Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]([NH:12][CH2:13][CH2:14][OH:15])[C:6]=1[N+:16]([O-:18])=[O:17].[CH3:19][O-:20].[Na+]>CO>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([O:20][CH3:19])[CH:8]=[C:7]([NH:12][CH2:13][CH2:14][OH:15])[C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(NCCO)cc(Cl)cc1NCCO
Agent: [Na+]
Solvent: CO
Product: COc1cc(NCCO)c([N+](=O)[O-])c(NCCO)c1

Procedure:
0.09 mole (25 g) of 2-(β-hydroxyethyl)amino-6-(β-hydroxyethyl)amino-4-chloronitrobenzene in 100 ml of a 25% sodium methylate solution in methanol was heated over a boiling water bath. After heating for 1 hour 30 minutes the desired product was precipitated out of the reaction medium by adding 250 g of ice water. After filtering and hot drying under vacuum in the presence of P2O5, the desired product was recrystallized from 96° ethanol. It melted at 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:23][C:25]([CH2:26][OH:27])=[CH:28][N:22]=1)[NH:6]2
Reactant: CN(c1ccc(Cl)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=CC(Br)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1ccc(Cl)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 90 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
A mixture of 4-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.51 g), bromomalonaldehyde (0.30 g) and N,N-dimethylacetamide (15 ml) was stirred at 90° C. for 4 hr. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. To a mixture of the obtained crystals, tetrahydrofuran (5 ml) and methanol (5 ml) was added sodium borohydride (55 mg) at 0° C., and the mixture was stirred at the same temperature for 1 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.30 g, yield 52%) as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point 225-226° C.
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[Br:8][CH2:9][C:10](Cl)=[O:11].C(N(CC)CC)C>C(OCC)C>[Br:8][CH2:9][C:10]([O:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:11]
Reactant: CC(O)CC(=O)O
Reactant: O=C(Cl)CBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(CC(=O)O)OC(=O)CBr
Temperature: 5 °C
Yield: 70 %

Procedure:
5 g (0.048 mol) of 3-hydroxybutyric acid and 0.062 mol of bromoacetyl chloride were dissolved in 100 ml of diethyl ether. This solution was stirred in an ice bath, and while maintaining the solution at a level of not higher than 5° C., 20 ml of diethyl ether containing 5.35 g (0.053 mol) of triethylamine was dropwise added over a period of 30 minutes. After the dropwise addition, the mixture was stirred at room temperature for 10 hours. Then, triethylamine hydrochloride was filtered off from the reaction solution, and the filtrate was washed three times with distilled water. The ether solution thereby obtained was dried over anhydrous sodium sulfate, and then diethyl ether was distilled off. As a result, a slightly yellow desired compound was obtained in a yield of 70%.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:30][O:29][C:22](=[O:28])[CH2:23][C:24]1[C:11]([C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:25]=1[CH3:27]
Reactant: Nc1sc2c(c1C(=O)c1ccc3c(c1)OCO3)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Yield: 82.9 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(benzo[d][1,3]dioxol-5-yl)methanone (0.301 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.328 g (83%) of the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:34])=[C:23]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:13]([C:12]1[CH:11]=[CH:10][C:9]([N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:34])=[C:23]([O:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=2)[N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)=[CH:16][CH:15]=1)#[N:14]
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and benzoic acid 5-bromomethyl-2-fluoro-phenyl ester (CAB02146, 1.55 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) and water (50 mL) were added. The mixture was transferred into a separation funnel and washed with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc, Rf: 0.32) to give a white solid. Yield: 1.16 g (56%). 1H-NMR (400 MHz, CDCl3) δ=4.91 (s, 2H), 6.67 (d, J=9.0 Hz, 2H), 7.07 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 7.18 (dd, J=9.4, 8.6 Hz, 1H), 7.24 (dd, J=7.0, 2.3 Hz, 1H), 7.49-7.56 (m, 2H), 7.58 (d, J=9.0 Hz, 2H), 7.62-7.70 (m, 1H), 8.15-8.20 (m, 2H), 8.21 (s, 2H). LRMS (FAB+): 414.2 (100, [M+H]+).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:20]2[N:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31]C)=[O:30])=[CH:22][N:21]=2)[CH:4]=1.C[Si](C)(C)[O-:38].[K+].OO>C1COCC1.O.C(O)(=O)C>[CH3:1][S:2]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:20]2[N:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([OH:31])=[O:30])=[CH:22][N:21]=2)[CH:4]=1)=[O:38]
Reactant: C[Si](C)(C)[O-]
Reactant: COC(=O)c1cccc(-c2cnc(-n3cc(SC)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1cn(-c2ncc(-c3cccc(C(=O)O)c3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Prepared from methyl 3-(2-(3-(methylthio)-6-(morpholine-4-carbonyl)-1H-indol-1-yl)pyrimidin-5-yl)benzoate (precursor of example 192) in two reaction steps comprising an ester hydrolysis with potassium trimethylsilanolate in THF and water and an oxidation of the thioether with hydrogen peroxide in acetic acid. White solid. Yield: 90 mg. Melting range: 230-235° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH:28]=[CH2:29].O>CN(C=O)C>[CH2:29]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12]1)[CH:28]=[CH2:27]
Reactant: C=CCI
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and allyl iodide (23 μL, 0.25 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 302.1, found 302.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[S:14](Cl)(=[O:17])(=[O:16])[NH2:15].C(N(CC)CC)C>C(#N)C>[CH3:13][C:6]1[C:5]2[CH:4]=[CH:3][C:2]([O:1][S:14](=[O:17])(=[O:16])[NH2:15])=[CH:11][C:10]=2[O:9][C:8](=[O:12])[CH:7]=1
Reactant: NS(=O)(=O)Cl
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(=O)oc2cc(OS(N)(=O)=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A slurry of 7-hydroxy-4-methylcoumarin (17.6 g, 0.10 mole) in acetonitrile (100 ml) was treated with a total of 84 ml of 3 M sulfamoyl chloride (0.255 mole) in acetonitrile. The mixture was then treated dropwise with triethylamine (25.8 g, 0.255 mole). The reaction temperature was allowed to rise to 45° C. without any cooling. The mixture was stirred overnight at ambient temperature. The precipitate was collected, triturated with water, and dried in a vacuum oven at 70° C. for 15 hr to give 10.5 g (41%) of white powder, mp 161°-164° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>>[CH:17]1[CH:18]=[CH:19][C:14]([NH:13][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=CNc1ccccc1
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1

Procedure:
combining in a reaction zone paranitrochlorobenzene and a molar excess of formanilide at condensation temperature for forming 4-nitrodiphenylamine and
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].Br.N([O-])=O.[Na+].[OH-:17].[Na+]>O>[CH3:11][C:7]1[C:3]2[C:4](=[O:5])[O:6][C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[O:17][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: Cc1cccc(N)c1C(=O)O
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc2c1C(=O)Oc1ccccc1O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Cuprous bromide was added in one portion to a hot solution (90° C.) of 2-amino-6-methylbenzoic acid (10 g, 66 mmol) and HBr (26 mL, 40%) in H2O (160 ml). This was followed by the dropwise addition of a solution of NaNO2 (13.7 g, 198 mmol) in H2O (40 ml) over a period of 25 min. The reaction mixture was maintained at same temperature for 1 h and then was heated under reflux for another 0.5 h before it was cooled to room temperature and stirred for 2 h. Upon completion, the reaction mixture was carefully poured into ice water (1000 ml), and 5% NaOH solution was added until a pH of 14 was reached. The resulting suspension was filtered. The filtrate was acidified with diluted HCl to a pH of 1 and extracted with Et2O, Charcoal was added, and the resulting mixture was heated to reflux, filtered and evaporated by a rotatory evaporator to give a crude compound, which was recrystallized from Et2O/PE to afford the product (9.28 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[S:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[N:15]=[CH:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:18]([C:16]3[N:15]=[CH:14][S:13][CH:17]=3)=[O:19])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cccc2ccc(Cl)nc12
Reactant: O=C(O)c1cscn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2ccc(Cl)nc12)c1cscn1
Yield: 67 %

Procedure:
A solution of 2-chloroquinolin-8-amine (222 mg), thiazole-4-carboxylic acid (129 mg, 1 eq), HATU (570 mg, 1.5 eq), and DIEA (246 uL, 2.0 eq) in DMF (3 mL) was stirred at room temperature overnight. The product was precipitated by the addition of water (20 mL), the product was collected by filtration and recrystallized from methanol to obtain the product as a grey solid (194 mg).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][C:21]([O:23]C)=O)[CH:3]=1.[CH3:25][NH2:26].CO>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][C:21]([NH:26][CH3:25])=[O:23])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)OC
Reactant: CN
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)NC
Reaction time: 16 h
Yield: 76 %

Procedure:
To a suspension of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxy-2-oxoethoxy)benzamide (1.074 g, 3 mmoles) (prepared in Example 15), in a 1N solution of methylamine in toluene (10 ml) was added 3 ml of methanol and the mixture stirred for 16 hours. This was concentrated in vacuo and the residue crystallized from methanol-ether to give 815 mg (76%) of the title compound as white solid; mp. 149°-151° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: COCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
6-Amino-9-benzyl-2-(2-methoxyethoxy)purine (93 mg, 0.31 mmol) and bromine (1 ml) were dissolved in methylene chloride (100 ml). The solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (75 mg, yield 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[CH3:14][N:15]([C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>O=S(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:25]3[CH2:26][CH2:27][C@@H:23]([N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:24]3)=[O:13])[S:10][C:3]=12
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 37 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (1.05 g, 4.94 mmole), SOCl2 (10 ml), tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate 34b (0.989 g, 4.94 mmole) and Et3N (0.689 ml, 4.94 mmole) in a manner as previously described for example 9d to give a brown oil (0.723 g, 0.30%). 1H NMR (300 MHz, CDCl3) δ8.62 (1H, d, J=5.1 Hz), 7.85 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.82 (1H, m), 3.93 (3H, m), 3.63 (1H, m), 2.82 (3H, s), 2.12 (2H, m), 1.47 (9H, s); ESIMS (MH+): 396.05.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([C:17]#[N:18])[CH:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:25]NC(=O)CCC(N)=O.O.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([C:17]#[N:18])[C:16]([I:25])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(cc(C#N)c2-c2ccccc2)C1
Reactant: NC(=O)CCC(=O)NI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(c(I)c(C#N)c2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
A solution of 7-cyano-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (8.6 g, Reference Example 4(b)) in dry dimethylformamide (80 mL) was treated with N-iodosuccinamide (6.07 g) over 10 minutes. After stirring at room temperature for a further 4 hours the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, further washed with water, then dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give the title compound (7.50 g) as a buff solid, m.p. 174–178° C. 1H NMR [(CD3)2SO]: δ 7.58–7.48 (m, 5H), 4.43 (s, 2H), 3.97 (t, 2H), 3.65 (t, 2H) and 1.46 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[S:10])[CH:5]=[CH:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:11][C:12](=[O:14])[CH3:13])[S:10][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC(=S)Nc1cccc(I)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC(=NC(C)=O)Nc1cccc(I)c1

Procedure:
19.1 g (0.05 M) of N-(3-iodophenyl)-N'-acetylthiourea, 4.2 g (0.03 M) of potassium carbonate, 3.8 ml (0.06 M) of methyliodide and 100 ml of acetone are boiled during 4 hours. The acetone is distilled off. Water is added to the residue, it is heated up to 50°-60° and is ground. The sediment is filtered. After drying 19.8 g (100% of the theoretical yield) of N-(3-iodophenyl)-N'-acetyl-S-methylisothiourea are obtained with a melting point of 80°-90° C. After being twice recrystallized from ethanol and isopropanol, 9.9 g (50% of the raw product) of N-(3-iodophenyl)-N'-acetyl-S-methylisothiourea are obtained with a melting point of 92°-93°.
Reaction SMILES: C(N(CC)C(C)C)C.[C:9]1([C:15]2[N:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([NH2:34])[CH:29]=[CH:28]2>C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([NH:34][C:21]([C:18]1[CH:17]=[N:16][C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:20][CH:19]=1)=[O:22])[CH:29]=[CH:28]2
Reactant: Nn1ccc2cc(F)ccc21
Reactant: O=C(Cl)c1cnc(-c2ccccc2)nc1
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
Diethyl-iso-propylamine (2.30 mmol) is added to a stirred solution of 2-phenyl-pyrimidine-5-carboxylic acid chloride (1.15 mmol) and 5-fluor-indol-1-ylamine (1.15 mmol) in DCM (20 mL) at rt. The reaction mixture is stirred at rt overnight and concentrated in vacuo. The residue is dissolved in EtOAc (30 mL), then washed with 5% HCl (10 mL), water (10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10-40% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (185 mg, 49%) as a solid. MS: 333 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.56 (s, H) 7.02 (m, H), 7.10-7.38 (m, 4H), 7.55 (s, 3H), 8.53 (s, 2H), 8.70-9.40 (br, 2H). IC50=3 nM.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:5][CH2:6][C:7]#[N:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH:3]([CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:5][CH2:6][C:7]#[N:8])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCC(CO)CCCC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(CCCC#N)COS(C)(=O)=O
Reaction time: 3 h

Procedure:
To a solution of 2679 g of 6-hydroxy-5-(2-propenyl)-hexanenitrile in 25 l of methylene chloride is added 2681 ml of triethylamine. The mixture is cooled to -10° in an ice salt bath and a solution of 2103 g of methanesulfonyl chloride in 2 l of methylene chloride is added dropwise over 3 h keeping the temperature at -5°. After addition is complete, the mixture is stirred for 3 h in an ice salt bath and then overnight at 10°. The mixture is washed with water, saturated sodium bicarbonate solution, water and then brine, dried over sodium sulfate, evaporated to dryness, and dried at 45°/3 mm Hg (=4.00 mbar) to yield 6-methylsulfonyloxy-5-(2-propenyl)-hexanenitrile.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[Cl:20][C:21]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cccc(Cl)c1Cl
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Clc1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1Cl

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2,3-dichlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 370.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.58 (s, 1H); 8.44 (d, J=5.5 Hz, 1H); 7.93 (br s, 1H); 7.85 (d, J=8.3 Hz, 1H); 7.19 (t, J=5.8 Hz, 1H); 6.86 (d, J=5.5 Hz, 1H); 5.88 (br s, 1H); 4.86 (d, J=6.4 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[NH2:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[F:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1
Reactant: Fc1ccc(F)c(F)c1
Reactant: Cn1ccc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(F)cc4F)cc23)n1

Procedure:
The compound of Example 92 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2,4-trifluorobenzene, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][CH:17]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][N:18]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([O:15][CH2:16][CH:17]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:20][CH2:19][N:18]2[C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Reactant: Oc1cccnc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(COc2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diisopropylazodicarboxylate (2.67 mL, 13.5 mmol) in THF (25 mL) was added dropwise over 1 h to a solution of 4-tert-butyl 1-benzyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (4.52 g, 12.9 mmol), 3-hydroxypyridine (1.35 g, 14.2 mmol) and triphenylphosphine (3.55 g, 13.5 mmol) in THF (75 mL) at 15° C. After complete addition, the reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was concentrated under reduced pressure and purified by column chomatography (10 to 40% EtOAc in Hexanes gradient). This gave 0.9055 g (16%) of the title compound. Rf=0.35 in 80% EtOAc/Hexanes; LC-MS: RT=9.85 min; [M+H]+=428.2.