Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:18]/[C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc[nH]1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: NC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 34 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (30 mg, 0.17 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). Pyrrole-2-carboxaldehyde (16 mg, 0.18 mmol) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (10 ml) and the precipitated solid was collected by filtration and washed with water to give 15 mg of (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxamide as a yellow/brown solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:5]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:7][C:8]=1[C:9]([O:11]CC)=[O:10].Cl.C(O)(=O)C>O.C(O)C>[CH3:3][C:4]1[N:5]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1sc(-c2cccnc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2cccnc2)sc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of sodium hydroxide (22 g. 0.55 mole) in water (300 ml.) was mixed with a solution of ethyl 4-methyl-2-(3-pyridyl)-5-thiazolecarboxylate (124 g., 0.50 mole) in 95% ethanol (150 ml.). The mixture was heated and stirred for about ten minutes on a steam bath, and then allowed to stand for one hour without further heating. When the ice-cooled reaction mixture was neutralized with dilute hydrochloric acid and acidified with acetic acid, a thick precipitate of finely divided white solid was obtained. The solid was collected by filtration, washed thoroughly with water, and dried in an oven at 110° C. The product (106 g., 96% yield) melted with decomposition at 249°-250° C.
Reaction SMILES: [O-2].[Cd+2:2].[C:3]([OH:6])(=[O:5])[CH3:4]>>[C:3]([O-:6])(=[O:5])[CH3:4].[Cd+2:2].[C:3]([O-:6])(=[O:5])[CH3:4]
Reactant: CC(=O)O
Agent: [Cd+2]
Agent: [O-2]
Product: CC(=O)[O-]
Temperature: 90 °C

Procedure:
Cadmium oxide (0.127 g, 1 mmol) and acetic acid (0.500 g) were reacted at 220° C. for 10 min, cooled to 90° C., then a cadmium acetate (precursor) was formed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[CH2:17][C:18]([OH:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:25])[CH2:12][C:11]1=[O:26]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:17][C:18]([OH:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:25])[CH2:12][C:11]1=[O:26]
Reactant: CCCCC(C)(O)C/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC
Agent: [Pd]
Solvent: CCO
Product: CCCCC(C)(O)CCC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC
Reaction time: 0.4 h
Yield: 85.5 %

Procedure:
(±) methyl-11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate (100 mg) in 15 ml of ethanol containing 100 mg of 4% palladium on carbon is hydrogenated at room temperature and atmospheric pressure for 24 minutes. The solution is filtered and evaporated. The residue is chromatographed on silica gel (60% ethyl acetate/40% hexane as eluent) to give 86 mg of desired product as a viscous oil. 1H NMR (CDCl3): ∂0.93 (t, C.20 CH3); 1.18 (d, C.16 CH3 ; 3.68 (s, OCH3); 4.17 (q C.11 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: OB(O)c1ccccc1F
Product: COc1ccc2c(-c3ccccc3F)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-5,6-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 379(MH+).
Reaction SMILES: C1C2C(COC([NH:18][CH:19]([CH:43]3[CH2:48][CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44]3)[CH2:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]4[N:33]([CH2:34][CH2:35][CH2:36][O:37][CH3:38])[C:32]5[CH:39]=[CH:40][CH:41]=[CH:42][C:31]=5[N:30]=4)[CH2:24]3)=[O:22])=O)C3C(=CC=CC=3)C=2C=CC=1.FC(F)(F)C(O)=O.N1CCCCC1>C(Cl)Cl.CN(C=O)C.CC#N.O>[NH2:18][CH:19]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]2[N:33]([CH2:34][CH2:35][CH2:36][O:37][CH3:38])[C:32]3[CH:39]=[CH:40][CH:41]=[CH:42][C:31]=3[N:30]=2)[CH2:24]1)=[O:22]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)CC(NC(=O)OCC3c4ccccc4-c4ccccc43)C3CCN(C(=O)OC(C)(C)C)CC3)C2)nc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c([C@@H]2CCCN(C(=O)CC(N)C3CCNCC3)C2)nc2ccccc21
Yield: 60 %

Procedure:
Compound 28A (0.293 mmol max, crude oil) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen and dissolved in CH2Cl2(2 mL). Trifluoroacetic acid (2 mL) was then added and the solution was stirred at room temperature for 2 hr. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in DMF (3 mL) and piperidine (0.500 mL) and allowed to stir at room temperature for 3 hr. This reaction solution was then directly purified by preparative LC/MS (5-50% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford 3-amino-1-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-3-(piperidin-4-yl)propan-1-one (94) as its bis-trifluoroacetic acid salt and as a clear oil (0.176 mmol, 0.118 g, 60% yield over 3-steps). ESI-MS: m/z 428.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6].[CH2:20]([CH2:22][NH2:23])[OH:21]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH:23][CH2:22][CH2:20][OH:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6]
Reactant: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1O
Reactant: NCCO
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2ccc(NCCO)c(Cl)c2)cc1O
Temperature: 140 °C

Procedure:
A solution of 3-chloro-4-fluoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (1.0 g, 3.58 mmol, from above) in dimethylsulfoxide (5.0 mL) was treated with ethanolamine (10.0 mL) (Aldrich) and heated at 140° C. for 50 minutes in a microwave reactor. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous phase was acidified with 2N hydrochloric acid. The precipitate was filtered, washed with water and dried. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The two solid samples were combined and dried to give 3-chloro-4-(2-hydroxy-ethylamino)-N-(3-hydroxy-4-methyl-phenyl)-benzamide. (Yield 1.13 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][N:35]([CH2:37][CH2:38][CH2:39]Cl)[CH3:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>CN(C)C=O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][N:35]([CH2:37][CH2:38][CH2:39][O:16][C:13]2[CH:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:15][N:14]=2)[CH3:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Reactant: COc1ccc(C2CC(=O)NN2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Temperature: 100 °C
Yield: 64 %

Procedure:
17 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one were dissolved in 200 ml of dimethylformamide. 11 g of potassium carbonate were added to the solution and the reaction mixture was heated at 100° C. under a nitrogen atmosphere for 0.5 hours. A solution of 21 g of 3-[N-(2-(3,4-di-methoxyphenyl)-ethyl)-N-methylamino]-propylchloride in 150 ml of dimethylformamide was then added dropwise. After 2 hours the salts which formed were filtered out, the filtrate was evaporated to dryness, and the residue was dissolved in ethyl acetate. The solution was subsequently washed with 7% strength aqueous sodium hydroxide solution in order to remove unreacted 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one, dried with sodium sulfate and evaporated to dryness. The residue which remained was 35 g of oily crude product. This product was purified by chromatography over finely particulate silica gel under slightly elevated pressure (flash chromatography) using tert-butyl methyl ether/methanol 10:1 as eluent. 22.3 g of the title compound were obtained as an oil. IR spectrum of the base (as film): 1513 cm-1, 1260 cm-1, 1236 cm-1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[CH:24][CH:25]=2)=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CCOc1cc(CC(=O)OC)c(CC)c(OCC=C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(O)cc2)c(CC(=O)OC)c1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
Methyl 3,5-diallyloxy-2-ethylphenylacetate (1.0 g, 3.3 mmol) obtained in Example 5, Step 3 was dissolved in trifluoroacetic acid (9.0 mL), and 4-hydroxybenzoic acid (1.4 g, 10 mmol) and trifluoroacetic anhydride (1.2 mL) were added thereto, followed by stirring at room temperature for 20 hours. To the mixture were further added 4-hydroxybenzoic acid (0.92 g, 6.6 mmol) and trifluoroacetic anhydride (1.4 mL), followed by stirring for 6 hours. The reaction mixture was added dropwise to a saturated aqueous solution of sodium hydrogencarbonate (0.10 L), and the resulting mixture was extracted with ethyl acetate (50 mL×4). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in a 7 mol/L solution of ammonia in methanol (100 mL), followed by stirring at room temperature for 1 day. After the reaction mixture was concentrated under reduced pressure, 3 mol/L hydrochloric acid (40 mL) was added thereto, followed by extraction with ethyl acetate (50 mL×3). The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/10-1/2) to obtain methyl 3,5-diallyloxy-2-ethyl-6-(4-hydroxybenzoyl)phenylacetate (0.84 g, 57%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>>[N:23]1([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with azetidine (1.2 equiv) to give 157 (15.9 mg, M+1 353.0)
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[N:20]=[C:19](Cl)[C:18]([CH3:22])=[C:17]([CH3:23])[N:16]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[NH2:14][C:15]1[N:20]=[C:19]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:18]([CH3:22])=[C:17]([CH3:23])[N:16]=1
Reactant: Cc1nc(N)nc(Cl)c1C
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1nc(N)nc(-c2cccc3ccccc23)c1C
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A stirred heterogeneous solution of 1-naphthyl boronic acid (0.382 g), 2-amino-4-chloro-5,6-dimethylpyrimidine (0.350 g), tetrakis(triphenylphosphine)palladium(0) (0.153 g), ethyl alcohol (8 mL), water (4 mL), 1,2-dimethoxyethane (8 mL) and sodium carbonate (0.85 g), was heated to reflux (about 80° to 90° C.) for 14 hours. The solution was then cooled to room temperature, filtered and extracted with ethyl acetate. The solvent was removed under reduced pressure and the resultant yellow solid was recrystallized to give 2-amino-5,6-dimethyl-4-(naphth-1-yl)-pyrimidine (0.213 g), m.p. 213.5°-215.1° C.
Reaction SMILES: [O:1]=[C:2]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].S(O)(O)(=O)=O.[NH2:18]O.C(=O)([O-])O.[Na+].Cl>CO.O>[F:12][C:9]([F:10])([F:11])[C:6]1([C:2]2[O:1][N:5]=[C:4]([NH2:18])[CH:3]=2)[CH2:8][CH2:7]1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1cc(C2(C(F)(F)F)CC2)on1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
A mixture of 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (1 g, 5.65 mmol) (prepared as described in example 137A step 1), hydroxylamine sulfate (1.11 g, 6.78 mmol) and sodium hydrogencarbonate (1.2 g, 14.13 mmol) in a mixture of 10% methanol in water (20 mL), was heated at 65° C. for 15 h. After cooling to rt, the mixture was adjusted to pH 1 with concentrated hydrochloric acid and separated into two equal 10 mL batches and placed into two separate 20 mL microwave vials fitted with a stirrer bar. After sealing, each batch was placed in a Biotage Microwave Synthesizer and heated (with stirring) at 140° C. for 5 min. Each batch was cooled and neutralized with saturated aqueous sodium hydrogencarbonate solution. Both processed batches were combined and concentrated in vacuo and the aqueous solution extracted, twice, with dichloromethane. The combined organic layers were washed with brine, separated, dried over MgSO4 and filtered. Concentration in vacuo afforded 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (687 mg, 64%) as a light yellow solid which taken on without further purification. LC-MS (ESI) m/z 193 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].CCN(CC)CC>C1COCC1.[Cl-].[Na+].O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:10]=[C:9]([N:4]2[CH:5]=[CH:6][C:7](=[O:8])[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[N:3]2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 40 °C
Yield: 28 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (500 mg, 1.57 mmol), (trimethylsilyl)acetylene (0.222 mL, 1.57 mmol), Et3N (0.329 mL, 2.36 mmol), CuI (4.5 mg, 0.0236 mmol), Pd(PPh3)2Cl2 (55.1 mg, 0.0785 mmol) and PPh3 (10.3 mg, 0.0393 mmol) in THF (7.5 mL) was heated to 40° C. for 8 h under Ar. To the suspension was added (trimethylsilyl)acetylene (0.111 mL, 0.785 mmol). The suspension was heated to 40° C. for 14 h under Ar. To the suspension was added (trimethylsilyl)acetylene (0.0888 mL, 0.628 mmol). The suspension was heated to 40° C. for 96 h under Ar. The mixture was diluted with brine, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by column, chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (148 mg, 28% yield) as a brown solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 0.26 (9H, s), 6.64 (1H, d, J=7.9 Hz), 7.75-7.92 (2H, m), 8.00-8.15 (2H, m), 8.90 (1H, d, J=8.3 Hz).
Reaction SMILES: [S:1]([NH:11][C:12]1[N:17]2[C:18]3[N:24]=[CH:23][CH:22]=[CH:21][C:19]=3[CH:20]=[C:16]2[C:15](O)=[CH:14][N:13]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CS(Cl)(=O)=O>C(Cl)Cl>[S:1]([NH:11][C:12]1[N:17]2[C:18]3[N:24]=[CH:23][CH:22]=[CH:21][C:19]=3[CH:20]=[C:16]2[CH:15]=[CH:14][N:13]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)Nc2ncc(O)c3cc4cccnc4n23)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2nccc3cc4cccnc4n23)cc1
Reaction time: 0.33 h
Yield: 76.3 %

Procedure:
A solution of 9-tosylamino-6-hydroxypyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine (170 mg, 0.48 mmol) and TEA (133 μl, 0.96 mmol) was dissolved in CH2Cl2 (25 ml), methanesulfonylchloride (37 μl, 0.48 mmol) was dropwise added and the mixture was stirred for 20 min. The solution was washed with water and the organic solutions was dried and evaporated. The crude mixture was purified by flash column chromatography. Elution with CH2Cl2/MeOH (98/2) gave 23a (124 mg, 78%) as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:26][C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:32](I)[CH3:33]>>[CH2:32]([N:29]1[CH:28]=[C:27]([CH2:26][N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:12])[CH:31]=[N:30]1)[CH3:33]
Reactant: CCI
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCOc3c2cccc3[N+](=O)[O-])cc1
Product: CCn1cc(CN(C(=O)C2CCOc3c2cccc3[N+](=O)[O-])c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using N-(4-isopropylphenyl)-8-nitro-N-[(pyrazol-4-yl)methyl]chroman-4-carboxamide (2.9 g) and ethyl iodide (1.1 mL) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (2.9 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]#[N:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[N:15]=[N:16][NH:17][N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nn[nH]n1
Yield: 52.2 %

Procedure:
The title compound of Example 11 (8.34 g, 42.5 mmol), sodium azide (3.04 g, 46.8 mmol), and ammonium chloride (2.50 g, 46.8 mmol) were stirred in DMF (30 mL) at 100° C. for 12 h. The reaction was concentrate and partitioned with DCM and 3 M HCl. The organic extracts were dried over sodium sulphate, filtered and concentrated. The resulting solid was triturated with ether and filtered to afford the title product (5.31 g, 52%) as a white solid.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21]#[N:22].N(OCCC(C)C)=O>CN(C=O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[CH:2]=[C:3]([C:21]#[N:22])[C:4]([S:19][CH3:20])=[N:5]1
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#N
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methylsulfide 5 (37 mg, 0.1 mmol) in DMF (5 mL) was warmed up to 65° C. and treated dropwise with excess isoamyl nitrite. After a few minutes nitrogen gas bubbled off the reaction mixture. The stirring was continued for 30 min. The reaction was cooled down to room temperature, diluted with ethyl ether (10 mL) and washed with brine (5×15 mL). The organic layer was dried (magnesium sulfate) and the solvents removed at reduced pressure, leaving a dark oil residue The desired product was obtained upon flash chromatography eluting with ethyl acetate-hexanes (5%), to yield 19 mg (54%) of desired product 8. 1H-NMR (δ, CDCl3): 7.95 (1H, s); 7.78 (2H, s); 2.6 (3H; s). MS: M+1=352 (calculated: 352).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]([C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43]>C(#N)C>[C:42]([C:46]1[CH:51]=[CH:50][C:49]([S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:54])=[O:53])=[CH:48][CH:47]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(C(C)(C)C)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 43 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0294 g, 0.0637 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0530 mL, 0.382 mmol) and 4-tert-butylbenzenesulfonyl chloride (0.0440 g, 0.191 mmol) to obtain 4-(4-tert-butylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0180 g, yield 43%).