Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]1[S:27][C:26]([CH2:28][OH:29])=[CH:25][CH:24]=1.CC(C)([O-])C.[K+]>COCCOC>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:29][CH2:28][C:26]5[S:27][C:23]([F:22])=[CH:24][CH:25]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: OCc1ccc(F)s1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)s4)cc3=O)cn12
Temperature: 120 °C
Yield: 36.8 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (285 mg), (5-fluorothiophen-2-yl)methanol (109 mg), potassium tert-butoxide (93 mg) and DME (5 ml) was heated at 120° C. for 30 min under microwave irradiation. Additional potassium tert-butoxide (93 mg) and (5-fluorothiophen-2-yl)methanol (109 mg) in DME (0.5 ml) were added to the reaction mixture, and the resulting mixture was heated at 120° C. for further 30 min under microwave irradiation. The mixture was quenched with water and extracted with EtOAc/MeOH. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOH-IPA to give the title compound (120 mg) as an off-white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[SH:16][CH2:17][C:18]1[NH:19][C:20]([CH3:43])=[C:21]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[NH2:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=1>O1CCCC1>[NH2:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([S:16][CH2:17][C:18]2[NH:19][C:20]([CH3:43])=[C:21]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=3)[C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:50])=[CH:47][CH:46]=1
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)NC(CSC(=O)c2ccc(N)cc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of dicyclohexylcarbodiimide (g 1.5) in tetrahydrofuran is added dropwise to a solution of 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (g 2.7) and p-aminobenzoic acid (g 1.0) in tetrahydrofuran (20 ml) cooled to 0° C. in nitrogen atmosphere, the mixture is stirred at 0° C. for 15 minutes and then warmed to room temperature for 18 hours. The precipitate formed is filtered and the solvent is evaporated in vacuum. The residue is dissolved in ethyl acetate (150 ml) and washed with water (3×40 ml), with a sodium bicarbonate solution (3×30 ml) and then once again with water (3×20 ml). After drying on sodium sulphate and evaporation in vacuum of the solvent, the residue is purified by chromatography on silica gel (g 100) eluting with petroleum ether/ethyl acetate (8/2). The product is recrystallized from isopropyl ether. 3,2 g of 2-(p-aminobenzoylthio)methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine are obtained; m.p. 78°-80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C:11]([CH3:21])([CH3:20])[C:10]=3[CH:9]=2)[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.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>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:17]=[CH:16][C:15]4[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C:11]([CH3:21])([CH3:20])[C:10]=4[CH:9]=3)[N:3]=2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(Br)n3)ccc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
100 mg (0.29 mmol) of 2-bromo-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine and 135 mg (0.44 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester are dissolved in 2 ml of 2M sodium carbonate solution and in 2 ml of dimethoxyethane. The reaction mixture is degassed a number of times, 34 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium are added under nitrogen atmosphere, and the mixture is irradiated in the microwave for 30 min, subsequently evaporated, and saturated sodium hydrogencarbonate solution is added. This mixture is extracted three times with ethyl acetate, the combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by column chromatography on silica gel.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].[Li]CCCC.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[C:22]1([CH2:25][C:26](=[O:40])[C:27]([NH:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:35](=[O:36])[O:34][CH2:33]3)=[O:28])[CH2:24][CH2:23]1.[Cl-].[NH4+]>C1COCC1>[OH:40][C:26]([C:1]#[C:2][CH2:3][CH2:4][CH3:5])([CH2:25][C:22]1([C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=2[F:11])[CH2:24][CH2:23]1)[C:27]([NH:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:35](=[O:36])[O:34][CH2:33]2)=[O:28]
Reactant: C#CCCC
Reactant: O=C(CC1(c2cc(C(F)(F)F)ccc2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC#CC(O)(CC1(c2cc(C(F)(F)F)ccc2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution that consists of 1-pentyne (0.94 ml) in THF (9 ml) was mixed at −78° C. with nBuLi (0.6 ml, 1.6 M in hexane). It was allowed to stir for 30 minutes at −78° C., and then a solution of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide (200 mg) in 3 ml of tetrahydrofuran was added. Then, it was allowed to come to 23° C. over about 3 hours, and it was stirred for 10 more hours at this temperature. Then, the reaction mixture was poured into ice-cold, saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried on sodium sulfate. The crude product was chromatographed on silica gel. 130 mg of product was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>C1C=CC=CC=1>[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32](=[O:33])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:18])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([CH3:20])[CH3:21]
Reactant: CN(C)c1ccc(CNc2ccc(F)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [(4-dimethylaminophenyl)methyl](4-fluorophenyl)amine (0.52 g) in benzene (5 mL) was added 2,6-diisopropylphenyl isocyanate (0.46 mL) and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The obtained crystals were subjected to recrystallization from a mixed solvent of diisopropyl ether and hexane to give N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-fluorophenyl)urea (0.38 g). melting point: 124–125° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([C:12]2[S:13][C:14]([C:23]([O:25]CC)=[O:24])=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[O:11])[CH2:4]1.C1COCC1.C(O)C.[Na].[OH-].[K+]>C(O)C>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([C:12]2[S:13][C:14]([C:23]([OH:25])=[O:24])=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[O:11])[CH2:4]1
Reactant: CCOC(=O)c1sc(C(=O)OCC2CCC(OC)C2)nc1-c1ccccc1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC1CCC(COC(=O)c2nc(-c3ccccc3)c(C(=O)O)s2)C1

Procedure:
To a stirred solution of (±)-2-(3-methoxycyclopentylmethylcarboxy)-4-phenyl-thiazol-5-carboxylic acid, ethyl ester (0.01 mol), which may be prepared as described in Step (d) above, in a solvent such as ethanol, aqueous ethanol, or THF-ethanol, is added a solution of sodium or potassium hydroxide in ethanol at a concentration of from 1 M to about 2 M, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the mixture is rotary evaporated to remove most of the organic solvents, and the concentrated mixture is washed with ethyl acetate. The aqueous layer is acidified with hydrochloric acid to a pH of about 2 to about 4, and the product which precipitates is filtered off to give (±)-2-(3-methoxycyclopentylmethylcarboxy)-4-phenyl-thiazol-5-carboxylic acid, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([N:11]2[CH2:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=O.C([NH2:24])=O.C[O-].[Na+].CO>CN(C=O)C>[C:18]([O:17][C:15]([N:7]1[CH2:8][CH2:9][CH:10]([N:11]2[CH2:14][CH2:13][CH2:12]2)[CH:5]([C:3](=[O:2])[NH2:24])[CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1CCC1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC2)C(C(N)=O)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-azetidin-1-yl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.66 g. 2.21 mmol) in anhydrous DMF (13 mL) was added formamide (370 μL, 9.32 mmol). The mixture was heated to 100° C. and a solution of sodium methoxide in MeOH (25 w/w. 330 μL, 1.44 mmol) was added with heating being continued for 2 h. The reaction mixture was cooled to RT, then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester in DCM (40 mL) was added TFA (5 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give a 1:1 cis:trans mixture of the title compound as a colourless oil (280 mg, 69%).
Reaction SMILES: C([Li])CCC.[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]([CH:27]=[O:28])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CON(C)C(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH:24]([CH3:25])[CH3:26])[C:22]([C:27](=[O:28])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
n-Butyllithium (3.12 ml of 1.6 M solution in hexane, 5.0 mmol) was added to a stirred solution of 2-anilino-4-(2-formyl-1-isopropylimidazol-5-yl)pyrimidine (Example 10; 558 mg, 2.0 mmol) in anhydrous THF (20 ml) cooled to −70° C. The mixture was stirred for 30 minutes and then N-methoxy-N-methylbenzamide (660 mg, 4.0 mmol) was added and the reaction mixture was allowed to warm and stirred at ambient temperature for 18 hour. The reaction mixture was quenched with water (20 ml), and extracted with EtOAc (4×25 ml). The organic extracts were washed with brine (2×50 ml), dried and the volatiles removed by evaporation and the residue triturated with ether and the solid collected by filtration to give the title compound (303 mg, 43%) as a pale yellow crystalline solid. NMR (CDCl3): 1.55-1.70 (m, 8H), 5.52-5.68 (sept, 1H), 6.99 (d, 1H), 7.09 (dt, 1H), 7.18 (br s, 1H), 7.30-7.40 (m, 2H), 7.45-7.54 (m, 2H), 7.55 (s, 1H), 7.56-7.62 (m, 3H), 8.09 (d, 2H), 8.49 (d, 1 H); m/z 384.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:17][S:18](O)(=[O:20])=[O:19]>ClCCCl>[CH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCC(C)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCC(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 80 °C

Procedure:
To a solution of commercially available sec-butylbenzene (1.34 g; 10 mmol) in 1,2-dichloroethane (50 mL) was added phosphorus pentachloride (2.5 g; 12 mmol) followed by chlorosulfonic acid (1.3 mL; 20 mmol) slowly. The mixture was heated at 80° C. overnight, then cooled to room temperature and mixed with ice water (150 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (2×10 mL). The organic phases were combined and dried over magnesium sulfate and concentrated under reduced pressure to give an orange oil which was used without further purification (2.3 g).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[CH:6]3)[CH:2]=1)=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Agent: O=S(=O)(O)O
Product: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
To a solution of 1,8-naphthalic anhydride (25 g, 0.13 mol) in conc. H2SO4 (100 mL) was added dropwise a solution of conc. HNO3 (7.85 g, 0.13 mol) in conc. H2SO4 (25 mL) at 0° C. After the addition was complete, the resulting mixture was allowed to warm to RT, stirred for 90 min and then poured into ice-H2O. The solid was filtered by suction, washed with H2O, and re-crystallized from glacial AcOH to yield 3-nitro-1,8-naphthalic anhydride (24.5 g). 1H NMR (300 MHz, CDCl3): δ 9.11 (s, 1H), 9.06 (s, 1H), 8.58 (d, J=7.5 Hz, 1H), 8.43 (d, J=7.8 Hz, 1H), 7.82 (t, J=7.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]([C:14](=O)[CH3:15])[C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[NH2:18]O>C(O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:15])=[N:18][O:13][C:11]=2[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(C(C)=O)C(C)=O)cc1Br
Reactant: NO
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2c(C)noc2C)cc1Br
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A mixture of 3-(3-bromo-4-methoxyphenyl)pentane-2,4-dione (40 mg, 0.14 mmol) and hydroxylamine hydrochloride (30 mg, 0.43 mmol) in 95% ethanol (0.50 mL) was refluxed for 4 h. After cooling to RT, the mixture was taken up in 30 mL of ether and washed with 10 mL of saturated sodium bicarbonate solution followed by 10 mL of brine. Drying over sodium sulfate and concentration afforded 40 mg of crude product which was purified by flash column chromatography, eluting with 50% dichloromethane in hexane, to yield 28 mg of the title compound as a white solid. Mass spectrum (NH3/CI): m/z=282 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[NH:2]1.O.O.[NH2:14]N>CCO>[C:1]1([OH:11])[N:14]=[N:2][C:3]([OH:10])=[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=12
Reactant: NN
Reactant: O=C1NC(=O)c2cnccc21
Solvent: CCO
Solvent: O
Product: Oc1nnc(O)c2cnccc12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To 2H-pyrrolo[3,4-c]pyridine-1,3-dione 1 (25.01 g, 169 mmol) dissolved in EtOH (250 mL) and H2O (250 mL) was added hydrazine hydrate (23 ml, 464 mmol). The solution was warmed to reflux and stirred for 1 h. After cooling to 40° C., the solution was brought to pH 4 with 5 N HCl whereupon precipitation of a light yellow solid occurred. After cooling to room temperature, the precipitate was filtered, washed with water, air dried for 2 h, and dried under high vacuum for 24 h at 40° C. to provide a quantitative yield of pyrido[3,4-d]pyridazine-1,4-diol 2. 1H NMR (d6-DMSO) δ 11.67 (bs, 2H), 9.33 (s, 1H), 9.02 (d, J=5.5 Hz, 1H), 7.89 (d, J=5.5 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:8][C:7]1=[O:15])(=[O:5])=[O:4].[H-].[Na+].Cl.[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([CH2:29][CH2:30][CH2:31][CH2:32][F:33])[C:25]([CH2:27]Cl)=[N:26][C:22]=2[CH:21]=1>CN(C=O)C.O>[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([CH2:29][CH2:30][CH2:31][CH2:32][F:33])[C:25]([CH2:27][N:8]3[C:9]4[CH:10]=[N:11][CH:12]=[CH:13][C:14]=4[N:6]([S:3]([CH3:2])(=[O:5])=[O:4])[C:7]3=[O:15])=[N:26][C:22]=2[CH:21]=1
Reactant: FCCCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)n1c(=O)[nH]c2cnccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(=O)n(Cc2nc3cc(Cl)ccc3n2CCCCF)c2cnccc21
Reaction time: 0.33 h

Procedure:
To a solution of 1-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one hydrochloride 10 (720 mg, 2.626 mmoles) in 10 mL of extra dry DMF was added sodium hydride (210 mg, 5.253 mmoles, 60% dispersion in oil) portionwise at room temperature. After 20 minutes, a solution of 5-chloro-2-(chloromethyl)-1-(4-fluorobutyl)-1H-benzo[d]imidazole hydrochloride 9 (440 mg, 1.313 mmoles) in 5 mL of DMF was added dropwise. Stirring was continued overnight at room temperature. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The resulting slightly orange oil was triturated in DCM and the precipitate was filtered off. It was further washed with DCM, then isopropylether and dried under high vacuum, to provide the title product 3-((5-chloro-1-(4-fluorobutyl)-1H-benzo[d]imidazol-2-yl)methyl)-1-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one P34 as a white solid in 40% yield; m/z=452 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4]([CH2:7][CH:8]=1)(=[O:6])=[O:5].[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>CCOCC>[Br:9][CH2:1][C:2]1[CH2:3][S:4]([CH2:7][CH:8]=1)(=[O:6])=[O:5]
Reactant: CC1=CCS(=O)(=O)C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=S1(=O)CC=C(CBr)C1
Temperature: 0 °C
Yield: 34.2 %

Procedure:
In a reaction vessel, 21.0 gms (0.1591 moles) 3-methyl sulfolene, 28.32 gms (0.1591 moles) N-bromo succinimide, 1.9 gms (0.0008 moles) benzoyl peroxide and 250 ml chlorform were combined. The resulting mixture was heated to reflux and then refluxed for 20 hours. The reaction mixture was cooled to 0° C. and then filtered to remove the succinimide. The filtrate was stripped until only a small amount of solvent remained. The remaining solids were removed by filtration, and the remainder of the solvent was stripped to give an orange oil. Ether was added to the oil. After a few minutes, the solids crystallized. Filtration and drying yielded 11.5 gms of the product. The NMR and IR spectra confirmed the structure.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[CH2:14](Cl)[CH:15]=[CH2:16].[OH-].[Na+]>O>[CH2:16]([NH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12])[CH:15]=[CH2:14]
Reactant: C=CCCl
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNc1c(C(C)C)cccc1C(C)C
Yield: 84.3 %

Procedure:
A solution containing 2,6-diisopropyl aniline (35.4 g, 0.2 mol) and allyl chloride (7.6 g, 0.10 mol) was refluxed for 12 hr and then poured into water (400 ml). Adding an aqueous NaOH solution to the reaction mixture made the mixture basic. After extraction with diethyl ether (3×50 ml) and distillation (73.25 Pa, 92° C.), 18.33 g (84.3%) of N-allyl-2,6-diisopropyl aniline was isolated. Nd30=1.5205. 1H-NMR (ppm,CDCl3): δ=7.10(d, 2H, Ph-Hm), 6.81(t, 1H, Ph-Hp), 6.05(m, 1H, CH═C), 5.34(d, 1H, C═C—Htrans), 5.16(d, 1H, C═C—Hcis), 3.71(broad, 1H, NH), 3.50(d, 2H, CH2—C═C), 3.26(m, 2H, CH(Me)2), 1.28(d, 12H, C═C(CH3)2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([OH:24])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([O:24][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(O)C3)c2CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(OCc4ccccc4)C3)c2CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 200 mg (0.56 mmol) 10-(3-hydroxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 10 mL anhydrous THF maintained at 0° C. for 30 minutes was added 320 mg (6.72 mmol, 60% dispersion in mineral oil) NaH under an atmosphere of nitrogen and the reaction was stirred at 0° C. for 30 minutes. 0.8 mL (6.80 mmol) benzyl bromide was added and the reaction was heated at 65° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated. 25 mL EtOAc was added and the organic layer was washed with H2O (2×20 mL), and dried over Na2SO4. After filtration and evaporation the product was purified by column chromatography (silica, heptane/EtOAc 3:7).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29]OS(C)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCN(C)C1=O.O>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 45.4 %

Procedure:
A mixture of 2.2 g (8.7 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, 3.7 g (13 mmol) (S)-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (preparation described in Tetrahedron 2006, 62, 4584-4589) and 5.7 g (18 mmol) cesium carbonate in 44 ml dry 1,3-dimethyl-3,4,5,6-tetrahydropyrimidinone (DMPU) was stirred for 48 h at 80° C. The reaction mixture was diluted with 100 ml water and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated to dryness. Residual DMPU was removed by kugelrohrdistillation in high vacuo (ca. 1 mbar) at 120° C. Flash chromatography gave the title compound (1.7 g, 46%) as a light yellow solid.