Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH2:11].C([O-])([O-])=O.[Na+].[Na+].Cl[C:19]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:22]=[C:21]([S:33][CH3:34])[N:20]=1>CN1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:19]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:22]=[C:21]([S:33][CH3:34])[N:20]=1
Reactant: NCCc1c(F)cccc1Cl
Reactant: COc1ccc(-c2cc(Cl)nc(SC)n2)cn1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2cc(NCCc3c(F)cccc3Cl)nc(SC)n2)cn1
Temperature: 175 °C
Yield: 94.5 %

Procedure:
A mixture of 2-(2-chloro-6-fluoro-phenyl)-ethylamine [1.02 g, 5.88 mmol, Intermediate (23)], Na2CO3 (1.65 g, 19.6 mmol), and 4-chloro-6-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrimidine [1.05 g, 3.92 mmol, Intermediate (38)] in N-methyl pyrrolidine (10 mL), is heated to 175° C. for 3 hours. The reaction mixture is diluted with water, and extracted with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate, filtered, and concentrated. The residue is subjected to short-path chromatography on silica gel eluting with EtOAc to afford [2-(2-chloro-6-fluoro-phenyl)-ethyl]-[6-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrimidin-4-yl]-amine [1.5 g, Example 30]. LCMS: RT=3.37 minutes, MS: 405 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[Si:22]([O:29][NH2:30])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[Si:22]([O:29]/[N:30]=[C:11]1\[NH:10][C@@H:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Br:20])[CH2:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:21])[C:5]\1=2)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: CC(C)(C)[Si](C)(C)ON
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/O[Si](C)(C)C(C)(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (31I, 366 mg, 1.0 mmol), O-(tert-butyldimethylsilyl)hydroxylamine (588 mg, 4.0 mmol), Hg(OAC)2 (640 mg, 2.0 mmol) and toluene (5 mL) was heated at 100° C. for 2 h. The mixture was cooled to r.t. and filtered through celite. Filtrate concentrated and the resulting oily residue was triturated with dry methanol to afford a pale yellow solid. Filtered and dried to afford ((R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-tert-butyldimethylsilyloxime (105a, 384 mg, 80%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (s, 3H), 0.23 (s, 3H) 0.97 (s, 9H) 2.70 (s, 3H) 2.91 (dd, J=16.42, 8.08 Hz, 1H) 3.19 (ddd, J=16.36, 4.86, 1.26 Hz, 1H) 4.99 (ddd, J=7.77, 5.12, 2.02 Hz, 1H) 7.05 (td, J=8.27, 2.65 Hz, 1H) 7.33 (dd, J=8.08, 2.78 Hz, 1H) 7.39 (dd, J=8.72, 5.94 Hz, 1H). MS (ES) [M+H] calculated for C20H28BrFN5OSi, 480.12; found 480.30.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:26]4/[C:27](=[O:35])[N:28]=[C:29]([NH:31][CH:32]5[CH2:34][CH2:33]5)[S:30]/4)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:36]#[N:37])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>>[CH:32]1([NH:31][C:29]2[S:30][C:26](=[CH:25][C:22]3[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([C:36]#[N:37])=[C:15]4[O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:27](=[O:35])[N:28]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(/C=C4\SC(NC5CC5)=NC4=O)cc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cnc2ccc(C=C3SC(NC4CC4)=NC3=O)cc2c1OC1CCNCC1

Procedure:
Similar procedure as described in example 30 was used, starting from 4-{3-cyano-6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinolin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (example 33) and 4N HCl/Dioxane to give 6-(2-cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-(piperidin-4-yloxy)-quinoline-3-carbonitrile; hydrochloride. LC-MS m/e 420 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C)C=O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[N:15]1[CH2:14][CH2:13][N:12]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:4][CH:5]=2)=[O:11])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CCl)cc4)CC3)c2cc1OC
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CN5CCCCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.7 %

Procedure:
In 10 ml of toluene was suspended 593.5 mg (2.16 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), and 362.6 ml (2.16 mmol) of 4-(chloromethyl)phenyl isocyanate was added thereto, followed by stirring at room temperature for 3 hours. After the reaction mixture was filtered, the obtained crystals were washed with diisopropyl ether and dried under reduced pressure to give 916.8 mg (2.08 mmol, 96%) of N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide. In 10 ml of dimethylformamide was dissolved 422.9 mg (0.96 mmol) of the obtained N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide, and 0.28 ml (2.83 mmol) of piperidine was added thereto, followed by stirring at room temperature for 7 hours. Then, the reaction mixture was poured into water and the precipitated crystals were collected by filtration, followed by purification by silica gel column chromatography to give 430.9 mg (0.88 mmol) of the desired compound as colorless crystals.
Reaction SMILES: C[O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[C:34](=[O:35])[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26]5)[C:20]=4[CH3:36])=[N:17][N:16]=[C:15]([C:37]([NH2:39])=[O:38])[C:11]=3[NH:12][C:13]=2[CH:14]=1.BrB(Br)Br.ClCCl>ClCCl.CO>[OH:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[C:34](=[O:35])[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26]5)[C:20]=4[CH3:36])=[N:17][N:16]=[C:15]([C:37]([NH2:39])=[O:38])[C:11]=3[NH:12][C:13]=2[CH:14]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nnc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1c(-c2nnc(C(N)=O)c3[nH]c4cc(OCCO)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 18.7 %

Procedure:
To a homogeneous, light orange solution of 7-(2-methoxyethoxy)-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide (0.0973 g, 0.155 mmol) in dichloromethane (5 ml) under nitrogen at 0° C. was added 1M tribromoborane/dichoromethane (0.496 ml, 0.496 mmol) over 5 min. After 5 min, the cold bath was removed, and the heterogeneous solution was stirred to room temperature. One hour later, the reaction was immersed in an ice-water bath and ice water (15 mL) was added. The resulting mixture was basified with 1 N aqueous NaOH solution to pH ˜10 by litmus paper. EtOAc (50 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined extract was dried over MgSO4 and concentrated in vacuo to give a residue which was diluted with MeOH (1 mL) and purified by reverse phase HPLC. The appropriate fractions were collected, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined extract was dried over Na2SO4 and concentrated in vacuo to give the desired product (0.0148 g, 0.029 mmol, 18.8% yield) as a light yellow solid. LC/MS (M+H)=507.21; 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropoisomer) δ ppm 12.23 (s, 1H), 8.71 (br. S, 1H), 8.48 (s, 1H), 8.26 (t, J=6.2 Hz, 1H), 8.00 (br. S, 1H), 7.88-7.94 (m, 1H), 7.79 (d, J=8.0 Hz, 1H)), 7.72-7.77 (m, 1H), 7.58-7.70 (m, 3H), 7.41 (d, J=2.2 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.88 (dd, J1=8.9, J2=2.2 Hz, 1H), 4.84-4.97 (m, 1H), 4.01-4.14 (m, 2H), 3.71-3.85 (m, 2H), 1.81 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([S-:5])([CH3:4])[CH3:3].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[N:9]=1>CN(C=O)C.C(OCC)(=O)C>[C:2]([S:5][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[N:9]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[S-]
Reactant: Clc1cccc(Cl)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1cccc(Cl)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
A suspension of sodium 2-methylpropane-2-thiolate (188 mg, 1.68 mmol) in DMF was treated with 2,6-dichloropyridine (4865 μl, 1.46 mmol) at ambient temperature in a vial. The vial was capped and heated to 80° C. with rapid stirring of the colorless solution. After 12 hours, the reaction was cooled to ambient temperature and diluted with ethyl acetate. The ethyl acetate solution was washed with brine solution, dried with sodium sulfate, filtered, concentrated and purified on silica gel. Elution with 2% to 10% ethyl acetate/hexanes provided the title compound (271 mg, 1.34 mmol, 92.0% yield) as a light yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Br:54])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH:24]1C(C(C)C)CCC(C)C1)([CH:14]1C(C(C)C)CCC(C)C1)[CH2:10][C:9]2([CH:44]1C(C(C)C)CCC(C)C1)[CH:34]1C(C(C)C)CCC(C)C1)(=O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:54][C:6]1[CH:7]=[C:8]2[C:13](=[C:4]([CH2:1][CH3:2])[CH:5]=1)[O:12][C:11]([CH3:24])([CH3:14])[CH2:10][C:9]2([CH3:34])[CH3:44]
Reactant: CC(=O)c1cc(Br)cc2c1OC(C1CC(C)CCC1C(C)C)(C1CC(C)CCC1C(C)C)CC2(C1CC(C)CCC1C(C)C)C1CC(C)CCC1C(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred, cooled (ice bath) solution of 8-acetyl-6-bromo-2,2,4,4-tetramenthyl chroman (Intermediate 45, 0.95 g, 3.1 mmol) in trifluoroacetic acid (10 mL) was treated with triethylsilane (10 mL) and the resulting reaction mixture was allowed to warm to ambient temperature and stirred overnight. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with hexane (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent to afford the title compound as a clear oil, contaminated with a small amount to triethylsilane (0.51 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]1=[O:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)CC1Cc2ccccc2NC1=O
Product: COC(=O)CC1Cc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 89 %

Procedure:
Following a similar N-alkylation procedure described in example 6, the (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester (0.99 mmol) is alkylated with tert-butyl bromoacetate to give (1-tert-butoxycarbonylmethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester as a colorless oil, after purification by silica gel chromatography (hexane/EtOAc). Yield: 89%. MS: (ES+): 356.2 [M+23].
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9](C(OC(C)(C)C)=O)[C:8]=2[C:19]([O:21][CH3:22])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:19]([O:21][CH3:22])=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(-c2ccccc2)ccn1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1[nH]ccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 62.4 %

Procedure:
1-tert-Butyl 2-methyl 3-phenyl-1H-pyrrole-1,2-dicarboxylate (18.0 g, 59.7 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to 0° C. TFA (23.0 mL, 0.299 mmol) was added to the reaction mixture and the solution stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure to remove excess of TFA. To the resulting residue was added 10% sodium bicarbonate solution (50 mL) and the aqueous portion extracted with CH2Cl2. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 30% EtOAc/hexanes) to obtain methyl 3-phenyl-1H-pyrrole-2-carboxylate (7.50 g, 62.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.69 (s, 3H), 6.29 (t, J=2.8 Hz, 1H), 7.02 (d, J=2.8 Hz, 1H), 7.03 (m, 5H), 12.0 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[OH:14][C@:15]12[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:19][NH:18][CH2:17][CH2:16]2>>[OH:14][C@:15]12[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:19][N:18]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:17][CH2:16]2
Reactant: O[C@]12CCCCC1CNCC2
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(N2CC[C@@]3(O)CCCCC3C2)c2ccccc12
Yield: 22.3 %

Procedure:
The title compound (8 mg, 22% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and (S)-4a-hydroxyoctahydroisoquinoline (73 mg, 0.468 mmol).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][C@H:49]2[CH3:54])[N:44]([CH2:55][C:56](O)=[O:57])[CH2:43][C@H:42]1[CH3:59])=[O:40])([CH3:37])([CH3:36])[CH3:35].[F:60][C:61]([C:66]1[CH:67]=[C:68]2[NH:74][CH2:73][C:72]([CH3:76])([CH3:75])[C:69]2=[N:70][CH:71]=1)([F:65])[CH2:62][CH2:63][CH3:64]>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][C@H:49]2[CH3:54])[N:44]([CH2:55][C:56]([N:74]2[C:68]3[C:69](=[N:70][CH:71]=[C:66]([C:61]([F:65])([F:60])[CH2:62][CH2:63][CH3:64])[CH:67]=3)[C:72]([CH3:75])([CH3:76])[CH2:73]2)=[O:57])[CH2:43][C@H:42]1[CH3:59])=[O:40])([CH3:36])([CH3:37])[CH3:35]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Reactant: CCCC(F)(F)c1cnc2c(c1)NCC2(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CN1CCOC[C@H]1C)CC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
HATU (3.8 g, 9.9 mmol) and DIPEA (2.4 mL, 13.3 mmol) were added to a solution of (2R,5S)-4-carboxymethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 6.7 mmol) and 6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.6 g, 6.7 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 16 h and then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic phase was separated, washed with brine (3×), dried over MgSO4 and concentrated in vacuo. Chromatography (70% EtOAc in Petrol) gave the title compound (2.1 g) as a yellow solid. MS: [M+H]+=594.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])=[CH:7][C:6]=2[CH:18]=1.C1(P(C2CCCCC2)C2CCCCC2)C(C2C=CC=CC=2)=CC=CC=1.[OH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.C(O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:49]3[CH:50]=[CH:51][C:46]([CH2:45][OH:44])=[CH:47][CH:48]=3)=[CH:18][C:6]=2[CH:7]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccccc1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(CO)cc3)ccc2o1
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution (1.2 mL) of the product from Example 115A (350 mg, 1.1 mmol) in benzene (3.6 mL) was added to a mixture of palladium (II) acetate (11 mg, 0.05 mmol), and biphen-2-yl-dicyclohexylphosphine (28 mg, 0.08 mmol). The reaction mixture was then treated with 4-(hydroxymethyl)phenylboronic acid (87 mg, 0.57 mmol) in ethanol (500 μL) followed by 2M aqueous Na2CO3 (500 μL). The mixture was stirred thoroughly overnight. Additional ethanol (500 μL) was added and the mixture was stirred for four days, diluted with EtOAc, filtered, chromatographed through a short column of silica with a gradient of 0 to 2% MeOH/EtOAc, purified by HPLC [Waters Nova-Pak HR C18 column (25 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL/min.], and then rechromatographed through a short column of silica with MeOH/CH2Cl2 to provide the title compound (12% yield). MS (ESI APCI) m/z 336 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.21 (d, 3H), 1.42-1.58 (m, 1H), 1.77-1.91 (m, 2H), 1.99-2.13 (m, 1H), 2.35-2.77 (m, 3H), 2.97-3.18 (m, 2H), 3.2-3.4 (m, 2H), 4.64 (s, 2H), 6.61 (s, 1H), 7.42 (d, 2H), 7.45-7.48 (m, 2H), 7.60 (d, 2H), 7.72 (dd, 1H).
Reaction SMILES: C[C:2](C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]1([CH2:26][CH2:27][CH2:28][CH:29]([CH3:38])[CH2:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:21]2[O:22][C:18]([CH2:23][CH:24]=[O:25])([CH2:19][CH2:20]2)[CH2:17][O:16]1.CC(C)=O.[N+](=C)=[N-]>CCOCC.O.C(OCC)(=O)C.CC(O)C>[CH3:14][C:15]1([CH2:26][CH2:27][CH2:28][CH:29]([CH3:38])[CH2:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:21]2[O:22][C:18]([CH2:23][C:24]([O:3][CH3:2])=[O:25])([CH2:19][CH2:20]2)[CH2:17][O:16]1
Reactant: CC(C)=O
Reactant: CC(CCCC1(C)OCC2(CC=O)CCC1O2)COC1CCCCO1
Agent: O=[Cr](=O)=O
Agent: C=[N+]=[N-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CCOCC
Product: COC(=O)CC12CCC(O1)C(C)(CCCC(C)COC1CCCCO1)OC2
Yield: 83 %

Procedure:
An excess of Jones reagent (4 ml, 4 mM) is added slowly to a mixture of (1RS,4SR,5RS)-4-methyl-4-[4-methyl-5-(tetrahydropyran-2-yloxy)pentyl]-3,8-dioxabicyclo [3.2.1] octane-1-acetaldehyde (813 mg, 2.3 mM) and acetone (20 ml) at 0° C. The resulting mixture is stirred for thirty minutes and treated with 2-propanol (2 ml) followed by ethyl acetate (50 ml) and water (20 ml). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3×20 ml). The combined organic layers are dried (sodium sulfate) and the solvent is removed in vacuo to give a pale yellow oil. The oil is redissolved in ether (15 ml), treated with an excess of diazomethane in ether and stirred for ten minutes. The solvent is removed in vacuo to give methyl (1RS,4SR,5RS)-4-methyl-4-[4-methyl-5-(tetrahydropyran-2-yloxy)pentyl]-3,8-dioxabicyclo [3.2.1] octane-1-acetate as a pale yellow oil (625 mg, 83%). This material is homogeneous by thin layer chromatography and is used directly in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]([Cl:24])[C:4]=1[CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]1=[O:17].B(Br)(Br)Br>ClC(Cl)C.ClCCl>[Cl:2][C:3]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([Cl:24])[C:4]=1[CH2:5][C@@H:6]1[CH2:10][CH2:9][N:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]1=[O:17]
Reactant: COc1cc(Cl)c(CC2CCN(N3CCCCC3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1N1CCCCC1
Yield: 76.5 %

Procedure:
Cool a solution of 3-(2,6-dichloro-4-methoxy-benzyl)-1-piperidin-1-yl-pyrrolidin-2-one hydrochloride (0.27 g) in dichloroethane (10 mL) to −20° C. and add 1 M solution of boron tribromide in dichloromethane (2.5 mL). Stir the reaction at −20° C. for 1 hour and at room temperature 12 hours. Partition the mixture with dichloromethane (20 mL) and saturated sodium bicarbonate (15 mL). Separate the organic layer. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum to afford 0.18 g (76%) of the title compound. MS (m/z): 343 (M+).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:4]=[C:3]2[S:12]([NH:15][CH2:16][NH:17][C:2]=12)(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26](OCC)=[O:27]>CN(C=O)C>[Cl:7][C:6]1[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][C:3]2[S:12](=[O:14])(=[O:13])[N:15]([CH2:25][CH2:26][OH:27])[CH2:16][NH:17][C:2]=2[CH:1]=1
Reactant: CCOC(=O)CBr
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)NCNS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc2c(cc1Cl)NCN(CCO)S2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a solution of hydrochlorothiazide (ONBIO, Inc., Ontario, Canada) (13.82 g, 46.4 mmol) in DMF (50 mL) was added cesium carbonate (7.51 g, 23.0 mmol) and ethyl bromoacetate (7.69 g, 46.1 mmol) and the mixture was stirred for 18 hours at room temperature. The solids were removed via suction filtration, and the solvent was evaporated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/ether to give the title product (10.9 g, 61% yield) as white needles: mp 199-203° C.; 1H NMR (400 MHz, d6-DMSO) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.53 (s, 2H), 7.08 (s, 1H), 4.97 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); Mass spectrum (API-TIS) m/z 384 (MH+), 401 (MNH4+), 784 (2MNH430).
Reaction SMILES: COC[N:4]1[C:8]2=[N:9][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[C:20]1[S:21][C:22]2[C:28]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:27][CH:26]=[C:25]([O:35][CH3:36])[C:23]=2[N:24]=1.Cl>>[CH3:36][O:35][C:25]1[C:23]2[N:24]=[C:20]([C:5]3[NH:4][C:8]4=[N:9][C:10]([N:13]5[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]5)=[CH:11][CH:12]=[C:7]4[N:6]=3)[S:21][C:22]=2[C:28]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:27][CH:26]=1
Reactant: COCn1c(-c2nc3c(OC)ccc(N4CCOCC4)c3s2)nc2ccc(N3CCC(O)CC3)nc21
Agent: Cl
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(N5CCC(O)CC5)nc4[nH]3)nc12

Procedure:
0.035 g 1-[3-Methoxymethyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl]-piperidin-4-ol (0.07 mmol) was treated with 5N HCl (1 ml) at 90° C. for 0.5 h. The reaction mixture was concentrated, taken up in water (1 ml) and adjusted to pH 10 with ammonium hydroxide (25%), whereupon a precipitation formed. The precipitation was filtered and the crystals were triturated in hot ethanol. After drying in vacuo 0.018 g 1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl]-piperidin-4-ol (56%) was obtained as a yellow solid; M.p.: 228–230° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:19](Cl)(=[O:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>>[Br:7][C:6]1[C:2]([NH:1][S:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(=[O:21])=[O:20])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: Cc1onc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: Cc1onc(NS(=O)(=O)c2cccc3ccccc23)c1Br
Yield: 51 %

Procedure:
N-(4-Bromo-5-methyl-3-isoxazolyl)-1-naphthalenesulfonamide was prepared from 3-amino-4-bromo-5-methylisoxazole and 1-naphthalenesulfonyl chloride as described in Example 26 in 51% yield. Recrystallization from ethyl acetate/hexanes gave a crystalline solid, m.p. 167-170° C.