Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:11]2[CH:23]=[CH:22][C:14]3[O:15][C:16]([CH3:21])([CH3:20])[O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:49]([C:56]1[CH:63]=[CH:62][C:59]([CH2:60][NH2:61])=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.Cl>C1COCC1>[CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:61][CH2:60][C:59]3[CH:62]=[CH:63][C:56]([O:49][C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[CH:57][CH:58]=3)=[O:30])=[CH:32][CH:33]=2)[C:11]2[CH:23]=[CH:22][C:14]3[O:15][C:16]([CH3:21])([CH3:20])[O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)O)cc3)C(=O)CCC3CCCC3)ccc2O1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)NCc4ccc(Oc5ccccc5)cc4)cc3)C(=O)CCC3CCCC3)ccc2O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of 4-{[(3-cyclopentylpropanoyl)(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)amino]methyl}benzoic acid (212 mg) in THF (2 mL) was added NMM (57 mg). The mixture was chilled at 0° C. and isobutyl chloroformate was added at once (86 mg). The mixture was stirred for 15 min. at 0° C. then 4-phenoxybenzylamine (103 mg) was added and the resulting reaction mixture was stirred 3 h at rt. An aqueous solution oh HCl (1N, 2 mL) was added and the resulting mixture was extracted with Et2O. The combined organic layers were washed with water, brine, dried over MgSO4 filtered and evaporated to give a light yellow oil. Purification by chromatography (SiO2) gave the title compound as a colorless oil (241 mg, 81%). 1H NMR (CDCl3) δ 7.56-7.42 (m, 3H), 7.21-7.00 (m, 6H), 6.95-6.67 (m, 7H), 6.21 (t, J=4.9 Hz, 1H), 4.69 (s, 2H), 4.42 (s, 1H), 4.40 (s, 1H), 1.87 (t, J=7.2 Hz, 2H), 1.54 (s, 6H), 1.48-1.14 (m, 9H), 0.85-0.64 (m, 2M). M+(ESI): 633.0; M−(ESI): 631.0. HPLC, Rt: 5.3 min (purity: 97.7%).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([O:30][CH3:31])[CH:22]=1.ClC1C=CC(C(O)=O)=C(OC)C=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH:2]2[C:8]3=[N:9][C:10]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[CH:11][C:12](=[O:13])[N:7]3[CH2:6][CH2:5][O:4][CH2:3]2)=[O:26])=[C:23]([O:30][CH3:31])[CH:22]=1
Reactant: NC1COCCn2c1nc(-c1ccncc1)cc2=O
Reactant: COc1cc(F)ccc1C(=O)O
Agent: COc1cc(Cl)ccc1C(=O)O
Product: COc1cc(F)ccc1C(=O)NC1COCCn2c1nc(-c1ccncc1)cc2=O

Procedure:
By analogy with the method described in example 1 (step 1.4), using (+/−) 9-amino-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one and 4-fluoro-2-methoxy benzoic acid in place of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one and 4-chloro-2-methoxy-benzoic acid, the compound, 0.068 g (71%), was obtained as a powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21](=[O:23])=[O:22]>O1CCCC1>[Cl:20][C:16]1[N:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=1[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: Clc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine 3.76 g in tetrahydrofuran 25 ml is dropped at −78° C. n-butyllithium (23.2 ml). The mixture is stirred at 0° C. for 10 minutes and thereto is added 2,6-dichloropyridine 5.0 g in tetrahydrofuran 25 ml at −78° C. over a period of 20 minutes. The mixture is stirred at −78° C. for 3 hours. The reaction mixture is poured into powdered dry ice and is left at room temperature overnight. After removal of the solvent the residue is dissolved in a mixture of ethyl acetate and a 10% aqueous sodium hydroxide solution, and the water layer is separated and made acid with concentrated hydrochloric acid. The resulting colorless precipitate is filtered and washed with cold water to give 2,6-dichloronicotinic acid 4.50 g. mp 148-150° C., MS(ESI): 190(M−H)−
Reaction SMILES: [CH:1]12[CH:9]3[CH:3]([CH2:4][CH2:5][CH:6]3[CH2:7][CH2:8]1)[C:2]2=[O:10].C1C=CC(=O)/C(=C/NCCN/C=C2/C=CC=CC/2=[O:26])/C=1.OO>C(O)C>[CH:1]12[CH:9]3[CH:3]([CH2:4][CH2:5][CH:6]3[CH2:7][CH2:8]1)[C:2](=[O:10])[O:26]2
Reactant: O=C1C2CCC3CCC1C32
Reactant: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Agent: OO
Solvent: CCO
Product: O=C1OC2CCC3CCC1C32
Temperature: 25 °C
Reaction time: 24 h
Yield: 617.6 %

Procedure:
Into 0.5 ml of ethanol was dissolved tricyclo[4,2,1,03,9]nonane-2-one (13.6 mg, 0.1 mmol). Into this ethanol solution was added the Co (III) (salen) complex (3.7 mg, 5 μmol) having the above formula (XI). Into this solution was added 30% hydrogen peroxide aqueous solution (15 μI, hydrogen peroxide content 0.13 mmol), which was stirred at room temperature for 24 hours. After the completion of the reaction, the mixed liquid was concentrated, and the residue was chromatographed in a silica gel column with hexane/ethyl acetate (=8/2) as a developing solvent, thereby obtaining 2-oxatricyclo[5.2.1.04,10]decane-3-one (4.7 mg, yield 31%) having the above formula (VIII). The enantiomer excess percentage of the product was determined as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][NH:14]3)=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[N:3]=1.Br[CH2:25][CH2:26][O:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH2:25][CH2:26][O:27][CH3:28])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[N:3]=1
Reactant: COCCBr
Reactant: Cc1cc(C)n(-c2nc(Nc3ccccc3)c3nc[nH]c3n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCn1cnc2c(Nc3ccccc3)nc(-n3nc(C)cc3C)nc21
Temperature: 120 °C
Yield: 8.4 %

Procedure:
[2-(3,5-Dimethyl-pyrazol-1-yl)-9H-purin-6-yl]-phenyl-amine (300 mg, 0.88 mmol), 2-bromoethylmethylether (0.12 mL, 1.32 mmol), potassium carbonate (121 mg, 0.88 mmol) and acetonitrile were mixed and heated in a microwave oven at 120° C. for 40 min. Water was added resulting in a white precipitate. The crude product was purified by preparative LCMS to give [2-(3,5-dimethyl-pyrazol-1-yl)-9-(2-methoxy-ethyl)-9H-purin-6-yl]-phenyl-amine (27 mg, 9%) as a white crystalline compound.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].Br[C-:7]1C=CC=[CH:8]1.[C-:12]1([Br:17])[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:18].[C:19]1([P:25]([Cl:27])Cl)[CH:24]=[CH:23][CH:22]=[CH:21]C=1.ClP>C1COCC1>[C:5]1([C-:21]2[CH:22]=[CH:23][CH:24]=[C:19]2[PH:25][Cl:27])[CH:8]=[CH:7][CH:2]=[CH:3][CH:4]=1.[Br:17][C-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:18]
Reactant: [Li]CCCC
Reactant: ClP(Cl)c1ccccc1
Agent: [Fe+2]
Agent: Br[c-]1cccc1
Agent: PCl
Solvent: C1CCOC1
Product: ClPc1ccc[c-]1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
14.5 ml (23.2 mmol) of n-BuLi (1.6 M in hexane) are added dropwise to a solution of 8 g (23.2 mmol) of 1,1′-dibromoferrocene in 30 ml of THF at a temperature of <−30° C. The mixture is stirred for another 30 minutes at this temperature. It is then cooled to −78° C. and 3.15 ml (23.2 mmol) of phenyldichlorophosphine are added dropwise at such a rate that the temperature does not exceed −60° C. After stirring at −78° C. for a further 10 minutes, the temperature is allowed to rise to room temperature and the mixture is stirred for another one hour. This gives a suspension of the monochlorophosphine X1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:25]([C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11](C(OC(C)(C)C)=O)[N:10]=2)=[N:7][CH:8]=1.[H][H]>O1CCOCC1>[CH2:35]([O:34][C:32](=[O:33])[N:25]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)[N:5]=1)[C:26]1[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=1)[CH:36]=[CH2:37]
Reactant: [H][H]
Reactant: C=CCOC(=O)N(c1ccncc1)c1nc(-c2nn(C(=O)OC(C)(C)C)c3ccccc23)ncc1OC
Solvent: C1COCCO1
Product: C=CCOC(=O)N(c1ccncc1)c1nc(-c2n[nH]c3ccccc23)ncc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.22 g of tert-butyl 3-(5-methoxy-4-{[(prop-2-en-1-yloxy)carbonyl](pyridin-4-yl)amino}pyrimidin-2-yl)-1H-indazole-1-carboxylate (1-9-1, 2.43 mmol, 1 eq.) was suspended in 1,4-dioxane. 2.43 ml of hydrogen acid 4M in 1,4-dioxane (9.711 mmol, 4 eq.) were added dropwise. The reaction mixture was stirred for 24 hours at room temperature. 2.43 ml of hydrogen acid 4M in 1,4-dioxane (9.711 mmol, 4 eq.) were added dropwise again and stirred for further two hours. The reaction mixture was concentrated under vacuo. The residue was extracted with saturated aq. sodium hydrogen carbonate-solution and ethyl acetate. The aqueous layer was reextracted twice by ethyl acetate. The combined organic layers were dried over a silicone filter and concentrated under vacuo. Purification by flash chromatography (ethyl acetate/methanol 0-25%) provided 877 mg (1.96 mmol, 80.8%) of the analytically pure target compound.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])=[O:4].Cl.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[I:23].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[I:23])[C:12]1[O:13][C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=1
Reactant: CNc1ccccc1I
Reactant: COC(=O)c1ccccc1N=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CN(c1nc2ccccc2c(=O)o1)c1ccccc1I

Procedure:
A solution of 2-methoxycarbonylphenyl isocyanate (1.0 g, 5.6 mmol), N-methyl-2-iodoaniline, hydrochloride (1.6 g, 5.9 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.3 mmol) in 100 mL of toluene was refluxed under N2 for 72 hours. The sample was concentrated, and partitioned between chloroform and 10% HCl. The chloroform was dried (MgSO4), filtered, concentrated and chromatographed (silica gel, methylene chloride) to give the title compound as a yellow solid, mp 144°-148° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH2:23][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])[C:6]=2[CH:7]=1.Br[C:26]1[CH:31]=[CH:30][C:29]2C3(C[O:48][C:28]=2[CH:27]=1)C1C(=CC=CC=1)N(CCCCC)C3=O>>[CH2:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:6]3[CH:7]=[C:2]([O:48][C:28]4[CH:29]=[CH:30][CH:31]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]=3[O:24][CH2:23]2)[C:9]1=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCN1C(=O)C2(COc3ccc(Br)cc32)c2ccccc21
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Product: CCCCCN1C(=O)C2(COc3ccc(Oc4ccccc4)cc32)c2ccccc21
Yield: 10 %

Procedure:
Following the procedure as described in EXAMPLE 36, and making non-critical variations using 5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (10% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.32-7.10 (m, 5H), 7.06-6.82 (m, 6H), 6.42 (d, 1H), 4.95 (d, 1H), 4.71 (d, 1H), 3.82-3.62 (m, 2H), 1.75-1.63 (m, 2H), 1.43-1.34 (m, 4H), 0.85 (t, 3H); MS (ES+) m/z 400.4 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)#[N:2].[H][H]>N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: Cc1cccc(C#N)c1CNc1cccn2c(C)c(C)nc12
Agent: [Ni]
Agent: N
Product: Cc1cccc(CN)c1CNc1cccn2c(C)c(C)nc12
Yield: 12.3 %

Procedure:
To a solution of 8-(2-cyano-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.42 g, 1.44 mmol) in ammonia saturated ethanol/methanol (10/2.5)(30 ml) was added Raney nickel (50% in water)(0.45 g) The mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. Following filtration through celite, the solvents were evaporated under reduced pressure and the residue was purified by by column chromatography on silica gel using methylene chloride:methanol (10:2) as eluent. Recrystallization from methylene chloride/diethyl ether gave 0.052 g (12%) of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([O:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([OH:20])=[O:2])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A solution of rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid methyl ester (527 mg, 1.66 mmol) in ethanol (15 mL) was treated with a solution of potassium hydroxide (233 mg, 4.15 mmol) in water (2 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water (5 mL), and the ethanol was removed in vacuo. The aqueous layer was then acidified to pH 2 with 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residual oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 chloroform/methanol plus 1% acetic acid) to give rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid (487 mg, 97% yield) as a colorless oil: EI-HRMS m/e calcd for C14H16Cl2O3 (M+) 302.0477, found 302.0486.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:15]([NH2:18])(=[S:17])[CH3:16]>>[CH3:1][O:2][C:3]([C:4]1[N:18]=[C:15]([CH3:16])[S:17][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-phenyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.87 min; [M+H]+=234.3.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[N:6]=1)[CH2:2][CH3:3].C(=O)(O)[O-:23].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[O:23])[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccnc(Sc2cccc3cccnc23)n1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1ccnc(S(=O)c2cccc3cccnc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 710 mg. (2.38 m mole) of 8-(4-n-propoxy-2-pyrimidylthio)quinoline and 999 mg. of sodium bicarbonate (11.9 m mole) in 40 ml. of methylene chloride cooled to 0° C. was added dropwise over a period of 15 minutes 574 mg. (3.33 m mole) of m-chloroperbenzoic acid in 15 ml. of the same solvent. The reaction mixture was stirred for 30 minutes and was then allowed to warm to room temperature and stirred overnight. The reaction was diluted with methylene chloride and the organic layer washed successively with a saturated sodium bicarbonate solution, water and a saturated brine solution. The organic phase was separated, dried over magnesium sulfate and concentrated to give 745 mg. of crude product which was purified by chromatographing on silica gel, 367 mg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=[C:4]2[CH:3]=1.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]3[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=[C:4]3[CH:3]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][C:33]=3[Cl:35])[N:7]=2)=[N:13][CH:14]=1)#[N:19]
Reactant: CCOC(=O)c1cn2c(NCCNc3ccc(C#N)cn3)nc(Cl)cc2n1
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C(=O)O)cn23)nc1
Temperature: 120 °C

Procedure:
1 g (2.59 mmol) of ethyl 7-chloro-5-({2-[(5-cyanopyridin-2-yl)amino]ethyl}amino)imidazo[1,2-c]pyrimidine-2-carboxylate (Example 59A), 580 mg (2.98 mmol) of (2,4-dichlorophenyl)boronic acid and 716 mg (5.18 mmol) of potassium carbonate are introduced into a mixture of 25 ml of 1,2-dimethoxyethane and 10 ml of water under argon, and the mixture is carefully degassed before 300 mg (0.26 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated at 120° C. for 16 h. Filtration and subsequent purification by preparative HPLC result in 185 mg (14% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].Cl[CH2:15][CH2:16][CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][P:19](=[O:23])([O:24][CH2:25][CH3:26])[O:20][CH2:21][CH3:22])[CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CCOP(=O)(CCCCCl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)n(C)c(=O)n2C)OCC
Temperature: 70 °C

Procedure:
10.9 g (0.05 mol) of 1,3-dimethylxanthine were suspended in 150 ml of DMF, treated with 13.7 g (0.06 mol) of diethyl 4-chlorobutanephosphonate and 7.0 g (0.05 mol) of activated potassium carbonate and heated at 70° C. for approximately 4 hours. The solid was then filtered off, the filtrate was concentrated under reduced pressure and the oily residue which remained was taken up in ethyl acetate, filtered again and crystallized from diisopropyl ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]2[CH2:24][OH:25])[N:3]=1.Cl.[CH:27]12[O:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][NH:29][CH2:28]2.C(N(CC)CC)C>C(O)C>[CH:31]12[O:34][CH:27]([CH2:33][CH2:32]1)[CH2:28][N:29]([C:2]1[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:5]=[C:4]([N:17]3[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]3[CH2:24][OH:25])[N:3]=1)[CH2:30]2
Reactant: C1CC2CNCC1O2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(N3CC4CCC(C3)O4)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1

Procedure:
A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (1.3 g, 2.7 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.51 g, 3.4 mmol) in ethanol (15 mL) was treated with triethylamine (1.35 mL, 10 mmol) and heated with a heat gun briefly to reflux. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES+)=443.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].Br[CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:15])([F:17])[F:16]
Reactant: CCBr
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Product: CCN1CCN(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(4-Chloro-3-trifluoromethyl-phenyl)-piperazine and bromo-ethane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 293 (M+, 6), 292 (30),277 (29), 57 (bp), 56 (41).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:11]2=[N:12][CH:13]=[CH:14][C:15](O)=[C:10]2[S:9][CH:8]=1>ClCCCl>[Cl:3][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[C:7]([CH3:6])=[CH:8][S:9][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1csc2c(O)ccnc12
Solvent: ClCCCl
Product: Cc1csc2c(Cl)ccnc12
Reaction time: 8 h
Yield: 55.8 %

Procedure:
Phosphorous oxychloride (2.2 mL, 24 mmol) in 1,2-dichloroethane (12 mL) was charged with 3-methylthieno[3,2-b]pyridin-7-ol (2.0 g, 12 mmol). The reaction stirred overnight at reflux under nitrogen. The mixture was the cooled and concentrated. Saturated NaHCO3 solution was carefully added to neutralize the residue. The biphasic mixture was extracted with dichloromethane, dried, and concentrated. Flash chromatography (15% EtOAc/hexanes) of the crude material gave the title compound (1.23 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][CH:6]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=[O:22])[C:16]=12)=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([C:7]([NH:14][C:15]2[C:16]3[C:21](=[O:22])[O:20][C:18](=[O:19])[C:17]=3[CH:23]=[CH:24][CH:25]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: Nc1cccc2c1C(=O)OC2=O
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1C(=O)OC2=O)c1ccc(Cl)s1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To prepare the required acid chloride, 27.77 g of 2-chloro-5-thiophenecarboxylic acid (0.171 mol) are suspended in 50 ml of thionyl chloride (0.685 mol) and stirred at 90° C. for 90 min (after 15 min, a clear solution is formed). The resulting solution is concentrated under reduced pressure, twice subjected to azeotropic distillation with toluene, dissolved in 60 ml of toluene and, over a period of 40 min and at 20° C., added dropwise to a solution of 17.98 g (110.2 mmol) of 3-aminophthalic anhydride in 200 ml of pyridine. The mixture is stirred at RT overnight, the pyridine is evaporated under reduced pressure and the residue is twice stirred with toluene and re-evaporated. 1 l of ethyl acetate and 0.5 l of KH2PO4 buffer (pH=4-5) are added and the mixture is then shaken vigorously and filtered off with suction, and the solids are washed with ethyl acetate, pressed thoroughly dry and dried under reduced pressure over P2O5. The mother liquor is extracted three times with ethyl acetate and evaporated and the residue is stirred with ethyl acetate and filtered off with suction. This gives a total of 19.77 g (58.3% of theory) of the target compound of m.p. 195° C.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)=[S:11])=[CH:5][CH:4]=[C:3](Cl)[CH:2]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)=[S:11])=[CH:1][CH:2]=1
Reactant: S=C(NCCc1ccc(Cl)cc1)Nc1ccc(Br)cn1
Reactant: CO
Product: COc1ccc(CCNC(=S)Nc2ccc(Br)cn2)cc1

Procedure:
N-[2-(4-chlorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (II-9) yield: 71%; mp 180-183° C.; UV (MeOH) λmax: 206, 209, 219, 256, 275 and 305 nm; IR(KBr) ν 3221, 3153, 3086, 3022, 2931, 1674, 1593, 1562, 1533, 1473, 1406, 1340, 1304, 1265, 1227, 1169, 1138, 1092, 1016, 820, 752, 714 cm−1; 1H NMR (CDCl3) δ 11.40 (br s, 1H), 9.34 (br s, 1H), 8.15-8.14 (d, 1H), 7.84-7.80 (dd, 1H), 7.46-7.30 (m, 4H), 6.92-6.89 (d, 1H), 4.10-4.07 (q, 2H), 3.13-3.08 (t, 2H); 13C NMR (CDCl3) δ 179.2, 151.6, 146.3, 141.3, 137.1, 130.2, 128.6, 113.5, 112.8, 46.8 and 34.2; Maldi Tof found: 372.0 (M+1), calculated: 371.0; Anal. (C14H13BrClN3S) C, H, N, S.