Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:17]=[C:18]([C:21]([CH2:24]C)([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH2:9][P:10]1(=[O:16])[O:14][CH2:13][CH:12](C)[O:11]1)([CH2:4]C)([CH3:3])[CH3:2].CC(C)(CO)CO.C(C1C=C(C=C(C(CC)(C)C)C=1O)CP(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1)(CC)(C)C.C(C1C=C(C=C(C(C)(C)C)C=1O)CP(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1)(C)(C)C>>[C:21]([C:18]1[CH:17]=[C:8]([CH:7]=[C:6]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:19]=1[OH:20])[CH2:9][P:10]1(=[O:16])[O:11][CH2:12][CH2:13][O:14]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCC(C)(C)c1cc(CP2(=O)OCC(C)O2)cc(C(C)(C)CC)c1O
Agent: CC(C)(C)c1cc(CP(=O)(Oc2ccccc2)Oc2ccccc2)cc(C(C)(C)C)c1O
Agent: CC(C)(CO)CO
Agent: CCC(C)(C)c1cc(CP(=O)(Oc2ccccc2)Oc2ccccc2)cc(C(C)(C)CC)c1O
Product: CC(C)(C)c1cc(CP2(=O)OCCO2)cc(C(C)(C)C)c1O

Procedure:
Similarly, 1-(3,5-di-tert-amyl-4-hydroxybenzyl)-3-methyl-1-oxo-2,5-dioxa-1-phosphacyclopentane is made by substituting 1,2-propanediol for 2,2-dimethyl-1,3-propanediol and diphenyl 3,5-di-tert-amyl-4-hydroxybenzylphosphonate for diphenyl 3,5-di-tert-butyl-4-hydroxybenzylphosphonate in Example 2.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]3[N:21]=[CH:22][CH:23]=[C:19]3[CH:18]=[C:17]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:30]=4)[CH:25]=3)[N:16]=2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:35]([O:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C:17]1[N:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=3)[N:20]3[N:21]=[CH:22][CH:23]=[C:19]3[CH:18]=1)[CH:33]=[CH:32]2)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2nc(-c3ccc4cc(OCc5ccccc5)ccc4c3)cc3ccnn23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Nc2nc(-c3ccc4cc(OCc5ccccc5)ccc4c3)cc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of {4-[5-(6-benzyloxy-naphthalen-2-yl)-pyrazolo[1,5-c]pyrimidin-7-ylamino]-phenyl}-carbamic acid tert-butyl ester (compound C2)(450 mg), TFA (2 ml) and dichloromethane (10 ml) is stirred 4 h at ambient temperature. The reaction mixture is evaporated and coevaporated with toluene. The residue is partitioned between a aqueous saturated solution of sodium bicarbonate and ethyl acetate. After drying the organic phase is evaporated and the residue is dried in vacuum. A solid in quantitative yield is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10]Br.[C-:12]#[N:13].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:12]#[N:13]
Reactant: Fc1cc(Br)c(CBr)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cc(Cl)c(F)cc1Br
Temperature: 25 °C

Procedure:
A mixture of 1 mmol of 1-bromo-2-bromomethyl-4-chloro-5-fluoro-benzene and 4 mmol of sodium cyanide in 3 ml of dry N,N-dimethylformamide is stirred at room temperature till complete conversion is observed. The reaction mixture is quenched by the addition of water and the mixture is extracted with tert-butyl-methyl ether. The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>II.C(OCC)(=O)C.O1CCCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=3)=[CH:5][CH:4]=2)([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C3(O)CCN(Cc4ccccc4)CC3)cc2)=N1
Temperature: 25 °C
Yield: 34.7 %

Procedure:
Magnesium (3.10 g, 127 mmol), iodine (135 mg, 0.531 mmol), and 2-(4-bromophenyl)-4,5-dihydro-4,4-dimethyloxazole (27 g, 106 mmol) were added to tetrahydrofuran (120 mL), and the mixture was heated under reflux for 1 hour. This reaction mixture was cooled to mom temperature, then 1-benzyl-4-piperidone (21.7 mL, 117 mmol) was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and then a saturated aqueous ammonium chloride solution and ethyl acetate were added for partition. The aqueous layer was extracted with ethyl acetate, and then the organic layers were combined and washed serially with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under vacuum and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=3:1-1:1). The target fraction was concentrated under vacuum to obtain the title compound (13.4 g, 35%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2](=[O:1])[NH:3][CH:4]=2)=[O:8])=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(=O)[nH]c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a solution of 6-hydroxynicotinic acid (4.87 g, 35 mmol) in DMF (100 mL) at room temperature, was added potassium tert-butoxide (3.93 g, 35 mmol). The reaction mixture was stirred at 60° C. for 1 h. 4-Methoxybenzylchloride (8.30 g, 53 mmol) was added and the reaction mixture was stirred at 60° C. for 4 h. The DMF was evaporated under vacuum, the residue was dissolved in ether (200 mL) and washed with water (3×100 mL). The organic phase was dried with Na2SO4 and evaporated to give 4.41 g of 6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][S:11](O)(=[O:13])=[O:12].S(=O)(=O)(O)O.S(=O)(=O)(O)N.S(Cl)(Cl)=O>>[Cl:10][S:11]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([OH:9])=[O:8])(=[O:13])=[O:12]
Reactant: O=C(O)c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: NS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 120 °C

Procedure:
122.1 g (1.0 mol) of benzoic acid are introduced into a mixture of 349.5 g (3.0 mol) of chlorosulfonic acid, 20 g of 96% strength sulfuric acid and 1 g of sulfamic acid. The reaction mixture thus obtained is heated to 120° C. in the course of 3 hours and stirred until evolution of gas has ended. The mixture is then cooled to 70° C. and 119.0 g (1.0 mol) of thionyl chloride are added dropwise over the course of 2 hours. After it has been stirred at 80° C. for 30 minutes, the reaction mixture is added dropwise at 10° C. to ice water, and the precipitated crystals are filtered off with suction and washed with ice water. 232.1 g of 3-chlorosulfonylbenzoic acid (water content: 10%), corresponding to 208.9 g (94.7% of theory), calculated as dry material, having a melting point of 129°-131° C. are obtained.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])(=O)C.C(=O)(O)[O-].[Na+]>Cl>[NH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: CC(=O)Nc1cccc2c1C(=O)CCC2N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cccc2c1C(=O)CCC2N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
The compound prepared in (1) above (339 mg) was added to 10 ml of 1 N hydrochloric acid and heated under reflux for 1 hour. The mixture was cooled to room temperature, alkalinized with the addition of sodium bicarbonate, and extracted with chloroform. The extract was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (4:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 190 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][NH:27][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NCC(F)(F)F)s1
Yield: 84 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (87 mg, 84%) which was obtained as a yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=413.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([Cl:12])[N:5]=[CH:4][CH:3]=1.[Li+].[OH-]>O1CCOCC1.CO.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:12])[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccnc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Nc1ccnc(Cl)c1C(=O)O
Temperature: 85 °C
Yield: 66.7 %

Procedure:
Methyl 4-amino-2-chloronicotinate (21.0 g, 112.9 mmol) and LiOH (10.3 g, 247.5 mmol) was taken in a mixture of dioxane:MeOH:water (3:2:1, ml) and the reaction mixture was heated to 85° C. for 2 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in minimum volume of water and acidified (up to pH 4) with saturated citric acid. The aqueous solution was concentrated until precipitation just started. The mixture was allowed to stand overnight at 10° C. for complete precipitation. The resultant white solid was collected by filtration and recrystallized from isopropyl alcohol-hexane to afford 4-amino-2-chloronicotinic acid (13 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.59 (d, 1H), 6.47 (d, 1H), 6.37 (brs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:13]S(O)(=O)=O.OS(O)(=O)=O.O=S(=O)=O.II>>[F:1][C:2]1[C:10]([Cl:13])=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F

Procedure:
The chlorination of the 2,4,5-trifluorobenzoic acid is carried out in the melt, under pressure and/or in a solvent, for example chlorosulphonic acid or oleum, in the presence of halogen transfer agents, for example iodine. 2,4,5-Trifluoro-3-chlorobenzoic acid is obtained in this reaction. However, since the reaction mixture still contains unchanged starting material and some 2,4,5,-trifluoro-3,6-dichlorobenzoic acid, the crude mixture is treated, without intermediate isolation, with thionyl chloride. The desired 2,4,5-trifluoro-3-chlorobenzoyl chloride is then obtained by fractional distillation. However, it is more favorable to carry out the separation by distillation of the acid fluorides.
Reaction SMILES: [OH:1][C@@H:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[Br:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>ClCCCl.O>[Br:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:20]([O:1][C@@H:2]([CH3:10])[C:3](=[O:4])[N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:21]
Reactant: C[C@H](O)C(=O)N1CCCC1
Reactant: O=C(Cl)C(Br)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: C[C@H](OC(=O)C(Br)c1ccc(Cl)cc1)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a solution of (2S)-2-hydroxy-1-(pyrrolidin-1-yl)propan-1-one (24.0 g, 0.17 mol) in DCE (120 mL) was added triethylamine (84.69 g, 0.84 mol) and 2-bromo-2-(4-chlorophenyl)acetyl chloride (crude, 46.29 g, 0.17 mol) at 0° C. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with water (200 mL) and separated the organic layer. The organic layer was washed with 10% NaS2O3 (100 mL) and saturated sodium bicarbonate (60 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column on 100-200 mesh silica-gel (20-25% ethyl acetate-hexane) to afford (2S)-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl 2-bromo-2-(4-chlorophenyl)acetate 4 (37.5 g, 59%) as brown sticky gum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7](OC)=[O:8])([O-:3])=[O:2].O.[NH2:19][NH2:20]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([NH:19][NH2:20])=[O:8])([O-:3])=[O:2]
Reactant: NN
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CO
Solvent: O
Product: NNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
A mixture of methyl 3-nitro-5-(trifluoromethyl)benzoate (20 g, 80 mmol) and hydrazine hydrate (5.56 mL, 96 mmol) in MeOH (100 mL) was stirred for 16 h at 25° C. Then the solvent was concentrated to yield an off white solid of 3-nitro-5-(trifluoromethyl)benzohydrazide (20 g, 72.2 mmol, 90% yield): 1H NMR (400 MHz, CD3OD) δ 8.89 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H); ES-LCMS m/z 250 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:23]=2[C:24]([NH:26][CH2:27][C:28]#[CH:29])=[O:25])[C:18]([Cl:35])=[CH:17][N:16]=1>>[Cl:35][C:18]1[C:19]([NH:21][C:22]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:23]=2[C:24]([NH:26][CH2:27][C:28]#[CH:29])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow solid (36 mg, 19%). m.p.=236-241° C.; LCMS (m/e) 479 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 8.10 (s, 1H), 7.53 (d, 1H, J=7.4 Hz), 7.47-7.31 (m, 3H), 7.16 (s, 1H), 7.07-7.00 (m, 2H), 6.82 (d, 1H, J=8.1 Hz), 6.54-6.47 (m, 1H), 4.21-4.15 (m, 2H), 2.73 (t, 2H, J=7.3 Hz), 2.34 (t, 2H, J=7.1 Hz), 2.26-2.15 (m, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][C:9]([CH2:10][NH2:11])=[C:4]2[CH:3]=[CH:2]1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[CH:16]=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][C:9]([CH2:10][NH:11][C:13]3[N:18]=[C:17]([NH:19][C:20]4[CH:24]=[C:23]([CH:25]5[CH2:27][CH2:26]5)[NH:22][N:21]=4)[CH:16]=[CH:15][N:14]=3)=[C:4]2[CH:3]=[CH:2]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: NCc1cncc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2cncc3[nH]ccc23)n1
Temperature: 120 °C
Reaction time: 18 h
Yield: 11.1 %

Procedure:
A mixture of (1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine (236 mg, 1.61 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (344 mg, 1.46 mmol) and DIPEA (565 mg, 4.38 mmol) in IPA (2 mL) was stirred in a sealed tube at 120° C. for 18 h. The reaction mixture was cooled to RT and concentrated in vacuo. The crude residue was purification by preparative HPLC to afford 56 mg (11.1%) of the title compound as white solid: 1H NMR (500 MHz, CD3OD) δ 8.64 (s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.59 (d, J=3.0, 1H), 6.72 (d, J=3.0, 1H), 6.17-5.96 (m, 2H), 4.92 (s, 2H), 1.75 (s, 1H), 0.85 (d, J=4.5, 2H), 0.51 (s, 2H); MS (ESI) m/z: 347.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:4]=[C:3]1[NH2:13].[C:14]1([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:4]=[C:3]1[NH:13][C:22](=[O:23])[CH2:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cn1c(-c2ccccc2)cnc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: Cn1c(-c2ccccc2)cnc1NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-methyl-5-phenyl-1H-imidazol-2-amine (90c, 52.0 mg, 0.3 mmol) in pyridine (1.0 ml) was added 3-phenyl-propionyl chloride (60.7 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 16 hours, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give N-(1-Methyl-5-phenyl-1H-imidazol-2-yl)-3-phenyl-propionamide (90): 1H NMR (500 MHz, DMSO) δ: 7.16-7.48 (m, 10H), 6.87 (s, 1H), 3.42 (s, 3H), 3.07 (t, 2H), 2.92 (t, 2H). ESI-MS: 305.7 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([OH:17])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].Br[CH2:19][C:20]([NH2:22])=[O:21].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:4]1[N:5]([O:17][CH2:19][C:20]([NH2:22])=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: NC(=O)CBr
Reactant: CCCc1nc2cnc3ccccc3c2n1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1OCC(N)=O
Yield: 83.9 %

Procedure:
A solution of 2-propyl-1H-imidazo[4,5-c]quinolin-1-ol (2.0 g, 8.8 mmol), bromoacetamide (1.9 g, 14 mmol), and triethylamine (2.8 mL, 0.020 mol) in THF (100 mL) was heated at reflux overnight. The solvent was removed under reduced pressure, and dichloromethane (75 mL) and saturated aqueous sodium bicarbonate (25 mL) were added to the residue. The resulting mixture was filtered to provide 2.1 g of 2-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]acetamide as a solid. The organic layer was separated, and methanol was added until all solids were dissolved. The solution was then dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide an additional 0.13 g of material.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:33]4[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(-c3cnc(N)nc3)cc1-2
Yield: 11.9 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (53.4 mg, 0.130 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (34.4 mg, 0.156 mmol) were reacted to give 281 (6.6 mg, 12% yield, M+1 426.1)
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([CH:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: COC(=O)C(CCCc1ccccc1)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CCCc1ccccc1)C(C)O
Reaction time: 1 h

Procedure:
5.50 g (23.5 mmol) of methyl 2-acetyl-5-phenylpentanoate are introduced into 100 ml of methanol and the mixture is ice-cooled. 0.44 g (11.7 mmol) of sodium borohydride is added in portions and the mixture is stirred for a further 1 h. The solvent is then evacuated from the batch, and the residue is taken up in diethyl ether and washed with 1 N hydrochloric acid. The organic phase is then concentrated again and flash-chromatographed using the eluent petroleum ether/ethyl acetate 10/1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([F:9])[CH:3]=1.N([O-])=O.[Na+].[C:14]1(=[O:20])[NH:18][C:17](=[O:19])[CH:16]=[CH:15]1.C([O-])(=O)C.[Na+]>Cl.CC(C)=O.Cl[Cu]>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([C:16]2[C:17](=[O:19])[NH:18][C:14](=[O:20])[CH:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C1C=CC(=O)N1
Agent: Cl[Cu]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: O=C1C=C(c2ccc(Br)cc2F)C(=O)N1
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (10.0 g, 52.6 mmol) in aqueous HCl (50 mL) was added aqueous NaNO2 (4.0 g, 57.9 mmol) at 0° C. The reaction mixture was stirred for 30 min. To this was added a solution of maleimide (7.65 g, 78.9 mmol) in acetone (50 mL). The pH was adjusted to 3-3.5 by addition of sodium acetate. To the resultant reaction mixture was added CuCl (1.05 g, 7.9 mmol) and it was stirred at 0° C. for 1 h and at r.t. for 6 h. Finally acetone was evaporated and the reaction mixture was diluted with water (20 mL) and extracted with DCM (2×50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 1:9 EtOAc:Pet. ether) to provide the title compound (2.6 g, 18%) as brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[C:4]=1[C:5]([NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)=[O:6].C(O)(=O)C.[CH3:36][C:37]([CH3:39])=O.C([BH3-])#N.[Na+]>CO>[CH:37]([N:10]1[CH2:11][CH2:12][CH2:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[C:20]([C:28]([F:31])([F:29])[F:30])=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:3]=2[O:2][CH3:1])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)([CH3:39])[CH3:36]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCNC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCN(C(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 35.7 mg (0.08 mmol) rac-2-methoxy-N-(3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide in methanol were added 28 ul (0.48 mmol) acetic acid, 59 ul (0.8 mmol) acetone and finally 30 mg (0.4 mmol) sodium cyanoborohydride. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed once with a 1N NaOH solution, once with water and once with brine. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 33 mg (85%) of the title compound as a white foam. MS (m/e): 489.4 (M+H).