Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=2[O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: Nc1nccc(Oc2ccccc2Br)n1
Product: Nc1nccc(Oc2ccccc2-c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)n1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 4-(2-bromophenoxy)pyrimidin-2-amine. MS (ESI): mass calcd. for C23H16FN5O, 397.13; m/z found, 398.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.55-8.45 (m, 1H), 8.18-8.08 (m, 1H), 8.07 (d, J=5.7, 1H), 7.55-7.28 (m, 8H), 7.22 (dd, J=8.0, 1.4, 1H), 6.08 (d, J=5.7, 1H), 4.95 (s, 2H).
Reaction SMILES: [P:1]([O:19][CH2:20][CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[CH2:39][NH:40][C:41]([NH:43][C:44]3[N:48]([C:49]4[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=4)[N:47]=[C:46]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:45]=3)=[O:42])=[CH:28][CH:29]=2)[CH:24]=[N:23]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].C1CC=CCC=1>CCO.CO.[Pd]>[P:1]([O:19][CH2:20][CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[CH2:39][NH:40][C:41]([NH:43][C:44]3[N:48]([C:49]4[CH:50]=[CH:51][C:52]([CH3:55])=[CH:53][CH:54]=4)[N:47]=[C:46]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:45]=3)=[O:42])=[CH:28][CH:29]=2)[CH:24]=[N:23]1)([OH:11])([OH:3])=[O:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCOP(=O)(OCc3ccccc3)OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCOP(=O)(O)O)c2)cc1
Yield: 80.9 %

Procedure:
Dibenzyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethyl phosphate (1.920 g, 2.35 mmol) was suspended in EtOH (0.05M, 50 mL) and cyclohexa-1,4-diene (3.56 ml, 82.14 mmol) and 10% Pd/C (20%/weight, 0.384 g) were added. The reaction mixture was refluxed overnight. The reaction mixture was filtered through GF paper and washed with MeOH. The organic layers were concentrated under reduced pressure to afford the crude material, which was dissolved in MeOH and passed through a Gellman acrodisk (0.45 um) filter to remove trace of palladium contamination. After evaporation of the solvent, the resulting gum was triturated in CH3CN and solids formed were collected by filtration and dried under high vacuum for 3 hours to provide 1.21 g (89%) of the desired compound. MS (APCI+) m/z 637 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.00 (s, 1H), 7.71 (d, 1H, J=9 Hz), 6.88-7.37 (m, 10H), 6.24 (s, 1H), 4.61 (br, 1H), 4.28 (d, 2H, J=5.7 Hz), 4.19 (dd, 2H, J=5.2 Hz), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:20]([OH:26])([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:21]1)=[O:5]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccc(F)c3F)C2)c1

Procedure:
The compound of Example 4 was prepared according to the general preparation protocol A from 2,3-difluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([N:35]5[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]5)=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: CS(=O)(=O)N1CCNCC1
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to 1-methanesulfonylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 55 mg of 125. MS (Q1) 528.1 (M)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:25]3[CH2:27][CH2:26]3)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1nn(-c2ccc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(C3CC3)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 100 °C
Yield: 46.4 %

Procedure:
To a mixture of (1aR,5aR)-2-(5-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.030 g, 0.077 mmol), cyclopropylboronic acid (0.020 g, 0.230 mmol), potassium phosphate (0.049 g, 0.230 mmol) and tricyclohexylphosphine (4.30 mg, 0.015 mmol) in toluene/H2O (1.5 mL/0.050 mL) under nitrogen atmosphere, palladium (II) acetate (1.721 mg, 7.67 μmole was added and the reaction mixture was heated at 100° C. for 2 hours in a heavy walled sealed tube under microwave irradiation. The reaction mixture was concentrated and the product was purified by preparative HPLC twice. The corresponding fractions were collected and lyophilized to provide the title compound (12.6 mg) as a white solid. LCMS m/z=353.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)[C:5]([C:27]#[N:28])=[C:4]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37](=[O:40])[NH:38][CH3:39])[CH:32]=2)[N:3]=1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:1][C:2]1[N:3]=[C:4]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH:38][CH3:39])=[O:40])[CH:32]=2)[C:5]([C:27]#[N:28])=[C:6]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH2:17])=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(OCCNC(=O)OC(C)(C)C)cc3)c2C#N)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(OCCN)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
413 mg (0.74 mmol) of tert-butyl (2-{4-[2-amino-3,5-dicyano-6-({[2-(methylcarbamoyl)pyridin-4-yl]methyl}sulfanyl)pyridin-4-yl]phenoxy}ethyl)carbamate (Example 45A) were dissolved in 4.3 ml of dichloromethane. After addition of 4.2 g (6.88 mmol) of trifluoroacetic acid, the mixture was stirred at RT for 2.5 h. The reaction mixture was evaporated. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1CCCC1.[C:12]([C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)#N.[OH-].[Na+]>O>[CH:12]([C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)=[O:7]
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: O=CC1(c2ccccc2)CCC(=O)CC1
Yield: 96.7 %

Procedure:
To a well stirred suspension of 2.74 g. (0.072 mole) of lithium aluminum hydride in 170 ml. of tetrahydrofuran, a solution of 34.8 g. (0.143 mole) of 4-cyano-4-phenylcyclohexanone, ethylene ketal in 1700 ml. of tetrahydrofuran is added in a period of about 20 minutes. The mixture is stirred at room temperature for about 1.75 hours, then cooled in an icebath and treated successively with 2.8 ml. of water, 2.8 ml. of 15% sodium hydroxide solution and 8.2 ml. of water. The resulting inorganic gel is collected on a filter and rinsed with ether. The combined filtrates are then evaporated to dryness. A solution of the residue in 525 ml. of tetrahydrofuran and 52.5 ml. of 2.5 N hydrochloric acid is stirred at room temperature for about 15 minutes, treated with 17 g. of sodium bicarbonate solution and then evaporated to dryness. Ether is added to the residue and the organic layer evaporated to dryness to yield 34.07 g. (96.7% yield) of crude 4-formyl-4-phenylcyclohexanone, ethylene ketal, having a melting point of 51° to 66°C. Its infrared (IR) and NMR confirm its expected structure.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:34][C@H:35]1[C@@H:40]([OH:41])[CH2:39][CH2:38][N:37]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:36]1.[N+:52]([C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=O)=[CH:57][CH:56]=1)([O-:54])=[O:53]>C1COCC1>[F:34][C@H:35]1[C@H:40]([O:41][CH2:59][C:58]2[CH:62]=[CH:63][C:55]([N+:52]([O-:54])=[O:53])=[CH:56][CH:57]=2)[CH2:39][CH2:38][N:37]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:36]1
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@@H](OCc2ccc([N+](=O)[O-])cc2)[C@H](F)C1
Temperature: 0 °C

Procedure:
To a solution of triphenylphosphine (120.1 g, 0.458 mol) in THF (2 L) was added DIAD (92.6 g, 0.458 mol) with stirring under nitrogen at 0° C. The resulting suspension was stirred for 40 min, and then a solution of benzyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate (58 g, 0.229 mol) and 4-nitrobenzoic acid (45.9 g, 0.275 mol) in THF was added slowly over 1.5 h. The resulting orange solution was allowed to warm to room temperature and stirred for 48 h. The mixture was concentrated under reduced pressure to a crude oil was purified by column chromatography (EtOAc:petroleum ether=1:40) to afford benzyl trans-3-fluoro-4-[(4-nitrobenzyl)oxy]piperidine-1-carboxylate as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17]([CH3:19])=O)[CH3:13]>C(O)C>[NH2:1][C:2]1[C:3]2[N:4]([C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:21])=[C:17]([CH3:19])[N:11]=2)[CH:5]=[C:6]([C:7]([NH2:9])=[O:8])[CH:10]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=O)c1cnc(N)c(N)c1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(N)cc(C(N)=O)cn12
Yield: 12 %

Procedure:
5,6-Diaminonicotinamide (2.0 g, 13.4 mmol), ethyl-2-chloroacetoacetate (2.38 g, 14.4 mmol) and ethanol (40 ml) were refluxed for 20 h. The precipitate was isolated by filtration and washed with ethanol and diethyl ether. The solids were suspended in water, basified with a sodium hydroxide solution and isolated by filtration. Washing the solids with water and diethyl ether gave 0.42 g (12%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])(=[O:15])=[O:14]>N1C=CC=CC=1>[I:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:13]([CH3:12])(=[O:15])=[O:14])(=[O:24])=[O:23])[CH:3]=2)[NH:7][N:6]=1
Reactant: Nc1ccc2[nH]nc(I)c2c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(I)c2c1
Yield: 82.4 %

Procedure:
N-(3-Iodo-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 25.7 g of 5-amino-3-iodo-1H-indazole, 440 ml of pyridine and 25.3 g of 2-(methylsulfonyl)benzenesulfonyl chloride. 39 g of N-(3-iodo-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a brown solid (mass analysis: Cl: m/z 478 (M+H)+, m/z 495 (M+NH4)+, m/z 260 (base peak)).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH3:31])[C:15]1=[O:32])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH3:31])[C:15]1=[O:32])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1N=C(c2ccccn2)c2ccccc2N(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)NC1N=C(c2ccccn2)c2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A solution of 3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (3.42 g, 7.82 mmol) in CH2Cl2 (90 mL) was cooled in an ice bath and treated with TFA (13.2 mL, 172 mmol). The cold bath was removed and the solution stirred at room temperature for four hours. The reaction mixture was washed with 1 M aq. K2CO3 and the aqueous back-extracted with CH2Cl2. The combined extracts were washed with H2O, dried (MgSO4) and concentrated to obtain 1.75 g (66% yield) of the title compound as an off-white foam. MS (IS+) 338 (m/e).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].Br[CH2:13][CH:14]1[CH2:16][O:15]1>CN(C=O)C>[O:15]1[CH2:16][CH:14]1[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC2CO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (2.0 g, 16.38 mmol) in DMF (30 mL) at 0° C. was added NaH (983 mg, 24.57 mmol) in portions. After 0.5 h, a solution of 2-(bromomethyl)oxirane (2.69 mg, 19.65 mmol) in DMF (5 mL) was added and the reaction mixture was warmed to room temperature for 5 h. The mixture was concentrated, dissolved in ethyl acetate and washed with water. The organic portion was dried over sodium sulfate, filtered and concentrated. The crude product was used in the next step without further purification. (2.1 g, yield 72%) MS (ESI+) e/z: 179.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[C:6]([CH2:17]Br)[O:5][N:4]=1.[Cl:19][Sn]Cl>CO.Cl>[CH3:1][O:2][C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])=[C:6]([CH2:17][Cl:19])[O:5][N:4]=1
Reactant: Cl[Sn]Cl
Reactant: COc1noc(CBr)c1-c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: COc1noc(CCl)c1-c1ccccc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 744.9 %

Procedure:
To a solution of 12 (0.3 g, 0.9 mmole) in MeOH (7ml) was added carefully a solution of SnCl2 2 H2O (0.72 g, 3.2 mmoles) in concentrated HCl (1 ml). The mixture was stirred at 80° C. for 21/2 hours and the solvent was evaporated. The residue was dissolved in an ice cooled solution of sodium hydroxyde (20 ml, 10N) and extracted with CHCl2. The combined organic extracts were dried, filtered and evaporated to give TLC pure 13 (1.6 g, 95%) as a yellow oil. CC (silica gel: 30 g; eluent: CH2Cl2) afforded 13 (1.55 g, 93) a TLC pure substance. 1H NMR 60 MHz (CDCl3) δ=3.75 (2H, broad s, exchangeable D20) 3.95 (3H, s) 4.4 (2H, s) 6.6-7.3 (4H, m). Mass spectrum, m/z -238/240 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH3:38])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH3:38])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (660 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (3 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (510 mg, yield: 82%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 122–123° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[NH:18][CH2:19][CH2:20][CH:21]=1.[CH2:24](Br)[CH:25]=[CH2:26]>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[N:18]([CH2:26][CH:25]=[CH2:24])[CH2:19][CH2:20][CH:21]=1
Reactant: COC(=O)CCC1=CCCNC1=O
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1CCC=C(CCC(=O)OC)C1=O
Temperature: -79 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
0.220 ml of NaHMDS solution (1.0 M in THF, 0.22 mM) was added to 0.5 ml of the THF solution containing 40 mg of 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (0.218 mM) prepared by the Step 1 in a dropwise manner at −79° C. and stirred at −79° C. for 30 mins. After 0.028 ml of allyl bromide (0.327 mM) was added to the reaction mixture, the mixture was stirred at 0° C. for 3 hrs. The reaction mixture was quenched by 2 ml of sat. NH4Cl solution and then the organic layer was extracted with 7 ml of ethyl acetate. The combined organic layer was washed with 2 ml of sat. NH4Cl solution and 2 ml of sat. NaCl solution. Then the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with EtOAc/hexane (1:2) solvent mixture as an eluant to give 36 mg of the title compound (I 1) (yield: 74%).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.O.[NH2:12][NH2:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH3:10][C:8]1[N:9]=[C:2]2[NH:12][N:13]=[CH:4][C:3]2=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)c(Cl)n1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: Cc1ccc2cn[nH]c2n1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
to a mixture of 2-chloro-6-methylnicotinaldehyde (5.0 g) and hydrazine monohydrate (6.24 mL) was added para-toluenesulfonic acid monohydrate (3.67 g), and the mixture was stirred at 130° C. for 18 hours. The reaction solution was cooled, and then thereto was added 10% aqueous citric acid solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give 6-methyl-1H-pyrazolo[3,4-b]pyridine [REx(104-1)] (3.61 g) as a brown powder.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.Br[CH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25].O>CN(C)C=O>[CH3:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[N:8]=[C:7]([S:9][CH2:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[NH:6][C:5]=2[CH:10]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc2nc(SCc3ccccc3C#N)[nH]c2cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To 5,6-dimethylbenzimidazole-2-thiol (713 mg, 4 mmol) in dimethylformamide (10 ml), triethylamine (836 μl, 6 mmol) and 2-bromomethylbenzonitrile (1176 mg, 6 mmol) were added. After stirring at 80° C. overnight, water was added to the mixture, followed by extraction with ethyl acetate. After the ethyl acetate phase was dried with anhydrous sodium sulfate, it was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain 2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzenecarbonitrile (1159 mg, yield 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]([CH3:25])[C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1)[C:5]#[N:6].[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][CH:30]=1.O=P(Cl)(Cl)Cl.Cl>O.C1(C)C=CC=CC=1>[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33]2[C:20]3=[CH:19][C:18]4[C:17]([CH3:21])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=4[CH:12]=[C:11]3[N:10]([CH3:25])[C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[N:1]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C#N)cc1N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(C2=Nc3cc(C#N)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-amino-4-[methyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzonitrile (32) (R4=CH3, 30.0 mmol), terephthalic acid monomethyl ester (30.0 mmol), POCl3 (69.0 mmol), and toluene (200 mL) is heated at 80° C. for 3 days. After cooling, the reaction mixture is treated with 1 N HCl (100 mL) and H2O (100 mL) and extracted with EtOAc. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by flash column chromatography (hexane:EtOAc=5:1) to give (33) (R4=CH3, Z=H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[N:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-])=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[NH2:17][C:10]1[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:7]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(-n2cnnn2)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-n2cnnn2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Yield: 51.5 %

Procedure:
A mixture of 0.36 g of 3,4-diethoxycarbonyl-5-nitro-6-phenyl-2-(tetrazol-1-yl)pyridine, 0.3 g of 10% Pd-C (50% wet) and 30 ml of ethyl acetate was stirred at room temperature for 2 hours in a stream of hydrogen. After the catalyst was filtered off, the reaction mixture was subjected to silica gel column chromatography with chloroform as the eluent, to give 0.172 g of the title compound.