Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:17]>C(O)C.[C].[Pd]>[ClH:17].[OH:16][CH2:15][C:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OCC1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OCC1(O)CCNCC1
Reaction time: 8 h

Procedure:
500 mg of 1-benzyl-4-(hydroxymethyl)piperidin-4-ol (synthesized according to the method described in J. Med. Chem., 1988, 486-491) was dissolved in 10 ml of ethanol, 300 mg of 10% palladium carbon and 0.38 ml of concentrated hydrochloric acid were added thereto, and the mixture was subjected to hydrogenation at room temperature overnight. The reaction mixture was filtrated to remove precipitates, the precipitates were wasted with ethanol and water, and the filtrate was concentrated under reduced pressure. The obtained residue was turned into powder by adding diethylether to obtain 374 mg of the objective compound as white powder.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=O)[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:31]1[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[S:49](C)=O>>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:49])[NH:18][C:19](=[O:22])[N:20]([C:31]4[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CS(C)=O
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Product: CCOC(=O)c1ccc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)cc1
Temperature: 100 °C

Procedure:
A mixture of the product of example 2 step (ii) (1.5 g), potassium carbonate (1.71 g) and ethyl 4-fluorobenzoate (0.835 g) in dimethylsulphoxide (20 ml ) was heated at 100° C. for 20 hours. Cesium carbonate(1.6 g) was added and the mixture heated at 100° C. for 5 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography 20-30% ethyl acetate in isohexane. Yield 0.72 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].[CH:17]1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[N:39]=[C:40]([C:42]1[C:43]2[CH2:44][CH2:45][CH:46]([OH:51])[C:47]=2[CH:48]=[CH:49][CH:50]=1)[NH2:41].[Na+].[Cl-]>CN(C=O)C>[CH:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[O:9][N:41]=[C:40]([C:42]3[CH:50]=[CH:49][CH:48]=[C:47]4[C:43]=3[CH2:44][CH2:45][CH:46]4[OH:51])[N:39]=2)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([CH3:2])[CH3:17]
Reactant: NC(=NO)c1cccc2c1CCC2O
Reactant: On1nnc2ccccc21
Reactant: CCOc1ccc(C(=O)O)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4O)no2)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
In a microwave vial, a stirring solution of 4-ethoxy-3-(trifluoromethyl)benzoic acid (200 mg, 0.97 mmol) in DMF was treated with HOBt (172 mg, 1.26 mmol) and EDCI (242 mg, 1.26 mmol) at room temperature. The reaction was stirred for 20 min followed by addition, in a single portion, of N′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (243 mg, 1.26 mmol). The reaction was stirred for additional 30 min at room temperature and then heated to 130° C. for 35 min in the initiator. The reaction was diluted using a saturated solution of NaCl and extracted with EtOAc (80 ml×3). The organic phase was dried over Na2SO4 anhydrous and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (9:1) to offer the product as pale yellow solid in 63% yield (229 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:17](Cl)=[O:18]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:15][O:14][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])[NH:1][C:17](=[O:18])[NH:6][C:4]2=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(N)=O)c(N)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
108 mg (0.5 mmol) of 2-amino-5-methoxy-4-nitrobenzamide were dissolved in 5 ml of tetrahydrofuran and 5 ml of chloroform, and oxalyl chloride (solution in toluene) was added. The mixture was stirred at 60° C. for 5 hours and then concentrated in vacuo. Addition of toluene was followed by renewed concentration. 120 mg (100%) of the desired product were obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>O1CCOCC1>[CH3:19][C:16]1[O:15][C:14]([CH2:13][NH:12][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1
Reactant: CN1CCC(N)CC1
Solvent: C1COCCO1
Product: Cc1ccc(CNc2ccc3c(NC4CCN(C)CC4)cccc3n2)o1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
(5-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (150 mg, 0.47 mmol) was dissolved in 2 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. 4-Amino-1-methyl-piperidine (165 mg, 1.45 mmol), sodium tert.-butylate (117 mg, 1.22 mmol), 1,1′-bis(diphenylphosphin)ferrocen (41 mg, 0.074 mmol) and 1,1′-bis(diphenylphosphin)ferrocen-palladium(II)chloride (19 mg, 0.023 mmol) were added. The reaction mixture was stirred in a sealed tube at 120° C. overnight. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->90:10:1 gradient). The title compound was obtained as a brown solid (36 mg, 22%), MS: m/e=351.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[Se:10](=O)=O>C(O)C.O>[Br:1][C:2]1[C:3]2[C:4](=[N:8][Se:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1N
Reactant: O=[Se]=O
Solvent: CCO
Solvent: O
Product: Brc1cccc2n[se]nc12

Procedure:
The specific preparation is described as follows: refluxing 3-bromo-1,2-diaminobenzene in ethanol solution, then adding into selenium dioxide dissolved in hot water, after that, refluxing for 2 hours. The precipitation is recrystallized with ethyl acetate after being filtered to get 4-bromo-2,1,3-benzoselenadiazole finally.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH3:27])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]=1[CH3:41])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH3:27])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:16]=1[CH3:41])#[N:14]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CC(=O)N(C)C)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(=O)N(C)CC(=O)N(C)C)nc2c1C#N
Reaction time: 0.83 h
Yield: 14.4 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (52 μl, 408 μmol) was added at 150° C. to a dimethyl sulfoxide (6 ml) solution of 4-cyano-N-[2-(dimethylamino)-2-oxoethyl]-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-125) (134 mg, 340 μmol) and triethylamine (62 μl, 442 μmol), followed by stirring at the same temperature for 50 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (20:1, v/v) gave the entitled compound (24 mg, 14%) as an amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(O)CC(=O)c3ccccc32)c1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(C2CC(=O)c3ccccc32)c1
Reaction time: 16 h
Yield: 23.2 %

Procedure:
A solution of 3-(3-methoxyphenyl)-3-hydroxyindan-1-one (2.3 g) in 25 ml methylene chloride was stirred at 0°, then treated sequentially with 1.6 ml triethylsilane and 3.3 ml of boron trifluoride etherate. The mixture was warmed to 25° and stirred for 16 hours, then diluted with water and extracted with additional methylene chloride. After drying (MgSO4) and concentration, the residue was chromatographed on silica gel to provide the title compound as a light yellow oil (0.5 g, 23%). NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1C(=O)Cl
Reaction time: 3 h

Procedure:
A round bottom flask containing the 2-chloro-6-methyl-benzoic acid (1.5 g, 8.79 mmol) and a stirring bar is charged with dry DCM (10 mL). Stirring is initiated. After several min, a solution of thionyl chloride (in DCM (2M), 6.6 mL, 13.2 mmol) is added via syringe. 2 drops of DMF are then added. The reaction immediately began to bubble gently. After 2 h bubbling ceases. After 3 h, the solvent is removed from the reaction mixture in vacuo. The oily residue is redissolved in DCM (6 mL) and the solvent once again removed in vacuo. The residue is dissolved in dry DCM (6 mL) and used without further purification in the next reaction sequence.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].P(OCC)(OCC)(O[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>>[CH2:14]([C:6]1[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CCOP(=O)(OCC)OCc1ccccc1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Product: O=Cc1ccc(Cc2ccccc2)o1
Yield: 34.9 %

Procedure:
The title compound was synthesized from 5-formylfuran-2-ylboronic acid (0.80 g, 5.7 mmol) and benzyl diethyl phosphate (1.5 g, 6.3 mmol) using the same conditions used to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde. Purification by flash chromatography yielded 5-benzyl-furan-2-carbaldehyde as a brown solid (0.37 g, 65%). 1H NMR (400 MHz, CDCl3) δ ppm 9.56 (s, 1H) 7.29-7.38 (m, 3H) 7.24-7.28 (m, 2H) 7.17 (d, J=3.5 Hz, 1H) 6.19 (d, J=3.6 Hz, 1H) 4.07 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([OH:19])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.[Cl:31]C(OCC)=O.[CH:37]([NH:40][CH2:41][CH2:42][NH2:43])([CH3:39])[CH3:38]>C1COCC1>[ClH:31].[ClH:31].[CH:37]([NH:40][CH2:41][CH2:42][NH:43][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[O:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:13]=1)([CH3:39])[CH3:38]
Reactant: CC(C)NCCN
Reactant: Cc1csc(Nc2cc(Oc3ccccc3C(=O)O)ccn2)n1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2cc(Oc3ccccc3C(=O)NCCNC(C)C)ccn2)n1
Product: Cl
Yield: 149.9 %

Procedure:
Using the method of Example 32, 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (0.100 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol), ethyl chloroformate (0.03213 mL, 0.3360 mmol), N-isopropyl-ethylenediamine (0.1143 mL, 0.9164 mmol) in THF (2 mL) were reacted to provide N-(2-(isopropylamino)ethyl)-2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzamide dihydrochloride (0.122 g, 81.62% yield) as an off white solid. 1H NMR (DMSO) δ 8.63 (bs, 1H), 8.55 (m, 1H), 8.18 (d, 1H), 7.76 (dd, 1H), 7.62 (dt, 1H), 7.42 (dt, 1H), 7.27 (d, 1H), 6.59 (s, 1H), 6.56 (m, 1H), 6.53 (m, 1H), 3.42 (m, 2H), 3.25 (m, 1H), 2.86 (m, 2H), 2.23 (d, 3H), 1.17 (d, 6H); Mass spectrum (esi) m/z=412 (100) (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:9]([C:28]2[N:32]([CH3:33])[N:31]=[N:30][N:29]=2)[CH:10]=[CH:11][C:12](=[O:27])[CH2:13][CH:14]([OH:26])[CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+:42]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[C:9]([C:28]2[N:32]([CH3:33])[N:31]=[N:30][N:29]=2)[CH:10]=[CH:11][C:12](=[O:27])[CH2:13][CH:14]([OH:26])[CH2:15][C:16]([O-:18])=[O:17])=[CH:6][CH:7]=1.[Na+:42]
Reactant: Cn1nnnc1C(C=CC(=O)CC(O)CC(=O)OCc1ccccc1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnnc1C(C=CC(=O)CC(O)CC(=O)[O-])=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 24 °C
Reaction time: 6 h
Yield: 57.6 %

Procedure:
Phenylmethyl 9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-5-oxo-6,8-nonadienoate (0.34 g, 0.62 mmole) was dissolved in tetrahydrofuran (4 mL) and water (1 mL). 1N Sodium hydroxide (0.62 mL, 0.62 mmole) was added, and the solution was stirred for 6 hours at 24° C. The mixture was diluted with water (10 mL) and washed with diethyl ether (3×50 mL). The aqueous portion was lyophilized to give 0.17 g (52%) of the title compound; m.p.=166°-180° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.C(N(C(C)C)C(C)C)C.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[OH:13][CH2:12][CH2:11][NH:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:34]2[CH2:35][CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: CSc1nc(Cl)c(C#N)c(NCCO)n1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1nc(NCCO)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Reaction time: 7 h
Yield: 70 %

Procedure:
A solution of 0.47 g (1.9 mmol) of 4-chloro-6-(2-hydroxy-ethylamino)-2-methylsulfanyl-pyrimidine-5-carbonitrile (Timkevicius, S., Chemija 1997, 1, 58-61) and 0.33 ml (1.9 mmol) of N-ethyl-diisopropylamine in 5 ml of dichloromethane was treated at 30° C. with 310 mg (1.9 mmol) of 4-phenyl-piperidine and stirred during 7 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, and the residue obtained was directly chromatographed on silica gel using a 99:1 mixture of dichloromethane and methanol as the eluent yielding 490 mg (1.33 mmol, 70% of theory) of the 4-(2-hydroxy-ethylamino)-2-methylsulfanyl-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=370.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Cl:14][C:15]1[S:19][C:18]([C:20](Cl)=[O:21])=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[S:19][C:18]([C:20]([NH:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[O:21])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=C(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g (2.7 mmol) tert. Butyl 3-amino-pyrrolidine-1-carboxylate are dissolved in 7 ml DCM, combined with 1.4 ml (10.1 mmol) TEA and 0.5 g (2.7 mmol) 5-chloro-thiophene-2-carboxylic acid chloride and stirred for one hour at RT. The reaction mixture is diluted with DCM and washed successively with dil. aqueous KHSO4 solution, sat. aqueous NaHCO3 solution and water. The combined organic phases are dried on sodium sulphate and evaporated to dryness i. vac.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Ca+2].[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([S:24]([CH2:27][N+:28]([O-:30])=[O:29])(=[O:26])=[O:25])=[C:19]([CH3:31])[CH:18]=1.C(=O)=O>O1CCCC1.C(OCC)(=O)C.C(O)C>[CH3:23][C:21]1[CH:22]=[C:17]([NH:16][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=[C:19]([CH3:31])[C:20]=1[S:24]([CH2:27][N+:28]([O-:30])=[O:29])(=[O:26])=[O:25]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)Cc2ccccc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Yield: 54 %

Procedure:
Phenylacetyl chloride (1.16 g, 7.5 mM) was added to a stirred suspension of calcium carbonate (1.0 g, 10.0 mM) and (4-amino-2,6-dimethylphenylsulfonyl)nitromethane (1.22g, 5.0 mM) in dry tetrahydrofuran (THF; 20 mL). The mixture was stirred for 16 hours during which time carbon dioxide was slowly released. Ethanol (1.0 mL) was then added and the mixture stirred for a further hour in order to decompose excess phenylacetyl chloride. Ethyl acetate (100 mL) was then added and the insoluble material removed by filtration. The filtrate was washed first with water (50 mL) containing 2M hydrochloric acid (2.0 mL) and then with saturated sodium chloride solution (2×40 mL) and then dried (MgSO4). The solvent was evaporated and the residue recrystallised from ethyl acetate. The solid obtained was washed with ether and air dried to give (2,6-dimethyl-4-[phenylacetamido]phenylsulfonyl)nitromethane as white crystals, having m.p. 158°-159° C. and in 54 % yield after recrystallisation from ethanol; microanalysis, found: C, 56.7; H, 5.0; N, 8.0%; C17H18N2O5S requires: C, 56.4: H, 5.0; N, 7.7%.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][CH2:36][Cl:37]>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:35][CH2:36][Cl:37])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: ClCCBr
Product: O=C(O)/C(=N\OCCCl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
The starting material was prepared by reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-hydroxyimino)acetate with 1-bromo-2-chloroethane followed by hydrolysis of the ester to give 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-(2-chloroethoxy)imino]acetic acid; n.m.r. in solvent C:-3.75(t, 2H); 4.36(t, 2H); 6.64(s, 1H); 7.35(s, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](O)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([Cl:28])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2Cl)cc1
Temperature: 25 °C
Yield: 29 %

Procedure:
A solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, in POCl3 was heated to reflux for 3 hours while stirring under nitrogen. The mixture was cooled to room temperature and poured into ice with constant swirling. The resulting white solid was extracted with ethyl acetate. The combined organics were washed with H2O, dried over MgSO4, and concentrated to a solid. The crude product was purified using flash chromatography (SiO2, eluting with 1:1 ethyl acetate/hexanes) to provide the desired product (yield: 0.151 g, 29%). mp 203–204° C. 1H NMR (300 MHz, DMSO d6) δ 3.29–3.36 (3H, obstructed by H2O), 7.60 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.14 (m, 2H), 8.25 (s, 1H). MS (DCI/NH3) m/z 395 (M+H)+, 412 (M+NH4)+. Anal. calc. for C17H12Cl2N2O3S: C, 51.66; H, 3.06; N, 7.09. Found: C, 51.67; H, 3.03; N, 6.93.
Reaction SMILES: C1([S:7]([C:10]2[CH:15]=[CH:14][C:13](N)=[CH:12][CH:11]=2)(=[O:9])=[O:8])C=CC=CC=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([F:29])=[C:25]([I:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:17].[CH:13]1[CH:12]=[CH:11][C:10]([S:7]([N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[C:25]([I:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)(=[O:8])=[O:9])=[CH:15][CH:14]=1
Reactant: Fc1cc2ncnc(Cl)c2cc1I
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Product: Cl
Product: O=S(=O)(c1ccccc1)N(c1ccccc1)c1ncnc2cc(F)c(I)cc12

Procedure:
Prepared according to Procedure A from 4-(benzenesulphonyl)phenylamine and 4-chloro-6-iodo-7-fluoroquinazoline. 1H NMR (400 MHz, DMSO-d6) δ: 10.89 (s, 1H), 9.3 (d, 1H), 8.79 (s, 1H), 8.07 (d, 2H), 8.0 (d, 2H), 7.94 (d, 2H), 7.67 (m, 2H), 7.61 (m, 2H). ESI-MS m/z 504 (M−1).
Reaction SMILES: C(N1CCN(C2C=CC([NH:20][C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=3)=CC=2)CC1)C1C=CC=CC=1.[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:30]1>>[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH:34][C:23]3[N:22]=[C:21]([NH2:20])[C:26]([F:27])=[CH:25][N:24]=3)=[CH:32][C:31]=2[O:30]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Fc1cnc(Cl)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Product: Nc1nc(Nc2ccc3c(c2)OCCO3)ncc1F
Yield: 127.1 %

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of N4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine (50 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (0.045 mL, 0.36 mmol) gave N4-[4-(N-benzylpiperazino)phenyl)]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (40 mg, 63%). 1H NMR (CDCl3): δ 2.64 (t, J=4.8 Hz, 4H), 3.20 (t, J=4.8 Hz, 4H), 3.59 (s, 2H), 4.24 (m, 4H), 6.61 (d, 1H, NH), 6.68 (br, 1H, NH), 6.76 (d, J=8.7 Hz, 1H), 6.88 (dd, J=2.4 and 8.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.28-7.36 (m, 5H), 7.47 (d, J=8.7 Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ −168.66; LCMS: ret. time: 18.05 min.; purity: 100%; MS (m/e): 513.10 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[Br:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Br.CCOCC>CN(C)C=O.CCOCC.O>[BrH:19].[C:22]1([CH2:21][CH2:20][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[N:11]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCc1ccccc1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CN1CCC(c2nn(CCc3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a stirred mixture of 0.86 g of sodium hydride (50% oil dispersion) in 50 ml of dimethylformamide was added, dropwise, 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 15 ml of hot dimethylformamide. The reaction mixture was stirred at ambient temperature for 1 hr and then a solution of 3.33 g of (2-bromoethyl)benzene in 10 ml of dimethylformamide was added dropwise. The reaction mixture was stirred for 21/2 days at ambient temperature, cooled to 0°, and water was added dropwise. The mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was dissolved in ether and a saturated hydrogen bromide/ether solution was added dropwise. The resultant solid was recrystallized two times from ethanol to yield 2.0 g (36%) of product, mp 163°-164° C.