Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][N:4]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1ccncn1
Reactant: O=C(C1CCNCC1)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccncn2)CC1)N1CCN(Cc2ccccc2)CC1
Yield: 45.3 %

Procedure:
4-Chloropyrimidine hydrochloride (3.5 g) was added to a stirred suspension of 1-benzyl-4-[4-piperidylcarbonyl]piperazine (6.6 g), triethylamine (12.8 ml) and ethanol (120 ml). The mixture was heated under reflux for four hours and evaporated in vacuo to yield a treacle like substance. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Na2SO4) and evaporated. The residue was absorbed onto alumina and purified using dry flash chromatography eluting with increasingly polar mixtures of dichloromethane and methanol (1:0 to 98:2). The material obtained was triturated with diethylether to give 1-(benzyl)-4-[1 -(4-pyrimidinyl)-4-piperidylcarbonyl]piperazine (3.8 g, 45% yield), mp 107-108.5° C.;
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:9]([Cl:19])[CH:8]=1.[O:20]=[C:21]1[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]1>C1COCC1>[Cl:19][C:9]1[CH:8]=[C:7]([C:21]2([OH:20])[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]2)[CH:18]=[CH:17][C:10]=1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1cc(Br)ccc1CN1CCCC1
Reactant: O=C1CC(C(=O)O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-BuLi in hexanes (101 mL, 254 mmol) was added over 15 min to a solution of 1-(4-bromo-2-chlorobenzyl)pyrrolidine (69.6 g, 254 mmol) in absolute THF (450 ml) under a flow of nitrogen at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Then a −78° C. chilled solution of 3-oxocyclobutanecarboxylic acid (14.4 g, 126.7 mmol) in absolute THF (150 ml) was added drop wise for 10 min at −78° C. The mixture was warmed to RT slowly and left stirring for 18 hrs and the resulting solution was used. LRMS m/z Calcd for C18H20NClO3, 309.8, found, 308.1 (M−H) APCI.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([NH:23]NC3C=CC=CC=3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.[CH3:32][N:33]([CH3:40])[CH2:34]/[CH:35]=[CH:36]/[C:37](Cl)=[O:38].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([NH:23][C:2]3[CH:3]=[C:4]([NH:16][C:37](=[O:38])/[CH:36]=[CH:35]/[CH2:34][N:33]([CH3:40])[CH3:32])[CH:5]=[CH:6][CH:7]=3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN(C)C/C=C/C(=O)Cl
Reactant: Clc1cc(Nc2cc(NNc3ccccc3)ncn2)ccc1OCc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncn2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
3-{[6-(3-chloro-4-(2-pyridyl)methoxyphenylamino)-pyrimidin-4-ylamino]phenylamine (IR-9) was dissolved in N-methylpyrrolidinone (1.2 mL) and added dropwise over 10 minutes to the ice-cold solution of (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride in acetonitrile. The reaction was stirred in an ice bath for 2 hr. To the mixture was added sodium bicarbonate to pH greater than 9. The oil that formed was extracted with EtOAc (3×25 mL). A portion of the material was insoluble and set aside. The organic layer was dried (MgSO4) filtered and evaporated to a dark red oil. Both oils contained substantial amount of product as shown by TLC: SiO2 CHCl3:MeOH/NH4OH (8:1) 19:1. The oils were combined and purified by flash column chromatography silica gel (25×300 mm) eluted first with 5% methanol/ammonium hydroxide 8/1 to remove non-polar impurities followed by 10% methanol/ammonium hydroxide 8/1 to elute 59 mg of product. The sample was further purified by a second flash column chromatography silica gel (25×250 mm) eluted with 10% methanol/ammonium hydroxide 8/1 to give the title compound (16.3 mg, 0.03 mmol, 6.4% yield). MS (ES+) 530 (M+): 552, (M+Na); 1H NMR (DMSO-d6, 500 MHz) δ (ppm): 10.04 (s, 1H), 9.19 (s, 1H), 9.14 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.88 (s, 2H), 7.57 (s, 1H), 7.36 (d, 1H, J=7.4 Hz), 7.29 (d, 2H, J=7.8 Hz), 7.22 (d, 2H, J=7.9 Hz), 7.18 (m, 2H), 6.74 (m, 1H), 6.30 (d, 1H, J=15 Hz) 6.10 (s, 1H), 5.24 (s, 2H), 3.06 (s, 2H), 2.18 (s, 6H) ppm; HPLC: tR=5.15 min, 97.5% (YMC-Pack ODS-A 4.6×100 mm, 80% water/20% acetonitrile to 5% water/95% acetonitrile over 5.5 min, hold to 9 min.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:12][CH2:11]1.ClC1C=CC=C(C(OO)=[O:40])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH2:21][S:22]([C:23]2[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:40])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2([CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[O:12][CH2:11]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.92 h
Yield: 71.7 %

Procedure:
To a toluene (30 ml)-methanol (3 ml) solution of the 2-(((3-methyl-4-(1,5,9-trioxaspiro[5.5]undec-3-ylmethoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (974 mg, 2.21 mmol) obtained in the step (10d), a toluene (1 ml)-methanol (1 ml) solution of 3-chloroperbenzoic acid (528 mg, 1.99 mmol as the content was regarded as 65%) was added dropwise at −65° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 55 minutes in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 20 g, elution solvent: dichloromethane, dichloromethane/methanol=10/1). The fractions containing the title compound were collected with ethyl acetate and concentrated. After diethyl ether was added to the residue, the solvent was distilled off to obtain the title compound (725 mg, yield: 71.7%) as a pale grayish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:21][OH:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[N:21][OH:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2ccc(SC)cc2)cc1Cl
Product: COc1ccc(C(Cc2ccc(SC)cc2)=NO)cc1Cl
Yield: 41 %

Procedure:
1-(3-Chloro-4-methoxyphenyl) -2-[4-(methylthio)phenyl]-ethan-1-one oxime was prepared in 41% yield from the reaction of 1-(3 chloro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one from Step 4 with hydroxylamine by the method outlined in Example 1, Step 1: 1H NMR (CDCl3 /300 MHz) δ 7.69 (d, J=2.22 Hz, 1H), 7.47 (dd, J=8.66, 2.22 Hz, 1H), 7.21-7.16 (m, 4H), 6.86 (d, J=8.66 Hz, 1H), 4.11 (s, 2H), 3.89 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8])(=[O:4])=[O:3].[NH2:11][C:12]([CH3:16])([CH3:15])[C:13]#[N:14].C(N(CC)CC)C>O1CCCC1>[C:13]([C:12]([NH:11][S:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:9])=[O:8])([CH3:16])[CH3:15])#[N:14]
Reactant: CS(=O)(=O)CCS(=O)(=O)Cl
Reactant: CC(C)(N)C#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C#N)NS(=O)(=O)CCS(C)(=O)=O
Temperature: 25 °C
Yield: 133.2 %

Procedure:
To a stirred solution of 5.00 g (24.2 mmoles) 2-(methylsulfonyl)ethylsulfonyl chloride (Example 32) in 50 ml dry tetrahydrofuran, a solution of 2.11 g (0.025 moles) 2-amino-2-methyl-propionitrile and 2.5 g (0.025 moles) triethylamine in 20 ml dry tetrahydrofuran were added dropwise over 13 minutes. During the course of the addition, the temperature of the mixture rose from 19° C. to 38° C. and a white precipitate formed. After the mixture cooled to room temperature, it was filtered. The solid, inorganic salts, was washed with tetrahydrofuran and ethyl ether. The filtrate and washings were stripped using a rotovap to give 8.2 g of a sticky white solid. Recrystallization of the solid from boiling ethanol gave 3.94 g of the above-identified product, melting point 151°-153° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]([C:9]1[N:10]([CH3:20])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)=[O:8]>CC(O)=O>[CH3:5][O:6][C:7]([C:9]1[N:10]([CH3:20])[C:11]2[C:16]([CH:17]=1)=[C:15]([N+:1]([O-:4])=[O:2])[C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc2cc(OC)ccc2n1C
Solvent: CC(=O)O
Product: COC(=O)c1cc2c([N+](=O)[O-])c(OC)ccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of concentrated HNO3 (2 mL) in AcOH (9 mL) was added to a solution of 8 (830 mg, 3.79 mmol) in AcOH (54 mL) at 0° C. Following the addition, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was poured over ice, filtered and the precipitate washed with H2O. The precipitate was dissolved in CH2Cl2 and filtered through a short column of silica gel to afford 9 (780 mg, 78%) as a yellow solid; Rf=0.53 (50% EtOAc/hexanes); 1H NMR (CDCl3): δ 7.58 (1H, d), 7.55 (1H, s), 7.18 (1H, d), 4.11 (3H, s), 4.02 (3H, s), 3.94 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8](Cl)[N:7]=1)=[O:5])[CH3:2].[CH3:13][CH:14]([SH:16])[CH3:15]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:16][CH:14]([CH3:15])[CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)S
Reactant: CCOC(=O)c1ccnc(Cl)n1
Product: CCOC(=O)c1ccnc(SC(C)C)n1
Yield: 68 %

Procedure:
2-Chloropyrimidine-4-carboxylic acid ethyl ester (0.024 g, 0.13 mmol) obtained in Step A and 2-propanethiol were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.02 g, 68%).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:21]CCBr.CO>C1COCC1>[C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Br:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)c1ccncc1
Reactant: BrCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccccc1)c1ccncc1Br
Temperature: -69 °C
Reaction time: 8 h

Procedure:
As described in Synthetic Communications 1997, 27, 1075-1086, a 4-necked RBF equipped with an overhead stirrer and a J-Kem internal temperature probe was placed N-phenylisonicotinamide (35.7 g, 0.18 mol) and anhydrous THF (700 ml). All material appeared to go into solution. This mixture was cooled to −69° C. in a dry ice/IPA bath. To this was slowly added nBuLi (158 ml of a 2.5 M solution in Hexanes) in three portions. While adding the first equivalent of nBuLi, an exotherm was observed raising the temperature to ca. −41° C. The orange reaction mixture was slightly heterogeneous. This was allowed to slowly warm to −5 to 0° C. over 1.5 hrs in a ice/brine bath. The reaction mixture was recooled to −72° C. and 1,2-dibromoethane (36 g, 0.189 mol) in 15 ml of THF was added. A slight exotherm was observed rising to −62° C. The reaction mixture was allowed to stir overnight. The reaction mixture was poured into a flask containing 10 vol. SiO2. Methanol (100 ml) was added and the mixture was concentrated under reduced pressure. The dried silica gel was then placed on top of a bed of silica gel. The plug of silica gel was washed with 40% ethyl acetate/Hexane as eluent. Concentration of 10 liters of solvent afforded an off-white solid. The material was placed in vacuum drying at 60° C. overnight to provide 34 g (68% th) of an off-white solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH2:11](Br)[CH3:12]>O.CO>[CH2:11]([S:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH3:12]
Reactant: Fc1ccc(S)cc1
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCSc1ccc(F)cc1
Yield: 79.1 %

Procedure:
To a stirring solution of NaOH (11.26 g, 281.6 mmol) in water (500 mL) was added dropwise a solution of 4-fluorothiophenol (25 mL, 234.6 mmol) in methanol (50 mL). After 15 minutes ethyl bromide (14.4 mL, 281.6 mmol) was added. After 6 hours more NaOH (1 g) was added and the reaction mixture was extracted with ether (3×300 mL). The combined organic extracts were treated with brine followed by MgSO4 then concentrated down to give 1-(ethylthio)-4-fluorobenzene (29 g, 80%) as a slightly yellow colored liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:26][CH3:27])[C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([CH2:22][CH2:23][O:24][CH3:25])[CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:29]#[CH:30].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH2:26]([N:13]([C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]([CH2:22][CH2:23][O:24][CH3:25])[CH3:21])[CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([C:30]#[C:29][CH2:28][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:27]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Temperature: 105 °C

Procedure:
To a solution of methyl 5-bromo-3-(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methylbenzoate (30 g, 68.02 mmol), 4-(prop-2-yn-1-yl) morpholine (25.51 g, 204 mmol) and triethylamine (20.61 g, 204 mmol) in DMF (300 mL) was bubbled Argon for 20 min. Then CuI (3.87 g, 20.36 mmol) and Pd (PPh3)4 (7.85 g, 6.79 mmol) were added and Argon was bubbled through for further 20 min. The reaction mixture was heated at 105° C. for 4 h and then cooled to room temperature. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with 10% MeOH/DCM (400 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound (21 g, 63.7% yield).
Reaction SMILES: [NH3:1].[CH:2]([CH2:15][C:16](Cl)=[S:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O.C(Cl)Cl>[CH:2]([CH2:15][C:16]([NH2:1])=[S:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=C(Cl)CC(c1ccccc1)c1ccccc1
Reactant: N
Solvent: ClCCl
Solvent: O
Product: NC(=S)CC(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
35 ml of ammonia in 40 ml of water are introduced into a three-necked flask provided with a condenser and a dropping funnel and the benzhydrylthioacetyl chloride dissolved in about 100 ml of methylene chloride is added drop by drop. Once the addition is complete, the organic phase is washed with a dilute solution of soda and dried over Na2SO4, the solvent is evaporated and the residue is taken up in diisopropyl ether; in this way, the benzhydrylthioacetamide is crystallised. 16.8 g of product (yield=86%) are obtained.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[O:10]=[C:11]1[NH:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH2:28][CH2:27][C:26](=[O:29])[NH:25][N:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.N1C=CC=CC=1>C(O)(=O)C>[O:29]=[C:26]1[NH:25][N:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:13]=[CH:12][C:11](=[O:10])[NH:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:28][CH2:27]1
Reactant: O=C1CCC(c2ccc(C3=NNC(=O)CC3)cc2)=NN1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=C1CCC(c2ccc(-c3ccc(=O)[nH]n3)cc2)=NN1

Procedure:
A solution of pyridinium bromide perbromide (0.6 g) in hot acetic acid (50 ml) was added dropwise over 10 minutes to a refluxing mixture of 1,4-bis(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzene (0.5 g) and pyridine (0.3 ml) in glacial acetic acid (100 ml). After addition the clear brown solution was stirred under reflux for 3 hours and was cooled and filtered. The filtrate was concentrated to small volume (ca 10 ml) and was treated with distilled water (100 ml) to yield a brown solid which was collected, washed with ethanol and ether and then dried. The crude material is recrystallised from acetic acid to afford the title compound, m.p. greater than 250° C., H NMR: δ (DMSOd6); 2.45 (2H, t), 2.95 (2H, t), 7.00 (1H, d), 7.88 (4H, m), 8.08 (1H, d) and 10.88 (1H, s).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)(=[O:28])[CH3:27]
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
To a cooled solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (8.0 g) and triethylamine (4.1 g) in dichloromethane (35 ml) is added dropwise acetyl chloride (3.2 g) in dichloromethane (20 ml). After stirring at ambient temperature for 20 hours, the reaction mixture is washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent yields a solid (6.2 g), of which 2.5 g is recrystallized from ethyl acetate to yield 1.4 g (56%) of product as a powder, mp 141°-142°.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:59]1[CH:64]=[C:63](B(O)O)[CH:62]=[N:61][CH:60]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:63]2[CH:64]=[N:59][CH:60]=[N:61][CH:62]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: OB(O)c1cncnc1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cncnc2)=C3c2cc(F)cc(F)c2)CC1
Yield: 34 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 50 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, and 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (34%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].N.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([S:5][CH2:4][CH2:3][NH2:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCS
Reactant: BrCc1ccccc1
Agent: Cl
Agent: N
Solvent: CO
Product: NCCSCc1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a suspension of 0.1 mole cysteamine hydrochloride in 20 mL methanol were added 13.6 mL of 25% ammonia solution, followed by dropwise addition of 0.12 mole benzyl bromide at room temperature. The mixture was stirred for 0.5 h, and the formed precipitate of S-dibenzylcysteamine was collected by filtration. The product was extracted with ether (3×100 mL) and the organic phase was successively washed with brine (2×100 mL), dried over MgSO4 and the solvent evaporated in vacuo. The crude product was essentially pure enough for the next step. It could, however be recrystallized from ethyl acetate. Yield 86%, of white solid. m.p. 85°-6° C. NMR (CDCl3) in agreement with the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9](=O)[O:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>N1C=CC=CC=1>[Cl:23][C:9]1[O:10][C:11]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1
Reactant: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(Cl)s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCCc1oc(Cl)nc1-c1ccc(Cl)s1
Temperature: 125 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl 4-[4-(5-chloro-2-thienyl)-2-oxo-4-oxazolin-5-yl]butanoate (12.5 g), phosphorus oxychloride (24.5 g) and pyridine (3.16 g) was heated to 120-130° C. and stirred for 45 minutes. The reaction mixture was poured into ice-water (200 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was washed in sequence with a 10% aqueous solution of sodium hydrogen carbonate (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) and dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 2-chloro-4-(5-chloro-2-thienyl)-5-oxazolebutanoate was obtained as a yellow oil (5.79 g, 48%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:27])[C:17](=[O:18])[C:16]2[C:19]([Sn](C)(C)C)=[CH:20][CH:21]=[CH:22][C:15]=2[O:14]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:19]2[C:16]3[C:17](=[O:18])[C:13]([CH3:12])([CH3:27])[O:14][C:15]=3[CH:22]=[CH:21][CH:20]=2)=[CH:4][N:3]=1
Reactant: CC1(C)Oc2cccc([Sn](C)(C)C)c2C1=O
Reactant: Cc1c(I)cnc(N)c1C#N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3c2C(=O)C(C)(C)O3)cnc(N)c1C#N
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.8 grams (0.007 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine, 2.3 grams (0.007 mole) of (2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)trimethyltin (prepared in Step D of this Example), and 0.5 gram (catalyst) of tetrakis(triphenylphosphine)palladium(O) in 25 mL of toluene is heated at reflux for about 22 hours. After this time the reaction mixture is cooled to ambient temperature and diluted with 50 mL of ethyl acetate. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to a residue. The residue is purified using column chromatography, yielding 2-amino-3-cyano-4-methyl-5-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)pyridine.