Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC.C(=O)C>>[CH3:11][NH:10][CH2:9][CH2:8][N:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[CH3:1]
Reactant: C[C@H]1CCCN1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: CNCCN1CCC[C@@H]1C

Procedure:
By using (S)-2-methyl-pyrrolidine (250 mg) as a starting material, the title compound (0.34 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 39, (2).
Reaction SMILES: CCl.[C:3]1([CH3:13])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[CH2:10][CH3:11].C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Br-:31]>C1COCC1>[Br:31][CH:10]([CH3:11])[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:13])=[O:12]
Reactant: CCC(=O)c1ccccc1C
Reactant: [Br-]
Agent: CCl
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)C(C)Br

Procedure:
To a 50 ml round bottomed flask with stirring bar and an argon inlet was added CH3Cl (10 ml), THF (5 ml), 1-o-tolyl-propan-1-one (318 mg, 2.14 mmol, and pyridium bromide perbromide (735 mg, 2.36 mmol). This solution was stirred at ambient temperature for 2 h. The reaction mixture was washed with 5% aqueous HCl, H2O, and brine. Drying (MgSO4), filtration and removal of sovent in vacuo gave an oil. This material was chromatographed (Silica gel, 5% EtOAc/Hexane) to affort the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([O:25]C)=O)[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:27].CO>>[N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([NH2:27])=[O:25])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N
Reactant: COC(=O)c1cccc2c(N[C@H](C)c3cccc([N+](=O)[O-])c3)ncnc12
Solvent: CO
Product: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc([N+](=O)[O-])c1

Procedure:
A suspension of Methyl 4-{[(1R)-1-(3-nitrophenyl)ethyl]amino}quinazoline-8-carboxylate (7.26 g, 20.60 mmol) in 7 N ammonia/methanol (100 mL)
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[C:43]([NH2:47])([CH3:46])([CH3:45])[CH3:44]>>[C:43]([NH:47][C:29]([C:26]1[C:24]2=[N:25][C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:21]([N:35]3[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]3)[C:22]([Cl:34])=[C:23]2[O:28][N:27]=1)=[O:31])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NC(C)(C)C)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and t-butylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:21])=[O:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccc(Cl)cc2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 20 °C

Procedure:
47 g of 3-p-chloro benzoyl-benzoic acid were added to 470 cc of thionyl chloride and the mixture was refluxed for 3 hours and then cooled to 20° C. The mixture was concentrated to dryness by distillation under reduced pressure to obtain a residue of 3-p-chlorobenzoyl-benzoic acid chloride which as far as is known is not described in the literature. 54.8 gm of the said acid chloride were added to 500 cc of methylene chloride and after cooling to 5° C., 1.5 liters of a solution of 15.2 g per liter of diazomethane in methylene chloride was added thereto over 20 minutes.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].N#N.[CH3:9][C:10]1[N:11]([CH:32]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH3:33])[C:12]2[C:17]([C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:15]=[C:14](B1OC(C)(C)C(C)(C)O1)[CH:13]=2.Br[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:9][C:10]1[N:11]([CH:32]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH3:33])[C:12]2[C:17]([C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:15]=[C:14]([C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH:13]=2
Reactant: Brc1cccnc1
Reactant: COC(=O)c1c(C)n(C(C)C2CCOCC2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(C)n(C(C)C2CCOCC2)c2cc(-c3cccnc3)ccc12
Temperature: 100 °C
Yield: 35.9 %

Procedure:
To a re-sealable vial was added K2CO3 (206 mg, 1.488 mmol), PdCl2(dppf)-CH2Cl2 adduct (60.8 mg, 0.074 mmol), and the vial was sealed. This vial was evacuated/backfilled with N2 (3×) before addition of (R or S)-methyl 2-methyl-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxylate (318 mg, 0.744 mmol) dissolved in 1,4-dioxane (4 mL), 3-bromopyridine (71.7 μl, 0.744 mmol), and water (400 μL). The reaction was evacuated/backfilled with N2 (3×) before heating to 100° C. The solution was cooled to room temperature and diluted with EtOAc. The solution was filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (10 g, EtOAc/hex (1:1)) to afford the title compound (101 mg, 0.267 mmol, 35.9% yield). LCMS 379 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][C:7](=[O:9])[CH:6]=[CH:5][CH2:4]1.[C:10](Cl)(=[O:12])[CH3:11].O>ClCCl>[C:10]([O:1][CH2:2][C@H:3]1[CH2:8][C:7](=[O:9])[CH:6]=[CH:5][CH2:4]1)(=[O:12])[CH3:11]
Reactant: O=C1C=CC[C@@H](CO)C1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC[C@@H]1CC=CC(=O)C1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
76 cm3 of triethylmmine are added to a solution, cooled to +5° C., of 62 g of (R)-5-hydroxymethylcyclohex-2-en-1-one [prepared according to the method described by Kenji Mori et al., Tetrahedron, Vol. 48, No. 24, 8075-8082 (1990) incorporated herein by reference] in 600 cm3 of dry dichloromethane, and then 38.4 cm3 of acetyl chloride are run in over the course of 30 minutes. After stirring at +5° C. for one hour and at 20° C. for one hour, 1 liter of water is added slowly to the mixture. The separated organic phase is washed with 1 liter of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 80 g of (R)-5-acetoxymetylcyclohex-2-en-1-one are obtained in the form of an orange-coloured oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27](OB(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].C(OC1C=C(C=C(OCC)C=1C1C=CSC=1)CC1C(N)=NC(N)=NC=1)C>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:8]2[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1[C:28]1[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[C:30]([O:31][CH3:32])[CH:29]=1)[CH3:2]
Reactant: COc1ccc(OB(O)O)cc1OC
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Agent: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccsc1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(OC)c(OC)c1

Procedure:
Starting from 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (414 mg; 1.0 mmol) and 3,4-dimethoxy-phenyl-boric acid (363 mg; 2.0 mmol), 328 mg (77%) 5-(3,5-diethoxy-4-thiophen-3-yl-benzyl)-pyrimidine-2,4-diamine [sic] are obtained as a yellowish powder after recrystallization from methanol.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O.C(O)C>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 2.1 g. of ethyl 4-(5H-dibenzo[a,d]cycloheptene-Δ5,α -acetamido) benzoate, 300 mg. of sodium hydroxide, 8 ml. of water, and 250 ml. of ethanol is refluxed for 4 hours, cooled, diluted with 500 ml. of water, and acidified with concentrated hydrochloric acid. After cooling and stirring for 30 minutes, the solid is collected, washed with water, dried, dissolved in 50 ml. of acetone, and filtered. To the filtrate is added 75 ml. of acetonitrile. The solvent is partially evaporated, and the solid is collected by filtration to yield 1.5 g. of the desired product as a white solid, m.p. 248°-250° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([CH:25]=3)[C:21](OC)=[O:22])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[BH4-].[Li+]>O1CCCC1>[OH:22][CH2:21][C:20]1[CH:25]=[C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:28][CH:27]=2)[CH:17]=[CH:18][C:19]=1[CH3:26]
Reactant: COC(=O)c1cc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)ccc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A reactor is charged with 100 mg (0.26 mmol) of methyl 5-(4-((4-methylpiperazin-1-yl)methyl)benzamido)-2-methylbenzoate (example 82, step 2) in 5 ml anhydrous tetrahydrofuran and 38 mg (1.75 mmol) of lithium borohydride is added. The mixture is stirred at room temperature for 16 hours. The mixture is then concentrated under reduced pressure, taken off into 60 ml of ethyl acetate, washed with 20 ml of a saturated NaHCO3 solution, 20 ml of water and 20 ml of a saturated NaCl solution. The organic phase is dried, evaporated and the residue is taken off and triturated into ethylic ester to give a solid (80 mg, 86%)
Reaction SMILES: Br[C:2]1[C:27](=[O:28])[N:26]2[C:5]([O:6][C@H:7]3[CH2:36][N:10]([C:11](=[O:35])[C@H:12]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[NH:13][C:14](=[O:29])[O:15][C@H:16]4[C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:19][CH2:18][CH2:17]4)[C@H:9]([C:37]([O:39][CH3:40])=[O:38])[CH2:8]3)=[CH:4][CH:3]=1.[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.S(=O)(=O)(O)[O-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:30]1([C@H:12]2[C:11](=[O:35])[N:10]3[CH2:36][C@@H:7]([CH2:8][C@H:9]3[C:37]([O:39][CH3:40])=[O:38])[O:6][C:5]3[N:26]([C:27](=[O:28])[C:2]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:3][CH:4]=3)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C@@H:16]([CH2:17][CH2:18][CH2:19]3)[O:15][C:14](=[O:29])[NH:13]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCCn1c(ccc(Br)c1=O)O2
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCCn1c(ccc(-c3ccccc3)c1=O)O2
Temperature: 80 °C
Yield: 75 %

Procedure:
An oven-dried 100 mL Kjeldahl Flask under nitrogen was charged with the product of Example 83 Step 1 (100 mg, 0.161 mmol), dioxane (5 ml), phenylboronic acid (24.48 mg, 0.201 mmol), cesium carbonate (65.4 mg, 0.201 mmol), tricyclohexylphosphine (13.51 mg, 0.048 mmol), and tris(dibenzylideneacetone)dipalladium(0) (17.65 mg, 0.019 mmol). Heated in an 80° C. oil bath for 20 hours. HPLC/MS looks good. Cooled. Poured into 2.5% potassium bisulfate. Extracted three times with ethyl acetate, washed combined organic portions with brine, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate. Subjected to ISCO chromatography eluting with a hexane/ethyl acetate gradient. Evaporation of fractions containing product gave the title compound as a white solid remained. (75 mg, 0.121 mmol, 75% yield). LCMS (ES+) m/z 620.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:36][CH2:37][C:38]1[N:42]([C:43]2[S:44][C:45]([CH2:57][CH3:58])=[CH:46][C:47]=2[C:48](=[O:56])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])[C:41]([CH3:59])=[N:40][N:39]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:48]([C:47]1[CH:46]=[C:45]([CH2:57][CH3:58])[S:44][C:43]=1[N:42]1[C:41]([CH3:59])=[N:40][N:39]=[C:38]1[CH2:37][NH:36][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:13])=[O:56]
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3cc(F)ccc3[nH]2)s1
Reaction time: 4 h
Yield: 15.8 %

Procedure:
5-Fluoroindole-2-carboxylic acid (0.50 g) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole ditosylate (2.07 g) were dissolved in dimethylformamide (40 ml). Triethylamine (1.6 ml) and 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 1.29 g) were added under ice-cooling, and the mixture was stirred for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with an aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was crystallized from ethyl acetate to give 0.23 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-5-fluoroindole-2-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1=[O:23]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][NH:17][C:18](=[O:23])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CN(Cc2ccc(Br)cc2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and piperazin-2-one (0.81 g, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (1.0 g, 93%). 1H NMR (CDCl3, 300 MHz): δ 7.49-7.43 (m, 2H); 7.24-7.16 (m, 2H); 6.20 (s, 1H); 3.53 (s, 2H); 3.38-3.32 (m, 2H); 3.15 (s, 2H); 2.66-2.59 (m, 2H).). LCMS (Method G): RT=2.54 min, M−H+=268.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:46][CH2:47][C:48]([C:55]1[CH:60]=[C:59]([CH3:61])[N:58]=[C:57]([NH:62][CH:63]([CH3:65])[CH3:64])[N:56]=1)([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([NH:46][CH2:47][C:48]([O:52][CH2:53][CH3:54])([O:49][CH2:50][CH3:51])[C:55]2[CH:60]=[C:59]([CH3:61])[N:58]=[C:57]([NH:62][CH:63]([CH3:64])[CH3:65])[N:56]=2)=[O:15])=[CH:11][C:10]=1[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Reactant: CCOC(CN)(OCC)c1cc(C)nc(NC(C)C)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(CNC(=O)c1cc(C)c(OCc2ccccc2)c(CC)c1)(OCC)c1cc(C)nc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
To a solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid (224 mg, 0.83 mmol) in DMF (5 mL), EDC (175 mg, 0.91 mmol) and HOBt (124 mg, 0.91 mmol) are added. The mixture is stirred at rt for 15 min before DIPEA (0.57 mL, 3.3 mmol) and a solution of crude [4-(2-amino-1,1-diethoxy-ethyl)-6-methyl-pyrimidin-2-yl]-isopropyl-amine dihydrochloride (174 mg, 0.83 mmol) in DMF (2.0 mL) is added. The mixture is stirred at rt for 4 h, diluted with EtOAc (30 mL), and washed with sat. aq. NaHCO3 (15 mL) and brine (15 mL). The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates with Heptane/EtOAc 1:1 to give 4-benzyloxy-N-[2,2-diethoxy-2-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-ethyl]-3-ethyl-5-methyl-benzamide (348 mg) as a yellow oil; LC-MS: tR=1.02 min, [M+H]+=535.22.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][O:25][CH2:24]4)[C:10]=3[C:17]=2[CH3:18])=[O:20])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12
Reactant: NCCCN1CCCC1
Product: Cc1c(C(=O)NCCCN2CCCC2)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 4-{4-fluoro-2-[(R)-(tetrahydro-pyran-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 3-pyrrolidin-1-yl-propylamine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>CO>[N+:25]([C:24]1[C:18]2[N:17]=[C:16]([NH:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[NH:20][C:19]=2[CH:21]=[CH:22][CH:23]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3c([N+](=O)[O-])cccc3[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=[N+]([O-])c1cccc2[nH]c(NCC3CCNCC3)nc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
After dissolving 4-[(4-nitro-1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (13 mg) in methanol (1 ml), a 4N hydrogen chloride-1,4-dioxane solution (1 ml) was added and the mixture was stirred at 60° C. for 1 hour. The solvent was distilled off under reduced pressure, aqueous sodium hydroxide and dichloromethane were added to the obtained residue, and extraction was performed with dichloromethane. The solvent was distilled off under reduced pressure to obtain (4-nitro-1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine. The compound was identified by LC-MS.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: CSc1cccc(N=C=O)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(SC)c3)c(=O)n(C3CCCC3)c12
Yield: 64.6 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(3-methylsulfanyl-phenyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (28 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-3-methylsulfanyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 434 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([S:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][S:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13])[CH3:19]
Reactant: COc1ccc2c(c1)C(=O)CCS2
Reactant: CCOC(OCC)N(C)C
Product: COc1ccc2c(c1)C(=O)C(=CN(C)C)CS2

Procedure:
The 3,4-dihydro-2-dimethylaminomethylene-7-methoxy-4-thia-1(2H)-naphthalenone starting material was prepared from 3,4-dihydro-7-methoxy-4-thia-1(2H)naphthalenone (1.0 g, 5.2 mmol [Degani, I. et al, Boll. Sci. Fac. Chim. Ind. Bologna (1966), 24(2-3) 75-91], and N,N-dimethylformamide diethyl acetal (2.7 ml, 15.6 mmol) to give the product as a mustard yellow solid (1.06 g). δH (CDCl3) 7.63 (1H, J 2.9 Hz), 7.60 (1H, s), 7.17 (1H, d, J 8. Hz), 6.90 (1H, dd, J 2.9, 8.4 Hz), 3.98 (2H, s), 3.83 (3H, s) and 3.15 (6H, s). MS(EI+) 249 (M+, 66%), 205 (13%), 177 (59%), 82 (100%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:27]=[N:26][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([NH2:25])=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.O>[CH2:34]([NH:36][C:37]([NH:25][C:22]1[N:23]=[CH:24][C:19]2[NH:18][C:17]3[N:26]=[CH:27][C:14]([C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:9][CH:10]=4)=[CH:15][C:16]=3[C:20]=2[CH:21]=1)=[O:38])[CH3:35]
Reactant: CCN=C=O
Reactant: Nc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Yield: 31 %

Procedure:
A suspension of 3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-amine (91.6 mg, 0.256 mmol) in DCM (9.1 mL) was treated with pyridine (22.8 μL, 0.282 mmol) and ethylisocyanate (33.2 μL, 0.423 mmol) and then the reaction mixture was heated under reflux for 5 h. The cooled reaction mixture was treated with saturated sodium bicarbonate and diluted with 20% MeOH in DCM and water. The layers were separated, the aqueous phase extracted into 20% MeOH in DCM, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by preparative HPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) to afford the title compound as a yellow solid (34 mg, 31%). 1H NMR (DMSO-D6, 400 MHz): 9.66 (t, J=5.4 Hz, 1H), 9.19 (s, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.91 (d, J=2.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.20 (s, 1H), 3.53-3.44 (m, 4H), 2.36 (m, 4H), 1.58-1.46 (m, 4H), 1.41 (m, 2H), 1.31-1.21 (m, 3H). LCMS (Method D): RT=8.06 min, M+H+=429.