Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[C:21]([C:22]2[CH:23]=[N:24][N:25]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]=2)=[CH:20][CH:19]=[CH:18][N:17]=1>CN1CCCC1=O>[C:27]([N:25]1[CH:26]=[C:22]([C:21]2[C:16]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:23]=[N:24]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ncccc2-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
In 4 separate microwave vessels were added equal amounts of the following (total/4): dissolved 4-aminophenol (0.054 g, 0.498 mmol) in 1-methyl-2-pyrrolidinone (4.7 mL), added cesium carbonate (0.309 g, 0.948 mmol). Each mixture was stirred at 20° C. for 5 minutes, after which was added 2-chloro-3-(1-trityl-1H-pyrazol-4-yl)pyridine (0.200 g, 0.474 mmol) and heated to 200° C. in the microwave for 6 minutes. The solutions were combined and extracted into EtOAc, washed 1×H2O, 1×NaCl, dried with Mg2SO4, filtered through fritted funnel, and concentrated. The crude residue was purified by silica gel chromatography using 25-70% EtOAc/Hexanes. The product fraction were concentrated to yield 4-(3-(1-trityl-1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine as brown oil. MS m/z=495 [M+1]+. Calc'd for C33H26N4O: 494.59.
Reaction SMILES: C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C(C)=C1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C.[Si:41]([O:48][CH2:49][C@@H:50]1[CH:55]=[C:54]([CH2:56][CH2:57][N+:58]([O-:60])=[O:59])[C@H:53](O)[CH2:52][N:51]1[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].[CH2:69]([O:76][NH:77][S:78]([C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=1[N+:87]([O-:89])=[O:88])(=[O:80])=[O:79])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>>[CH2:69]([O:76][N:77]([C@H:53]1[CH2:52][N:51]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:50]([CH2:49][O:48][Si:41]([C:44]([CH3:47])([CH3:45])[CH3:46])([CH3:43])[CH3:42])[CH:55]=[C:54]1[CH2:56][CH2:57][N+:58]([O-:60])=[O:59])[S:78]([C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=1[N+:87]([O-:89])=[O:88])(=[O:80])=[O:79])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C(CC[N+](=O)[O-])=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Agent: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1CO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared as a pale yellow oil (5 g, 30%) according to the procedure described for Intermediate 80, from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-(2-nitroethyl)-5,6-dihydropyridine-1 (2H)-carboxylate (Intermediate 219, 6.73 g, 16.3 mmol) and N-(benzyloxy)-2-nitrobenzenesulfonamide (7.40 g, 24.00 mmol).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:32])[CH2:27][NH:28]CCO)[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:33][C:34]([C:36]2[NH:37][CH:38]=[C:39]([C:41]#[N:42])[N:40]=2)=[O:35])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[BH-](OC(C)=O)(OC(C)=O)[O:44][C:45]([CH3:47])=O.[Na+].C=O>CO>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:32])[C:27]([CH3:2])([NH2:28])[CH2:47][CH2:45][OH:44])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:33][C:34]([C:36]2[NH:37][CH:38]=[C:39]([C:41]#[N:42])[N:40]=2)=[O:35])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CNCCO)CC3)cc2C2=CCCCC2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CCO)C(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 113.8 %

Procedure:
A solution of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl}-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 44, step (c), 50.0 mg, 0.085 mmol) in MeOH (3 mL) was treated with Na(OAc)3BH (39.5 mg, 0.19 mmol) and 37% aqueous formaldehyde (8.2 μL, 0.10 mmol). The mixture was stirred at room temperature for 5.5 h, and the solvents were removed in vacuo. Reverse phase HPLC (C-18 column) (10% to 50% acetonitrile in water with 0.1% TFA over 30 min) afforded the title compound (19.5 mg, 47%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.12 (d, 1H, J=8.4 Hz), 8.02 (s, 1H), 7.19 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J=2.0 Hz), 5.84-5.79 (m, 1H), 4.72-4.64 (m, 1H), 4.39-4.23 (m, 2H), 3.84-3.79 (m, 1H), 3.31-3.21 (m, 1H), 3.03-2.94 (m, 6H), 2.92-2.80 (m, 2H), 2.32-2.24 (m, 4H), 2.00-1.90 (m, 2H), 1.90-1.76 (m, 5H), 1.78-1.59 (m, 2H). LC-MS (ESI, m/z): Calcd. for C22H34N6O3 491.3 (M+H). found 491.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Br:10])[N:5]=[C:4]([NH2:11])[CH:3]=1.[C:12](Cl)([CH3:14])=[O:13].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Br:10])[N:5]=[C:4]([NH:11][C:12](=[O:13])[CH3:14])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: N#Cc1c(N)cc(N)nc1Br
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(N)c(C#N)c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
4,6-Diamino-2-bromo-nicotinonitrile (100 mg, 0.47 mmol) was dissolved in 1.0 mL of anhydrous pyridine. AcCl (225 μL, 2.35 mmol) was dropped in slowly. The resulting mixture was shaken overnight at ambient temperature. Water (5 mL) was added to the mixture mixture. The resulting brown solid was collected through filtration, washed with cold water, and dried in a vacuum oven to provide the title compound (100 mg, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:31]O)[C:24]([CH3:33])=[C:23]1[CH3:34].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:31][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:30]=2[N:22]([CH3:21])[C:23]([CH3:34])=[C:24]3[CH3:33])[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1c(C)n(C)c2c(CO)cccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cccc3c(C)c(C)n(C)c23)c2ccccc21
Reaction time: 12 h
Yield: 49.7 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (100 mg, 0.36 mmol) in THF (10 mL) were added (1,2,3-Trimethyl-1H-indol-7-yl)-methanol (103 mg, 0.54 mmol), DIAD (diisoproyl azo-dicarboxylate) (0.14 mL, 0.7 mmol) and triphenylphosphine (95 mg, 0.36 mmol) at room temperature. The solution was stirred at the same temperatrue for 12 hours. The solution was filtered and the filtrate was concentrated. The residue was purified by combFlash with 10% EtOAc in Hexane as the eluent to afford the desirable product 3-[2-Oxo-3-(1,2,3-trimethyl-1H-indol-7-ylmethyl)-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (80 mg, 49%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1/[CH:23]=[CH:24]/[C:25]([NH:27][NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33](C#N)=[CH:32][CH:31]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(N(CC)CC)C.[Cl:70]CCl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9](/[CH:23]=[CH:24]/[C:25]2[O:38][C:29]([C:30]3[CH:31]=[CH:32][C:33]([Cl:70])=[CH:34][CH:35]=3)=[N:28][N:27]=2)=[N:10][N:11]=[C:12]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=1
Reactant: ClCCl
Reactant: CS(=O)(=O)c1ccc(-c2nnc(/C=C/C(=O)NNC(=O)c3ccc(C#N)cc3)n2-c2ccccc2Cl)nc1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2nnc(/C=C/c3nnc(-c4ccc(Cl)cc4)o3)n2-c2ccccc2Cl)nc1
Reaction time: 2 h

Procedure:
4-chloro-N′-[(E)-3-[4-(2-chlorophenyl)-5-(5-methylsulfonyl-2-pyridyl)-1,2,4-triazol-3-yl]prop-2-enoyl]benzohydrazide 10 was dissolved into dichloromethane (10 mL) and triphenyl phosphine (0.27 g, 1.0 mmol), carbon tetrabromide (0.34 g, 1.04 mmol) and triethylamine (0.18 mL, 1.30 mmol) was added. The reaction was kept at room temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1:3) to give 2-(4-(2-chlorophenyl)-5-((E)-2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)-5-(methylsulfonyl)pyridine as a yellow solid. Yield: 0.03 g, 11%.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([CH3:28])[N:23]=[C:22]2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.[ClH:32]>>[ClH:32].[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([CH3:28])[N:23]=[C:22]2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=1)([OH:7])=[O:5]
Reactant: CCCc1nc(C)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CCCc1nc(C)c(CO)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A solution of 3.32 g of 1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-5-hydroxymethyl-4-methyl-2-propylimidazole in 100 mL of 10% aqueous hydrochloride acid was stirred at 25° C. for 16 hours. The solvent and excess hydrochloric acid then were removed under vacuum to provide 2.22 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-5-hydroxymethyl-4-methyl-2-propylimidazole.hydrochloride (mp 208°-210° C. (dec.)).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:21]([CH3:22])[CH2:20][CH2:19][C@@:15]4([C:16]=2[C:17]=1[OH:18])[C@@:10]3([O:24][CH3:25])[CH2:11][CH2:12][C:13](=[O:23])[CH2:14]4.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:21]([CH3:22])[CH2:20][CH2:19][C@@:15]4([C:16]=2[C:17]=1[O:18][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@:10]3([O:24][CH3:25])[CH2:11][CH2:12][C:13](=[O:23])[CH2:14]4
Reactant: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3
Reactant: Brc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2c(c1Oc1ccccc1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3
Yield: 59.2 %

Procedure:
To a solution of crude 16 (16 g) in dry pyridine (200 ml) was added bromobenzene (22.5 g, 143.29 mmol) and 18 g (159.178 mmol) of K2CO3 (freshly dried at 110° C. for 2 hour in a vacuum oven and quickly ground and sieved to 200 mesh). More pyridine (20 ml) followed by copper powder (1.5 g, 10 micron) was added and the mixture was refluxed (oil bath temp 140°-150° C.) for 20 hr under a N2 atmosphere with stirring. The solution was filtered hot, and the residue washed with hot pyridine. The filtrate was concentrated under reduced pressure to give crude 17 (10.5 g) as a foamy solid. The product was purified by chromatography on silia gel using graded methanol/chloroform to give 7.83 g (80% yield from 15) of 17 as a foamy solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:9]=[N:8][NH:7][C:6]=1[NH2:10])([O-:4])=[O:3].[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[N+:2]([C:5]1[CH:9]=[N:8][N:7]2[C:11]([OH:16])=[CH:12][C:13]([CH3:15])=[N:10][C:6]=12)([O-:4])=[O:3]
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(O)n2ncc([N+](=O)[O-])c2n1
Yield: 84.8 %

Procedure:
50 g of 4-nitro-2H-pyrazol-3-ylamine hydrochloride (prepared according to H. Dorn and H. Dilcher, Liebigs Ann. Chem., 707, 141, 1967) and 60 g of ethyl acetoacetate in 160 cc of acetic acid were introduced into a 500 cc three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer and a condenser. The reaction medium was refluxed for 12 h. The precipitate formed was filtered off at about 90° C. It was rinsed with diisopropyl ether and dried under vacuum over phosphorus pentoxide. 50 g of 3-nitro-5-methylpyrazolo[1,5-a]pyrimidin-7-ol were obtained in the form of yellow crystals. (Yield=84.5%; melting point=290° C. with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][CH:9]=1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:10][C:11](=[O:13])[CH3:12])=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CSCC1OC(C)=O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cscc1OC(C)=O
Yield: 91 %

Procedure:
4.04 parts of 3-acetoxy-dihydrothiophene-4-carboxylic acid methyl ester are reacted with 1.76 parts by volume of sulfuryl chloride in 50 parts by volume of chloroform in the course of one hour at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 3.64 parts (91% of theory) of 3-acetoxy-thiophene-4-carboxylic acid methyl ester of melting point 56°-58° C. are obtained.
Reaction SMILES: [Mg].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.C(Cl)(=O)C(Cl)=O.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([CH3:28])=[CH:23][C:19]=1C(O)=O>O1CCCC1.CN(C)C=O.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(O)C>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([CH3:28])=[CH:23][C:19]=1[C:4]([CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1cc(C(=O)O)c(Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)c1cc(C)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Magnesium (110 mg), ethanol (2 ml) and carbon tetrachloride (0.2 ml) were stirred at room temperature to activate them. A solution of ethyl malonate (0.7 ml) in tetrahydrofuran (6 ml) was added dropwise to the activated mixture, followed by stirring at 80° C. for 4 hours. After the reaction mixture was allowed to cool, it was chilled to -40° C. Oxalyl chloride (0.4 ml) and N,N-dimethylformamide (1 drop) were added to a solution of 2-chloro-4-fluoro-5-methylbenzoic acid (800 mg) in methylene chloride (2 ml). The mixture was stirred at room temperature for 3.5 hours, and the solvent and the like were distilled off. Toluene was added to the residue to conduct azeotropic distillation. The resultant residue was dissolved in tetrahydrofuran (5 ml), and the solution was added dropwise at -40° C. to the reaction mixture obtained previously. After the addition, the temperature of the reaction mixture was given back to room temperature to conduct stirring overnight. The solvent was distilled off, and 12N hydrochloric acid (1 ml) was added to the resultant residue to keep its pH at about 2. The residue was then extracted with chloroform, and the solvent was distilled off. Water (10 ml) and p-toluenesulfonic acid monohydrate (50 mg) were added to the resultant residue, and the mixture was stirred for 4 hours while heating under reflux. After the reaction mixture was allowed to cool, it was extracted with chloroform. An organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (1.0 g) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]1([S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:27](/[S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:26])\[C:28]#[N:29])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: N#CCS(=O)(=O)c1ccccc1
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
M33 was prepared with 3,5-di-t-butyl-4-hydroxybenzaldehyde and phenylsulfonly acetonitrile under similar conditions as decribed for M26.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:14]=1[O:21]C.Cl.N1C=CC=CC=1>Cl>[OH:9][C:6]1[CH:7]=[CH:8][C:3]2[O:23][C:12]([C:13]3[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=3[OH:21])=[N:11][C:4]=2[CH:5]=1
Reactant: COc1ccc(OC)c(NC(=O)c2cc(OC)ccc2OC)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(O)c(-c2nc3cc(O)ccc3o2)c1
Temperature: 200 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
A mixture of N-(2,5-dimethoxyphenyl)-2,5-dimethoxybenzamide (1.0 g, 3.1 mmol) and pyridine hydrochloride (2.0 g, 17.3 mmol) was stirred at 200° C. for 1 h. The mixture was cooled to room temperature and HCl (10 mL, 2 N) was added. The mixture was then extracted with EtOAc and the organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 2/1) gave a white solid (0.8 g, 76% yield, m.p. 309-311° C.); MS m/e 242 (M−H)+.
Reaction SMILES: C=O.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([F:25])=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:11])[CH:9]=1.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([F:25])=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:26])[CH2:14][C@@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:11])[CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(c1cc(Br)ccc1F)N1CCNC[C@@H]1c1ccc(F)cc1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(C(=O)c2cc(Br)ccc2F)[C@@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Formaldehyde (1.47 mL, 19.4 mmol of 37% aqueous solution) was added to (5-Bromo-2-fluoro-phenyl)-[(S)-2-(4-fluoro-phenyl)-piperazin-1-yl]-methanone (0.32 g, 0.65 mmol) in 10 mL of methanol. The mixture was stirred at ambient temperature for 1 h and then sodium triacetoxyborohydride (0.82 g, 3.9 mmol) was added and the resulting mixture was stirred overnight. The volatiles were removed in vacuo, and the residue was portioned between ethyl acetate and 1M sodium bicarbonate solution. The organic phase was washed with 1M sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to leave 0.21 g of product. LC/MS: Retention time, 2.14 min; (M+H)=395/397.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7](=[O:20])[CH:8]=[C:9]2[C:13]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=3[S:11][C:10]=12)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:21]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[C:7](=[O:20])[CH2:8][C:9]1[C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:5](=[O:6])[C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCNCCCC
Reactant: COc1ccc2sc3c(C(C)(C)C)oc(=O)cc3c2c1
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)Cc1c(C(=O)C(C)(C)C)sc2ccc(OC)cc12

Procedure:
A solution of 21.6 mg of 1-tert-butyl-6-methoxy-3H-[1]benzothieno[2,3-c]pyran-3-one from the Step D above and 29.1 mg di-n-butyl amine in 0.75 mL anhydrous DMF was heated at 70° C. for six hours. The reaction mixture was purified on RP-HPLC using 70˜100% MeCN gradient with 0.1% TFA. The product fractions were pooled and lyophilized to give the title compound as a white solid. LC-MS: 4.53 min. (m/Z=418.3, 440.2).
Reaction SMILES: [NH3:1].CS([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]3[CH:30]=[N:29][NH:28][C:15]3=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:9]=[CH:8][N:7]=1)(=O)=O>C1COCC1>[NH2:1][C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]3[CH:30]=[N:29][NH:28][C:15]3=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:9]=[CH:8][N:7]=1
Reactant: N
Reactant: CS(=O)(=O)c1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Solvent: C1CCOC1
Product: Nc1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
A solution of THF (20 mL) saturated with NH3 (g) at −20° C. was added over 5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (90 mg, 0.2 mmol, obtained in example 127) in a closed vessel. It was stirred at room temperature for 2 days and concentrated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 7 mg of the title compound (yield: 9%)
Reaction SMILES: OCCNCCN.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.ClC1N=NC(C2C=CC=CC=2)=CC=1C.Cl[C:32]1[N:33]=[N:34][C:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][C:37]=1[CH3:38]>>[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:32]2[N:33]=[N:34][C:35]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:36][C:37]=2[CH3:38])[CH2:10][CH2:9]1
Reactant: COc1ccc(-c2cc(C)c(Cl)nn2)cc1
Reactant: NCCN1CCOCC1
Agent: Cc1cc(-c2ccccc2)nnc1Cl
Solvent: NCCNCCO
Product: COc1ccc(-c2cc(C)c(NCCN3CCOCC3)nn2)cc1

Procedure:
Operation is carried out as in Example 1, replacing the N-(2-hydroxy ethyl) ethylenediamine by an equivalent quantity of 2-morpholino ethylamine and the 3-chloro 4-methyl 6-phenyl pyridazine by a corresponding quantity of 3-chloro 4-methyl 6-(4-methoxy phenyl) pyridazine.
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=O)=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].[NH2:34][CH2:35][CH2:36][OH:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:37][CH2:36][CH2:35][NH:34][C:30]([C:26]1[CH:25]=[C:24]2[C:4]3([CH2:5][CH2:6][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])[CH2:8][CH2:9]3)[C:3](=[O:33])[N:2]([CH3:1])[C:29]2=[CH:28][CH:27]=1)=[O:32]
Reactant: NCCO
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)NCCO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
To a solution of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (20 mg, 0.04 mmol) in anhydrous CH2Cl2 (5 mL) was added 2-aminoethanol (3.6 mg, 0.06 mmol), HOBt (12 mg, 0.09 mmol), EDCI (18 mg, 0.09 mmol) and DIEA (28 mg, 0.22 mol) at 0° C. and the mixture was stirred overnight at rt under N2. The reaction mixture was washed with 1 N aq HCl and water. The organic phase was dried over Na2SO4, filtered and concentrated to afford a residue, which was purified by prep TLC to give (E)-N-(2-hydroxyethyl)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide (8 mg, 40%). 1H NMR (CD3OD): 1.90 (m, 4H), 3.25 (s, 3H), 3.50 (m, 2H), 3.70 (m, 2H), 3.98 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H), 7.53 (m, 1H), 7.68 (m, 1H), 7.75 (m, 1H), 7.90 (m, 2H), 8.00 (m, 2H).