-Methoxy-2-pyridone (10) (0.805 g, 6.43 mmol) and freshly distilled POCl3 (8 mL) were heated at reflux for 15 h. Excess POCl3 was removed in vacuo and the resultant viscous oil was cooled in ice and carefully neutralised with saturated NaHCO3 solution. The mixture was extracted with EtOAc (×3) and the extracts were worked up in the standard manner to give a brown oil. This material was partially purified by vacuum distillation in a Kugelrohr apparatus (100° C., 0.07 mm Hg). The distillate was triturated with petroleum ether and a white precipitate was filtered off. The filtrate was concentrated and final purification by flash chromatography on silica gel using 30% EtOAc/hexanes as the eluant gave 2-chloro-4-methoxypyridine (11) as a colourless oil (0.586 g, 63%).
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl.O>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCN(S(C)(=O)=O)CC3)c2n1
Temperature: 0 °C
Yield: 0.1 %

Procedure:
A mixture of 75 mg (155 mmol) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidine and 65 mg (465 mmol) of powdered K2CO3 in CH2Cl2 was cooled to 0° C., and 27 mg (233 mmol) of methanesulfonyl chloride was added. The mixture was allowed to warm to room temperature, and after 2 hrs it was diluted with water and washed with aq. NH3. The organic layer was dried (Na2SO4) and concentrated under vacuum to give 80 mg (92% yield) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1-[1-(methylsulfonyl)-4-piperidinyl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidine: mp (MeOH) 273-276° C.; 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.82 (dd, J=8.4, 0.6 Hz, 1H), 7.46 (t, J=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.85 (tt, J=11.1, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m, 4H), 4.02 (m, 1H), 3.99 (m, 1H), 3.92 (m, 4H), 3.02 (dt, J=12.2, 2.5 Hz, 2H), 2.88 (s, 3H), 2.44 (dq, J=11.6, 4.2 Hz, 2H), 2.17 (m, 2H); Anal. Calcd. for C24H28F2N8O4S: C, 51.2; H, 5.0; N, 19.9. Found: C, 50.85; H, 5.0; N, 19.7%.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.O>C1COCC1>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: BrBr
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc([N+](=O)[O-])cc1Br
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Bromine (62.6 mλ; 1.2 mole) was dropwise added to 2-amino-5-nitropyridine (154.1 g; 1.1 mole) in THF (300 mλ) at room temperature. The resulting mixture was stirred for one hour and then poured into water (3 λ). The crystals thus formed were recrystallized from acetonitrile (500 mλ) to give 2-amino-3-bromo-5-nitropyridine (A) (194.4 g; 80%).
Reaction SMILES: [C:1]([O:5]C)(=O)[CH:2]=[CH2:3].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1.[CH3:18][C:19](C)([O-])C.[K+]>C1COCC1.CC(C)([O-])C.[K+]>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13]3([CH2:3][CH2:2][C:1](=[O:5])[CH2:19][CH2:18]3)[C:14]2=[O:17])=[CH:10][CH:9]=1
Reactant: C=CC(=O)OC
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: 20 °C
Reaction time: 6 h
Yield: 61.7 %

Procedure:
Methyl acrylate (6.6 L, 73 mol) was charged gradually in three equal portions (each 2.2 L, 24.6 mol) to a mixture of 6-bromo-1-indanone (8.00 kg, 37.9 mol), THF (16 L) and potassium tert-butoxide (210 g, 1.87 mol) at approximately 20-30° C. Additional potassium tert-butoxide (86 g, 0.77 mol), dissolved in THF (0.39 L), was charged after the first portion of methyl acrylate. More potassium tert-butoxide (86 g, 0.77 mol), dissolved in THF (0.39 L), was charged after the second portion of methyl acrylate. Further potassium tert-butoxide (4.64 kg, 41.3 mol) solution in THF (21 L) was then charged gradually at approximately 20-30° C. Solvent (21.5 L) was distilled off at approximately 65° C. and then a mixture of water (49 L) and 50%. aq KOH (2.3 L, mol) was added over approximately 10 min. at below 60° C. The reaction was held at 60° C. for approximately 6 h., then cooled to 20° C. over 1 h. and then filtered after holding at 20° C. for approximately 12 h. The solids were washed with a mixture of water (8 L) and THF (4 L), and then dried to give the title compound (7.47 kg, at 92% w/w NMR assay, 23.4 mol, 62% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.78-1.84 (m, 2 H), 1.95 (td, 2 H), 2.32-2.38 (m, 2 H), 2.51-2.59 (m, 2 H), 3.27 (s, 2 H), 7.60 (d, 1 H), 7.81 (m, 1 H), 7.89 (m, 1 H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])#N.S(=O)(=O)(O)O.[CH2:31]([OH:33])[CH3:32].C(=O)([O-])[O-:35].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH3:10][C:9]1[N:8]=[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:4]=1[CH2:3][C:1]([O:33][CH2:31][CH3:32])=[O:35]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CC#N
Reactant: O=C([O-])[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 5 -cyanomethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (5 g), conc. sulfuric acid (12 g) and ethanol (50 ml) was gently refluxed for 72 hours. The reaction mixture was poured into a suspension of chloroform (200 ml) and water (100 ml), and then adjusted to pH 8.5 with 10% aqueous sodium carbonate solution. The separated organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residual substance was recrystallized from diethyl ether-n-hexane to give ethyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinylacetate (3.7 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[N:23]1>>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(cnn4C)c3)ccn2c1=O
Yield: 98.5 %

Procedure:
Methyl 8-(1-methyl-1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (1-methyl-1H-indazol-5-yl)boronic acid (176.0 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (129.8 mg, 95%).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[CH:26]=[C:25]([O:27][CH2:28][CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[CH:24]=[CH:23][N:22]=2)[C:10]=1[CH3:34])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[OH:32][C:30]([CH3:33])([CH3:31])[CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([O:20][CH2:19][C:11]2[NH:12][C:13]3[C:18]([C:9](=[O:8])[C:10]=2[CH3:34])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:26]=1
Reactant: Cc1c(COc2cc(OCCC(C)(C)O)ccn2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(COc2cc(OCCC(C)(C)O)ccn2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 4-[(2-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}pyridin-4-yl)oxy]-2-methyl butan-2-ol (1.33 g) in ethanol-THF (1:4, 45 mL) was added 10% palladium-activated carbon (300 mg) under nitrogen atmosphere. The mixture was placed under hydrogen atmosphere, and then stirred at room temperature for 1 hour. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=97/3) to obtain 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one (783 mg) as a crystal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[C:10]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].BrN1C(=O)CCC1=O.BrBr>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]([CH2:18][CH3:19])([CH2:20][CH3:21])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCC(Br)(CC)C(=O)OC(C)(C)C
Agent: BrBr
Agent: O=C1CCC(=O)N1Br
Product: CCC(CC)(Sc1ccc(Br)cc1)C(=O)OC(C)(C)C

Procedure:
The synthesis was carried out similarly to Example II-1 from 4-bromothiophenol and 1,1-dimethylethyl 2-bromo-2-ethyl-butanoate [preparation, for example, similarly to Liebigs Ann. Chem. 725, 106-115 (1969); J. Am. Chem. Soc. 77, 946-947 (1955), and bromination with N-bromosuccinimide or bromine, for example similarly to Tetrahedron Lett. 1970, 3431; J. Org. Chem. 40, 3420 (1975)].