Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][N:15]=[CH:16][C:9]=12.[OH-].[K+].[I:24]I>CN(C=O)C>[Cl:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][N:15]=[C:16]([I:24])[C:9]=12
Reactant: II
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1ccnc2[nH]ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1ccnc2[nH]nc(I)c12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 4-(5-chloro-2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (21.0 g, 68.9 mmol) in DMF (100 mL) was added freshly ground (mortar/pestle) potassium hydroxide (11.6 g, 207 mmol) flakes followed immediately by iodine (26.2 g, 103 mmol) under N2 at 25° C. The dark reaction was heated to 50° C. for 6 hours. The mixture was quenched by addition of aqueous 10% NaHSO3 (75 mL). The suspension was further diluted by addition of water (100 mL) and filtered. The resulting precipitate washed with water, dried by toluene azeotrope, and then left under high vacuum for 2 days. The beige powder (26.5 g, 69%) was carried forward without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccsc1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccsc2)c1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 μmol) and 3-thiophenecarboxylic acid (38 mg, 300 μmol). Yield 47 mg (94%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Brc1ccc(CN2CCCCC2)cc1
Reaction time: 27 h

Procedure:
A solution of 4-bromobenzaldehyde (5 g), piperidine (2.9 mL), and acetic acid (1.5 mL) in DCE (65 mL) was treated with sodium triacetoxyborohydride (6.9 g). After 27 h, the resulting mixture was treated with saturated aqueous sodium bicarbonate (50 mL), and extracted with DCM (2×50 mL). The combined organic phases were dried (magnesium sulfate) and evaporated. Kugelrohr distillation of the residue (160° C., 5 mm Hg) gave the title compound as a pale yellow oil (5.9 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[CH3:5][C:6]([CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][CH2:9]1)=[O:7]>>[CH3:14][C:12]1([CH3:15])[CH2:11][CH2:10][CH2:9][CH:8]([C:6]([OH:7])([CH2:2][CH2:3][CH3:4])[CH3:5])[CH2:13]1
Reactant: CCCBr
Reactant: CC(=O)C1CCCC(C)(C)C1
Product: CCCC(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with 1-bromopropane replacing bromoethane and herbac replacing dehydroherbac.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:16][O:17][CH:18]([CH3:21])[CH2:19][Cl:20])[C:13]([OH:15])=[O:14])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]([CH2:16][O:17][CH:18]([CH3:21])[CH2:19][Cl:20])[C:13]([OH:15])=[O:14]
Reactant: CC(CCl)OC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(CCl)OC[C@@H](N)C(=O)O
Reaction time: 2.5 h
Yield: 96 %

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoic acid in MeOH (10 mL) was added Pd on Carbon (10 wt %, catalytic amount). The mixture was stirred under H2 (1 atm) for 2.5 hours and filtered through a plug of Celite® and rinsed with MeOH. Solvent was removed to give (R)-2-amino-3-(1-chloropropan-2-yloxy)propanoic acid as an off-white solid (308 mg, 96%). MS [M+H] found 182.1.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.O.O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10]
Reactant: Cc1ccc([N+](=O)[O-])c(Br)c1C
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N)c(Br)c1C

Procedure:
To a solution of 2-bromo-3,4-dimethylnitrobenzene (1.0 g, 4.35 mmole) in 10 mL DMF was added SnCl2.2H2O (4.92 g, 21.8 mmole). This solution was stirred overnight at room temperature 50 mL of H2O was added and the pH was adjusted to 8 with the addition of sat. NaHCO3 and extracted with 150 mL of EtOAC. The organic layer was dried over Na2SO4, filtered and evaporated yielding 2-bromo-3,4-dimethylaniline which was used as is in the conversion to 2-bromo-3,4-dimethyliodobenzene in a similar manner to that of Example 86. Compound 102 was prepared from 2-bromo-3,4-dimethyliodo-benzene using procedures similar to those of Examples 25 and 40. MS (ion spray): m/z 314.0/316.1 (M−H); 316.1/318.0 (M+H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.37 (d, 1H), 7.15 (d, 1H), 2.43 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)(O)(O)O.[CH3:19]O>>[CH3:19][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: O=P(O)(O)O
Product: CN(c1ccccc1)c1ccccc1
Temperature: 140 °C
Yield: 99.2 %

Procedure:
The reaction apparatus was filled with 2 kg (11.8 mol) of diphenylamine and 200 g (1.74 mol) of phosphoric acid. Methanol was introduced at a rate of 50 ml/h for 40 hours at a reaction temperature of 200°C. The reaction mixture was then cooled to 140°C and the upper phase run-off. 1.822 kg of N-methyldiphenylamine (99.2 %) were obtained.
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O.[CH2:20]([O:22][C:23]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24])[CH3:21]>C1COCC1>[CH2:20]([O:22][C:23](=[O:24])/[CH:25]=[CH:1]/[CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:21]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A solution of tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (8.4 g, 32.2 mmol) in dry THF (200 mL, 0.16 M) was treated with (ethoxycarbonylmethylene)triphenylphosphorane (12.8 g, 37.0 mmol) in one portion. After stirring at room temperature overnight, the solvent was evaporated, and the resulting residue was dissolved in ether. Heptane was added and the precipitated triphenylphosphine oxide was filtered off. The filtrate was concentrated and purified by flash chromatography (5-20% ethyl acetate in hexane) affording (E)-tert-butyl 3-(3-ethoxy-3-oxoprop-1-enyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as yellow oil (8.7 g, 82%). 1H NMR (CDCl3, 500 MHz) δ 7.21-7.14 (m, 2H), 7.14-7.07 (m, 2H), 6.74 (dd, J1=15.8 Hz, J2=4.8 Hz, 1H), 5.79 (dd, J1=15.8 Hz, J2=1.3 Hz, 1H), 4.72 (d, J=16.5 Hz, 1H), 4.35 (d, J=16.5 Hz, 1H), 4.11 (qw, J=14.4 Hz, 2H), 3.18 (dd, J1=15.8 Hz, J2=6.2 Hz 1H), 2.84 (d, J=15.8 Hz, 1H), 1.49 (s, 9H), 1.23 (t, J=14.4 Hz, 3H). ESI MS found for C19H25NO4 m/z [354.4 (M+23)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:19])[C:7](=[O:18])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([O:16]C)=[CH:10][CH:9]=3.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:19])[C:7](=[O:18])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([OH:16])=[CH:10][CH:9]=3
Reactant: COc1ccc2c(c1)-c1cc(Br)ccc1C(=O)C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1C(=O)c2ccc(Br)cc2-c2cc(O)ccc21

Procedure:
A mixture of 3-bromo-6-methoxyphenanthrene-9,10-dione from Step 3 above and excess BBr3 in CH2Cl2 was stirred at room temperature to afford 3-bromo-6-hydroxyphenanthrene-9,10-dione which was used directly in the next step (Step 5 below).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:5]
Reactant: COc1ccc(C#N)c(N)c1
Reactant: O=C=NC(=O)c1ccccc1
Product: COc1ccc(C#N)c(NC(=O)NC(=O)c2ccccc2)c1

Procedure:
Prepared as in Example 53a from 2-amino-4-methoxybenzonitrile and benzoyl isocyanate as white solid (99 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 6.87 (dd, J=2.5 Hz, 2.4 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=1.2 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 8.03 (d, J=2.8 Hz, 2H), 11.35 (s, 1H), 11.52 (s, 1H). MS 295 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:21]([CH2:22][CH:23]=[CH2:24])=[C:20]([O:25][CH2:26][O:27][CH3:28])[CH:19]=[C:18]([O:29][CH2:30][O:31][CH3:32])[C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]([O:25][CH2:26][O:27][CH3:28])[CH:19]=[C:18]([O:29][CH2:30][O:31][CH3:32])[C:3]=1[C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1
Reactant: C=CCc1c(OCOC)cc(OCOC)c(C(=O)C=Cc2ccc(OCOC)cc2)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(OCOC)cc(OCOC)c(C(=O)CCc2ccc(OCOC)cc2)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Then, an ethyl acetate solution of 21.1 g of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3'-(2-propenyl)chalcone was added to a suspension of 8.0 g of 5% palladium/carbon in 50 ml of ethyl acetate, in which a hydrogen gas had been sufficiently absorbed, and the mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation to obtain quantitatively 21.2 g of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-n-propylphenyl]-3-(4-methoxymethoxyphenyl)-1-propanone in the form of a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[C:21]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]>N1C=CC=CC=1>[C:21]([C:23]1[CH:24]=[C:25]([S:29]([NH:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[CH2:7][CH2:6]2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: c1ccncc1
Product: N#Cc1cccc(S(=O)(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a solution of (2-R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.200 g, 0.63 mmol) in 4 ml of pyridine at 0° C. was added 3-cyanobenzenesulfonyl chloride (0.127 g, 0.63 mmol). After 30 min, the reaction was allowed to warm to room temperature and was stirred for 2 h. The reaction was concentrated under vacuum, and the residue partitioned between 10% aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with water, then brine and dried over magnesium sulfate. The crude material was purified on silica gel (0 to 5% 7N ammonia in methanol/dichloromethane) to afford the title compound as a white foam (0.120 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:42])([CH3:41])[C:29]([NH:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1)=[O:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:38][CH2:37][C:36]1[CH:39]=[CH:40][C:33]([CH2:32][NH:31][C:29](=[O:30])[C:28]([CH3:41])([CH3:27])[CH3:42])=[CH:34][CH:35]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)C(=O)NCc1ccc(CN)cc1
Product: CC(C)(C)C(=O)NCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 75.9 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (299 mg, 0.704 mmol) and 4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamine (310 mg, 1.41 mmol). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (3:2) to obtain 7-chloro-6-{4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (265 mg, 76%). MS (ES+) m/z: 496 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:25][CH:24]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and [4-(trifluoromethyl)phenyl]methanol (111 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (125 mg, yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]([CH3:15])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]([CH3:15])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: CN(CC(=O)c1ccccc1)Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Into a 250 ml 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-phenylethanone (4.3 g, 14.01 mmol, 1.00 equiv) in methanol (50 mL). This was followed by the addition of NaBH4 (1.5 g, 39.47 mmol, 2.82 equiv) in several batches at 0° C. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 20 mL of acetone. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:80-1:20). This resulted in 3.4 g (79%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Product: CCc1ccc(-c2cc(NC(=O)c3cncnc3)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(4-ethylphenyl)-boronic acid (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 403.1384 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][CH3:30])=[O:28]>C(O)C.[Pd].O>[CH3:30][O:29][C:27]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)=[O:28]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: COC(=O)Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCN(C(=O)OC)CC1=O
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (Iselin, B. M. and Hoffmann, K., Helv. Chim. Acta, 1954, 37, 178) (14.0 g; 47 mmol) in aqueous ethanol (300 ml; 50%) was hydrogenated (ca. 300 kPa) in a PARR hydrogenation apparatus by using a 10% Pd-C catalyst (1.4 g). The reaction mixture was filtered and evaporated to dryness in vacuo. To an ice cooled solution of the residue in water (50 ml) was added with stirring an iced solution of potassium carbonate (19.4 g; 140 mmol) in water (20 ml) followed by addition of methyl chloroformate (11.3 g; 120 mmol). Stirring was continued at 0° C. for 30 minutes and at 25° C. for 30 minutes. The mixture was extracted with three 100 ml portions of ether. The combined and dried (Na2SO4) ether phases were evaporated in vacuo to give 10.0 g of crude product. Ball-tube distillation at 40-130 Pa (oven temperature 170° C.) gave IVa (9.0 g; 84%) as a colourless oil, which slowly crystallized, m.p. 36°-38° C. IR (film): 2980-2850 (several bands, m-s), 1700 (s), 1655 (s), 1620 (m) cm-1. 1H NMR (CCl4): δ12.3 (1 H, s), 4.13 (q, J 7 Hz) and 4.0-3.9 (m) (a total of 4 H), 3,62 (3 H, s), 3,43 (2 H, t, J 6 Hz), 2.4-2.1 (2 H, m), 1.30 (3 H, t, J 7 Hz).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:21][CH3:22].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:22][O:21][C:3]1[CH:4]=[C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])[CH:19]=[CH:20][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1Br
Product: COc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccccc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-3-methoxy-N-quinolin-7-ylbenzamide (D69) (76 mg, 0.21 mmol) and phenylboronic acid (28 mg, 0.23 mmol) as a white solid. MS(ES): MH+ 355, M-H+ 353.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:17]([N:24]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>O1CCOCC1>[CH2:35]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:6][CH:7]=2)[C:30]=1[N+:31]([O-:33])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(N)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1ccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl 4-aminophenyl(methyl)carbamate (36) (7 g, 31.5 mmol) and N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (11.2 g, 31.5 mmol) in dioxane (100 mL) was added Et3N (8 mL) and the reaction mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature, the solvent was evaporated before water (200 mL) and EA (100 mL) was introduced. The organic layer was separated and extracted with EA (60 mL×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 4-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl(methyl)carbamate (37) 9 g as yellow solid (yield 53%). LC-MS (ESI): m/z (M+1) 541.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: C1CCNC1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCCC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 67.1 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (50 mg, 0.10 mmol) in DCM (5 mL) was added pyrrolidine (0.025 mL, 0.30 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (34 mg, 67%). LC-MS m/z 507 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.87 (m, 4H), 2.31 (s, 3H), 3.33 (m, 4H), 4.11 (m, 2H), 4.23 (m, 1H), 7.13 (t, 2H), 7.44 (d, 1H), 7.48 (m, 1H), 7.70 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1)#[N:2].Cl>C1COCC1>[O:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5][CH:4]1[CH2:3][CH2:1][NH2:2]
Reactant: N#CCC1COc2ccccc2O1
Agent: Cl
Solvent: C1CCOC1
Product: NCCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The 2-cyanomethyl-(2,3 dihydrobenzo[1,4]dioxine) was dissolved in THF (50 mL) and 1M BH3 in THF (80 mL, 80 mmol) was added and the reaction mixture refluxed for 5 h, then stirred at ambient temperature for 16 h. With ice bath cooling, 2N HCl was added until pH=1.0 was achieved. The reaction mixture was then stirred for 1 h at room temperature and evaporated in vacuo to yield an oil. The oil was partitioned between 3N NaOH and diethyl ether, and the diethyl ether solution was washed with brine, dried (Na2SO4) and evaporated in vacuo to yield crude 2-(2,3 dihydrobenzo[1,4]dioxin-2-yl)ethylamine.