Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH2:50])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1>CN(C=O)C>[S:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH:50][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, 2.66 g (15.2 mmol) of N-methoxycarbonyl-(L)-valine, 5.46 g (28.5 mmol) of EDC and 2.57 g (19 mmol) of HOBT are dissolved in 42 ml of DMF. 7.9 ml (57 mmol) of TEA are added and after 20 min a solution of 4.46 g (9.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 2b) in 85 ml of DMF is added dropwise. After 1.5 hours, the reaction mixture is worked up analogously to Example 2c. Crystallisation from THF/ether yields the title compound: m.p: 114°-115° C.; HPLC20-100 : tRet =15.1; FAB MS (M+H)+ =626.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[S:31]([CH3:30])(=[O:33])=[O:32])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1S(C)(=O)=O
Yield: 76 %

Procedure:
Using a similar process to that described in Example 29, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (300 mg) was reacted with methane sulfonyl chloride to give the title product (250 mg, 76%); 1H NMR Spectrum: (DMSO d6) 1.88-2.12 (m, 4H); 2.99 (s, 3H); 3.30-3.34 (m, 2H); 3.94 (s, 3H); 4.02 (m, 1H); 4.15 (m, 2H); 7.15-7.30 (m, 2H); 7.40-7.55 (m, 2H); 7.81 (s, 1H); 8.36 (s, 1H); 9.62 (s, 1H); Mass Spectrum: (M+H)+ 481.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][NH:16][CH2:17][C:18]#[CH:19].C(N(CC)CC)C>O1CCCC1>[CH2:17]([N:16]([CH3:15])[S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[C:18]#[CH:19]
Reactant: C#CCNC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN(C)S(=O)(=O)c1ccc(OC)c(OC)c1
Yield: 64.8 %

Procedure:
3,4-Dimethoxybenzene sulfonyl chloride (11.8 g) in tetrahydrofuran (100 mL) is added slowly with stirring to a mixture of N-methylpropargylamine (3.5 g), triethylamine (5.05 g), and tetrahydrofuran (100 mL). The resulting mixture is refluxed 1 hour, cooled, filtered, and evaporated to dryness. The residue is treated with water, filtered, washed with water, and dried. Recrystallization from ethanol gave 8.7 g of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([N+:13]([O-:15])=[O:14])=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)Nc1ccc(F)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)acetamide (55 g) in concentrated sulfuric acid (165 ml) was added dropwise concentrated nitric acid (d 1.42, 154 ml) at 5°-10° C. during an hour with stirring in an ice-salt bath. After stirring for an hour at the same temperature, the reaction mixture was poured into ice water. The resulting precipitate was collected by filtration, sufficiently washed with water and recrystallized from acetonitrile to give the title compound (48.9 g) as yellow needles, mp 114°-115° C.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N+:13]1[CH:14]([C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:16][C:17]=1OCC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC.[CH3:32][N+:33]([O-:35])=[O:34]>C(Cl)Cl>[CH3:24][O:23][C:21]([CH:14]1[CH2:15][CH2:16][C:17](=[CH:32][N+:33]([O-:35])=[O:34])[N:13]1[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:22]
Reactant: C[N+](=O)[O-]
Reactant: CCOC1=[N+](Cc2ccccc2)C(C(=O)OC)CC1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(=C[N+](=O)[O-])N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To the mixture obtained in Example 1C (0.2 mol) in 130 mL CH2Cl2 at ambient temperature was added Et3N (33.5 mL, 0.24 mol) followed by CH3NO2 (13 mL, 0.24 mol). The mixture stirred at ambient temperature for 8 h then was diluted with CH2Cl2, the layers were separated and the organic layer was washed with 20 mL 5% H2SO4 and 20 mL brine. The organic layer was dried over anhydrous Na2SO4, concentrated and purified via column chromatography (SiO2, 50% hexanes-EtOAc) to give 10.2 g of the title compound (36.9 mmol). MS (DCl/NH3) m/z 277 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:33]1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C1CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])[C:11]([CH3:30])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:16][CH2:33]1
Reactant: Cc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-6-cyclopropyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.87-1.03, 1.60-1.69, 2.42, 2.71, 3.03, 3.25, 4.73, 4.99, 5.53, 7.12-7.66; MS (ESI+) for C23H21Cl2N3O m/z 426 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][Si](C(C)(C)C)(C)C)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(Cl)Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)c2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1cc(Br)c2[nH]ccc2c1
Reaction time: 1 h

Procedure:
Combine 7-bromo-5-(tert-butyldimethylsilanyloxy)-1H-indole and methylene chloride and treat with tetrabutyl ammonium fluoride (1.0 eq.) at 0° C. After the mixture is stirred for about 1 hour, pour into ethyl acetate, wash with brine, dry the organic layer over Na2SO4 and concentrate. Purify to give 7-bromo-5-hydroxy-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.[C:17](Cl)(Cl)=[S:18]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:6]=[C:17]=[S:18]
Reactant: NCc1cccc(F)c1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cccc(CN=C=S)c1
Temperature: -10 °C
Reaction time: 2.75 h
Yield: 51.4 %

Procedure:
A solution of 3-fluorobenzylamine (6.3 g, 0.05 mole) and triethylamine (15.4 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and filtered. The filtrate was treated with charcoal, then filtered and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column eluted with hexane:ethyl acetate (90:10) to yield 4.3 g (51%) of 3-fluorobenzyl isothiocyanate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:24])[N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:13]=1.S(OC)(O[CH3:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:10]=[C:11]([O:24][CH3:29])[N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:21])[F:22])[N:13]=1
Reactant: COS(=O)(=O)OC
Reactant: O=c1[nH]c(-c2c(F)cccc2F)nn1-c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc(-c2c(F)cccc2F)nn1-c1ccccc1C(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 3.75 g (11.0 mmol) of 5-(2,6-difluorophenyl)-2-(α,α,α-trifluoro-o-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 1.05 g (11.0 mmol) of dimethyl sulfate and 3.04 g (22.0 mmol) of potassium carbonate in acetone is stirred at the reflux temperature for 16 hours. The insoluble constituents are then filtered off and the evaporated residue is subjected to chromatography on silica gel using ethyl acetate/n-hexane (1:4) as the eluent. As the first fraction there is isolated the apolar secondary component 3-(2,6-difluorophenyl)-5-methoxy-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole, m.p. 118°-119° C.; mass spectrum: 355(75), 298(39), 159(100); 1H-NMR (CDCl3): 4.13 (s, OCH3). After further elution with ethyl acetate/n-hexane (2:3) and subsequent recrystallization from diethyl ether/n-hexane there is obtained pure 5-(2,6-difluorophenyl)-4-methyl-2-(α,α,α-trifluoro-o-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, m.p. 98°-99° C., IR spectrum: 1708 cm-1 ; mass spectrum: 355(75), 298(32), 159(100); 1H-NMR (CDCl3): 3.30 (s,N-CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=1[F:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2cc(F)cc(F)c2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2cc(F)cc(F)c2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
1.80 g of 5-(4-chlorophenyl)-6-methyl-4-(2,3,5-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.83 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2,3,5-trifluorophenyl)pyridazine (hereinafter, referred to as compound (viii) of the present invention).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.C[N:18](C=O)C>C1COCC1>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1c(F)ccc(C(=O)O)c1Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(F)ccc(C(N)=O)c1Cl

Procedure:
To a solution (60 ml) of 2-chloro-4-fluoro-3-methylbenzoic acid (5.66 g) synthesized by a known method in THF were added thionyl chloride (10.7 g) and DMF (0.2 ml) with stirring under ice-cooling, and the mixture was stirred at 70° C. for 3 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in dry THF (50 ml) and added dropwise to a mixture of concentrated aqueous ammonia (130 ml) and THF (86 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated crystals were collected by filtration, washed with diethyl ether and dried to give 2-chloro-4-fluoro-3-methylbenzamide (4.82 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Reactant: C#C[Si](C)(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#C[Si](C)(C)C)cnc12
Yield: 79.7 %

Procedure:
Prepared from 6-(4-chloro-phenyl)-3-iodo-8-methyl-imidazo[1,2-a]pyridine (example C.21 step 2) (3.686 g, 10 mmol) and trimethylsilylacetylene (2.8 mL, 20 mmol) as described in example C.20 step 4. Obtained the title compound as a yellow foam (2.70 g, 80%). MS (ISP) 339.1 [(M+H)+], 341 [(M+2+H)+].
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=3)[C:19]3[C:18](C4C=CC=CC=4)=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[B:44](OC)([O:47]C)[O:45]C.Cl>O1CCCC1>[C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][C:29]([B:44]([OH:47])[OH:45])=[CH:28][CH:27]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(C2(c3ccccc3)c3ccccc3-c3cccc(-c4ccccc4)c32)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)cc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
First, 4.0 g (10 mmol) of 9-phenyl-9-(4-bromophenyl)-phenyl-9H-fluorene was put in a 500 mL three-neck flask, the atmosphere in the flask was replaced with nitrogen, 100 mL of dehydrated tetrahydrofuran (abbreviation: THF) was then added to the flask, and the temperature was lowered to −78° C. Into this mixture solution, 7.6 mL (12 mmol) of a 1.59 mol/L n-butyllithium hexane solution was dropped, and the mixture was stirred for 2 hours. To this mixture, 1.4 mL (15 mmol) of trimethyl borate was added, and the mixture was stirred at −78° C. for 2 hours and at room temperature for 18 hours. After the reaction, this reaction solution was stirred while 1M diluted hydrochloric acid was added thereto until the solution became acid. This solution was subjected to ethyl acetate extraction, and an organic layer obtained was washed with a saturated saline. After the washing, magnesium sulfate was added to the organic layer to adsorb moisture. This suspension was filtered, the obtained filtrate was concentrated, and hexane was added thereto. The mixture was irradiated with ultrasonic waves and then recrystallized to obtain 3.5 g of the objective white powder in 97% yield. The reaction scheme of the synthesis method is shown in the following (A-1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:17]1[CH:18]=[N:19][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: Nc1ccc(I)cc1Cl
Reactant: O=C(O)c1ccnc(F)c1
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
synthesized as intermediate 1 by reacting 15.7 mmol of 2-chloro-4-iodoaniline with 23,55 mmol 2-fluoroisonicotinic acid. LC/MS [(5.9 min; 376 (M+1)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[CH:44][CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[CH:44][CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=C(O)CCc1ccc(Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCC(=O)O)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 3-(4-bromo-phenyl)-propionic acid (47 mg), in the same manner as Step A in Example 1-D-19, 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-propionic acid was obtained as a crude product (65 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[NH:16][C:15]([CH2:17][CH2:18][CH3:19])=[N:14][C:13]=1[C:20]([OH:23])([CH3:22])[CH3:21])=[O:11])[CH3:8].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C(#N)C>[CH2:7]([O:9][C:10]([C:12]1[N:16]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Br:24])=[CH:26][CH:27]=2)[C:15]([CH2:17][CH2:18][CH3:19])=[N:14][C:13]=1[C:20]([OH:23])([CH3:21])[CH3:22])=[O:11])[CH3:8]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
The mixture of 240 ml acetonitrile, 20.7 g (150 mmol) of K2CO3, 18 g (75 mmol) of ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate and 20.4 g (81.6 mmol) of 4-bromobenzylbromide was heated under reflux temperature for 7 h. The suspension is cooled, filtered and concentrated under reduced pressure to approximately ⅓ of the starting volume and stirred at about 0° C. for 1 h. The precipitate is filtered and dried at 35° C. for 1 h and afterwards suspended in 218 ml of water. The mixture is stirred for 2 h, filtered and dried again. 21.56 g of the crude product were isolated. Crude product was recrystallized from acetonitrile (87%, 55% of the synthesis)
Reaction SMILES: [CH3:1][N:2]([CH3:46])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:45])[C:14]3[N:15]([CH3:44])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:26]([N:28]5[CH2:33][CH2:32][N:31](C(OCC6C=CC=CC=6)=O)[CH2:30][CH2:29]5)=[O:27])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].C1CCCCC=1>CO.[Pd]>[CH3:1][N:2]([CH3:46])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:45])[C:14]3[N:15]([CH3:44])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:26]([N:28]5[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]5)=[O:27])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7]
Reactant: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(OC(=O)N4CCN(C(=O)OCc5ccccc5)CC4)ccc3n(C)c12
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCCC1
Product: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(OC(=O)N4CCNCC4)ccc3n(C)c12
Yield: 78.4 %

Procedure:
2.6 g of 1-[(2-dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-[(4-benzyloxycarbonyl-piperazino)carbonyloxy]-6H-pyrido[4,3-b]carbazole, 5 ml of cyclohexene and 1 g of 10% palladium-on-carbon in 260 ml of methanol are refluxed for 45 minutes. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is chromatographed on silica using a mixture of dichloromethane, methanol and ammonia (85:15:1) as eluant. The product obtained is washed with diethyl ether and ethanol to yield 1.6 g of the desired product, m.p.(cap): 230-234° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=O>C(O)C>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:15]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2cn3cccc(OCc4ccccc4)c3n2)cc1
Yield: 24.9 %

Procedure:
3-(Benzyloxy)pyridin-2-amine (2.52 g, 13 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (2.73 g, 13 mmol) in ethanol (30 mL) were heated at 75° C. for 16 hours. The mixture was concentrated and the residue was purified by silica gel chromatography, eluting with dichloromethane and then 10% methanol in dichloromethane to yield 1.03 g (25%) of 8-(benzyloxy)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine. 1H NMR (CDCl3): δ 8.01 (dd, 2H), 7.82 (s, 1H), 7.78 (d, 1H), 7.55 (d, 2H), 7.41 (m, 3H), 7.14 (t, 2H), 6.65 (t, 1H), 6.48 (d, 1H), 5.44 (s, 2H); MS m/z 319 (M+1).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([O-:13])=[O:12]>CN1C(=O)CCC1.C(OCC)(=O)C>[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Nc2nc3ccccc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
A mixture of 2-chlorobenzimidazole (10.0 g) and 4-nitroaniline (9.05 g) in NMP (130 mL) was stirred at 120° C. for 3 days. After this time, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (750 mL) and washed with water (750 mL). The aqueous layer was extracted with ethyl acetate (750 mL) and the combined organic extracts were washed with water (3×750 mL) then brine (750 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was triturated with 1:1 ethyl acetate/heptane (200 mL) and the solid that formed was collected by filtration to afford N-(4-nitrophenyl)-1H-benzimidazol-2-amine (4.00 g) as an orange solid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:11])[CH2:8][CH:9]=[CH2:10]>CCOCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:7]([O:11][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:8][CH:9]=[CH2:10]
Reactant: C1=COCCC1
Reactant: C=CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C=CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
To a chilled solution (0° C.) of 3,4-dihydro-2H-pyran (117 g, 1.4 mol) in anhydrous ether (600 mL) were added p-toluensulfonic acid (0.5 g) and 3-buten-1-ol (25.0 g, 0.35 mol). The resulting mixture was stirred at room temperature for 5 h and was then quenched by the addition of concentrated ammonium hydroxide (5 mL) and methanol (50 mL). The solvent was evaporated in vacuo, and ether was added to the residue. The precipitated ammonium p-toluenesulfate was filtered, the filtrate was concentrated, and the crude product was purified by flash column chromatography on silica gel (0-5% ethyl acetate in hexanes) to give 2-(3-butenyloxy)tetrahydropyran (49 g, 90%) as colorless viscous liquid: 1H-NMR (CDCl3, 300 MHz,) δ 5.80-5.89 [m, 1H, ═CH—C], 5.02-5.06 [m overlapping, 2H, ═CH2], 4.59-4.60 [m, 1H, 2-H of THP], 3.77-3.83 [m, 2H, —CH2O], 3.44-3.50 [m, 2H, CH2O of THP], 2.33-2.38 [m, 2H, CH2—CH═CH2], 1.51-1.71 [m, 6H, Hs of THP].