Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]#[N:10])[CH:5]=1.[CH2:13]([Mg]Br)[CH3:14].Cl.[OH-].[Na+]>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2([NH2:10])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: CC(C)(C)Cc1cc(C#N)no1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)Cc1cc(C2(N)CC2)no1
Reaction time: 2 h

Procedure:
To a mixture of 5 g (30.4 mmol) of 5-(2,2-dimethyl-propyl)-isoxazole-3-carbonitrile and 10.1 ml (34.1 mmol) of titanium(IV) isopropoxide in 150 ml of dry diethyl ether a solution of 22 ml of ethylmagnesium bromide (3 M in diethyl ether, 66.0 mmol) is added at −70° C. The reaction mixture is allowed to reach rt within two hours, 7.6 ml (60.6 mmol) of boron trifluoride-diethyl etherate are added and stirring is continued for one hour. After addition of 90 ml of 1M aq hydrochloric acid and 450 ml of diethyl ether two clear phases are obtained which are treated with 300 ml of 10% aq sodium hydroxide. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried over sodium sulfate and evaporated to afford a dark orange oil. After filtration over a C18-bond elut column (Varian) with THF/MeCN the oil is purified by HPLC (dissolved in 6 ml of tetrahydrofuran, 25 injections, XBridge C18 column, 19×150 mm, 5 μM, gradient of 95% MeCN in water to 10% MeCN in water, containing 0.02% of ammonium hydroxide). The combined product fractions are concentrated and the product is extracted with DCM to yield the product as an orange solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (123 mg, 1.30 mmol) in DCM (15 ml) was added to a stirred solution of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method A; 200 mg, 0.65 mmol), HOBT (150 mg, 0.98 mmol) and EDC (187 mg, 0.98 mmol) in DCM (15 ml) under nitrogen at room temperature. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was partitioned between DCM (50 ml) and water (25 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product as a yellow solid. The crude product was added to a Biotage column and was eluted with petroleum ether:ethyl acetate (3:1) to yield the title compound as a white solid. 75 mg. MS (electrospray): m/z [M+H]+=383
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[CH:17]1([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCCCOC1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCOC1CCCCC1)C(=O)OCC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
15 g of malonic acid diethyl ester are added dropwise at 50° C. to a solution of sodium ethylate, freshly prepared from 1.5 g of sodium and 30 ml of ethanol. This temperature is maintained for 1 hour and 11.7 g of 4-cyclohexyloxybutyl bromide are then added dropwise. When the addition is complete, the mixture is stirred for 3 hours at 60° C. and is concentrated considerably, 100 ml of ice water are added to the residue and the mixture is extracted 3 times with a total of 150 ml of methylene chloride. The combined organic phases are dried over sodium sulphate and the solvent is removed by distillation in vacuo, together with excess malonic acid diethyl ester. This gives 10.5 g of [4-(cyclohexyloxy)-butyl]-malonic acid diethyl ester in the form of a pale yellow oily residue.
Reaction SMILES: [K+].[Br-].[N+:3]([C:6]1[CH:11]=[CH:10]C(C)=[CH:8][CH:7]=1)([O-:5])=[O:4].[C:13]([OH:16])(=[O:15])[CH3:14]>>[N+:3]([C:6]1[CH:11]=[CH:10][C:14]([C:13]([OH:16])=[O:15])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [K+]
Product: O=C(O)c1ccc([N+](=O)[O-])cc1

Procedure:
In the presence of 40 g of Co(OAc)2 . 4H2O and 8 g of KBr, 600 grams of p-nitrotoluene was oxidized in 2500 ml of glacial acetic acid. The product was processed as in the above Example 15; after the addition of 600 more grams of p-nitrotoluene, the oxidation was performed again, and the procedure was repeated one more time. The reaction temperature in all three procedures was not increased above 130° C. Filtration of the 3 reaction solutions yielded 2096 grams of p-nitrobenzoic acid (95.5% of the theory). After the addition to the mother liquors of 400 ml of 1,2-dichloroethane for each batch, 247 grams of water (99.5% of the theory) were removed by azeotropic distillation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:17][CH2:16]2)[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:34]3[CH:35]=[CH:36][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=3)=[N:24][CH:25]=2)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(-c3ccc(S(C)(=O)=O)cc3)nc2)C2CC2)CC1

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenyl boronic acid following a procedure analogous to that described in Intermediate 6. LC (method 10): tR=1.92 min; Mass spectrum (ESI−): m/z=545 [M+HCOO]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[S:16])NN=N1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:15]=[S:16]
Reactant: O=[N+]([O-])c1ccc(F)c(-n2nn[nH]c2=S)c1
Agent: [Na]
Product: O=[N+]([O-])c1ccc(F)c(N=C=S)c1

Procedure:
1-(2-fluoro-5-nitrophenyl)-1,4-dihydro-5H-tetrazol-5-thione and its sodium salt;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([NH:22][C:23]1[S:27][C:26]2[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=2[C:24]=1[C:32]([NH2:34])=[O:33])=[O:21]>CN(C=O)C.O>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:19][C:20]([NH:22][C:23]2[S:27][C:26]3[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=3[C:24]=2[C:32]([NH2:34])=[O:33])=[O:21])[N:2]=1)#[N:11]
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: N#Cc1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)c2ccccc12
Temperature: 60 °C
Yield: 13 %

Procedure:
To a solution of 1H-indazole-3-carbonitrile (11 mg, 0.077 mmol) in DMF (500 μL) was added potassium carbonate and the whole was stirred at RT for 30 min before 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (24 mg, 0.077 mmol) was added. The reaction mixture was heated to 60° C. and this temperature was maintained for 1.5 h before the reaction mixture was cooled to RT, then diluted with water (5 mL). The organics were extracted with diethyl ether (10 mL), EtOAc (10 mL) and DCM (10 mL), then combined and the suspension concentrated to dryness. The residue was dissolved in DMSO (1 mL) and purified by preparative reverse phase HPLC to give the title compound as a white solid (4 mg, 0.01 mmol, 14%).
Reaction SMILES: [C:1]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].[BH4-].[Na+].[H][H].[B-](F)(F)(F)[O+](C)C>O1CCCC1.O>[OH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: [H][H]
Reactant: O=C(O)CCCCCCCC(=O)OCc1ccccc1
Agent: C[O+](C)[B-](F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCCCCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product from 11a (12.9 g; 46.3 mmol) was added in portions to a stirred mixture of sodium borohydride (1.70 g; 45.0 mmol) in dry tetrahydrofuran (25 mL). After the evolution of hydrogen subsided, a solution of boron trifluoride dimethyl etherate (4.6 mL; 5.7 g; 50 mmol) in dry tetrahydrofuran (15 mL) was added drop-wise. The exothermic reaction was moderated with a cold water bath. After stirring 4 h at ambient temperature, the reaction mixture was hydrolyzed with cold water (20 mL). The mixture was separated and the organic phase was evaporated; the residue was mixed with water (20 mL) and dichloromethane (70 mL) to give an emulsion that separated on standing overnight. The organic layer was washed with water (4×15 mL) until the washings were neutral to pH paper. Following drying (Na2SO4), filtration, and evaporation 11.95 g (98%) product was obtained (oil).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[C:22]([Cl:27])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH:29]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:34][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:22]([Cl:27])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: OC1CCCC1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1ccc(OC2CCCC2)c(Cl)c1

Procedure:
Starting with {(R)-4-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester and cyclopentanol using the method analogous to the one described above for example 3-1, {(R)-4-[(3-chloro-4-cyclopentyloxy-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester was obtained. MS cald. for C23H30ClN3O5S 495, obsd. (ESI+) [(M+H)+] 496.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])=[CH:23][CH:22]=1>>[OH:10][C@H:8]1[CH2:9][C@H:5]([C:3](=[O:4])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][C:28]3=[O:33])=[CH:25][CH:26]=2)[CH2:6][C@@H:7]1[NH:11][C:12]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:13]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)C[C@@H]1O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 4-(4-amino-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-2-hydroxy-4-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-cyclopentyl}-amide. Yellow solid. MS: 464.4 ([M+H]+)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:3]=1.[F:38][C:39]1[CH:40]=[C:41]([CH:59]=[CH:60][CH:61]=1)[CH2:42][N:43]1[C:47]([CH3:48])=[C:46](B2OC(C)(C)C(C)(C)O2)[C:45]([CH3:58])=[N:44]1.C(=O)([O-])[O-].[Na+].[Na+]>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].C1(C)C=CC=CC=1.C(O)C.O>[F:38][C:39]1[CH:40]=[C:41]([CH:59]=[CH:60][CH:61]=1)[CH2:42][N:43]1[C:47]([CH3:48])=[C:46]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:3]=2)[C:45]([CH3:58])=[N:44]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(CCN(C)C)CC5)cc4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCN(C)C)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of intermediate 1, 2-(4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)-N,N-dimethylethanamine (intermediate 49) (150 mg, 0.485 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (157 mg, 0.477 mmol) in sodium carbonate (76 mg, 0.716 mmol), PdCl2(dppf) (8.7 mg, 0.011 mmol), Toluene/ethanol/water (15/7.5/1.5 ml) to afford 192 mg yield % of the crude titled compound. MS: m/z=706.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]([OH:35])CO)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]=[O:35])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:17])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(O)CO)O3)ccc1OC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C=O)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of [8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (417 mg, 0.86 mmol) in THF (10 mL) was added NaIO4 (468 mg, 2.19 mmol) and H2O (4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and partitioned between sat. aq. sodium bicarbonate/ethyl acetate. The aqueous layer was extracted further with ethyl acetate (3×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (50 mL), dried over MgSO4, filtered and concentrated in vacuo to yield 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carbaldehyde (384 mg, 99%) as a white solid. ESI-MS m/z calc. 450.3. Found 451.3 (M+1)+; Retention time: 1.33 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([NH:32]N)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Br)c2)ccc1=O
Product: O=c1ccn(-c2cccc(Br)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 1-(3-Bromo-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-18) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=443.2 (M+H)+
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:19]3[C:20]4[N:12]([C:13](=[O:22])[NH:14][C:15](=[O:21])[C:16]=4[N:17]=[CH:18]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:28]1([CH2:27][N:14]2[C:15](=[O:21])[C:16]3[N:17]=[CH:18][N:19]4[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=5)=[CH:10][CH2:11][N:12]([C:20]=34)[C:13]2=[O:22])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1[nH]c(=O)n2c3c1ncn3C(c1cccc(C(F)(F)F)c1)=CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ncn3c2n(c(=O)n1Cc1ccccc1)CC=C3c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 63 %

Procedure:
To a stirred suspension of 5.0 g of 4-[3-(trifluoromethyl)phenyl]-6H,8H-pyrimido[1,2,3-cd]purine-8,10-(9H)-dione (prepared as described in Example 41) in 50 ml of dry N,N-dimethylformamide at room temperature, under nitrogen, was added 800 mg of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 2 hours, then 3.1 g of benzyl bromide was added and the mixture was stirred at room temperature for 40 hours. The mixture was evaporated to dryness and treated with water to give a solid. The solid was collected and washed with water and dried. The solid was dissolved in chloroform and passed through a short column of magnesium silicate. The eluate was dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate gave an orange solid. The solid was triturated with diethyl ether, then filtered. The solid was washed with ether, then hexane and dried to give 4.0 g of the desired product which was recrystallized from ethyl acetate, mp 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][NH:32][C:33]#[N:34].C(OCC)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[N:5]=[C:4]([N:32]([C:33]#[N:34])[CH3:31])[N:3]=1
Reactant: CNC#N
Reactant: CC1CCN(c2nc(S(C)(=O)=O)nc(Cl)c2-c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCN(c2nc(N(C)C#N)nc(Cl)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 83.3 %

Procedure:
To a solution of 4-chloro-6-[(4-methyl)-piperidin-1-yl]-2-methylsulfonyl-5-phenyl-pyrimidine (0.5 g, 1.37 mmol) in dimethylformamide (6 ml) was added potassium carbonate (0.38 g, 2.73 mmol) followed by methyl cyanamide (0.31 g, 5.47 mmol). After stirring the reaction mixture at room temperature for 19 hours the reaction mixture was diluted with water (75 ml), and extracted with ethyl acetate (75 ml). The organic phase was washed with water (75 ml), followed by saturated brine (75 ml), dried over magnesium sulfate and concentrated in vacuo to afford a yellow syrup. The crude product was chromatographed an silica gel eluting with 90:10 v/v hexane:ethyl acetate to afford 0.39 g (84% yield) of the title compound as a cololess syrup.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([CH3:42])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([NH:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[NH:18][C:17]=3[CH:16]=[C:15]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:40])[F:39])=[O:31])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:43]I>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[C:5]([CH3:42])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([NH:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[N:18]([CH3:43])[C:17]=3[CH:16]=[C:15]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:39])([F:40])[F:41])=[O:31])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(NCC(C)(C)CO)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2c1nc(NCC(C)(C)CO)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide powder (6.2 mg) was added to a solution of N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (80 mg) in DMF (2 mL), the solution was stirred at room temperature for 30 minutes, methyl iodide (8.7 μL) was added, and it was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (20 mg) as white powder. This was suspended in MeOH, 2N hydrogen chloride/EtOH (1 Eq) was added, it was stirred to obtain a solution, and the solvent was removed under reduced pressure. The residue was washed with diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (15 mg) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:32])[CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=2)[CH2:19]1)=O.C1(C)C=CC=CC=1>O1CCCC1>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][CH2:11][NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:32])[CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=2)[CH2:19]1
Reactant: COc1cc2c(cc1OC)CC(N(C)CCCNC(=O)Cc1cc(Cl)c(Cl)cc1N)CC2
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CC(N(C)CCCNCCc1cc(Cl)c(Cl)cc1N)CC2
Temperature: 80 °C

Procedure:
Next, 1-[2-(2-amino-4,5-dichlorophenyl)-1-oxo-ethylamino]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (4.8 g, 0.01 mol) is dissolved in absolute tetrahydrofuran (100 ml) and mixed with boron trifluoride-diethyl ether complex (1.25 g, 1.1 ml). Then, a 10M toluene solution of borane-dimethylsulphide complex (1.6 ml) diluted with absolute tetrahydrofuran (20 ml) is added to the reaction mixture with stirring, under a nitrogen atmosphere and with heating to reflux temperature, and the resulting mixture is refluxed for a further 8 hours. The solvent is distilled off in vacuo, the residue is heated in 6M hydrochloric acid (100 ml) to 80° C. for one hour, cooled and extracted twice with ethyl acetate. The hydrochloric acid solution is then made alkaline with 50% sodium hydroxide solution while cooling with ice water and extracted several times with methylene chloride. The extract is dried over magnesium sulphate, concentrated by evaporation in vacuo and the residue is purified by column chromatography over alumina N (170 g) [activity II, eluant: methylene chloride and increasing amounts of ethanol (up to 5%). Yield: 1 g.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C:10]2[N:15]=[CH:16][C:17]([C:19]([O:21]C)=[O:20])=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C:10]2[N:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc2c(c1)N(Cc1ccccc1)C(=O)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2c(c1)N(Cc1ccccc1)C(=O)CO2
Temperature: 100 °C

Procedure:
The product from Step 1 was dissolved in MeOH (1 mL) and water (0.5 mL) and placed in a 2 mL microwave vial with a magnetic stirrer bar. Lithium hydroxide (40 mg, 0.96 mmol) was added to the vial. The vial was capped and vortexed to dissolve the LiOH, and the reaction was heated for 5 minutes at 100° C. under microwave irradiation. The reaction was quenched by the addition of aqueous 1M HCl (960 μL). The volatiles were evaporated to dryness. This yielded a white/yellow solid which was used without further purification. LCMS (+ESI) m/z=285.0 [M+H]+.