Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[C:17]2[C:12]([C:13](=[O:38])[C:14]([CH3:37])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:41]([F:44])([F:43])[F:42].C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][C:9]1[C:18]([CH:19]([OH:20])[C:41]([F:44])([F:43])[F:42])=[C:17]2[C:12]([C:13](=[O:38])[C:14]([CH3:37])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1c(C2CCN(C(=O)OCc3ccccc3)CC2)oc2c(C=O)c(OCc3ccccc3)ccc2c1=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(C2CCN(C(=O)OCc3ccccc3)CC2)oc2c(C(O)C(F)(F)F)c(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of benzyl 4-[7-(benzyloxy)-8-formyl-3-methyl-4-oxo-4H-chromen-2-yl]piperidine-1-carboxylate (378 mg, 0.74 mmol) obtained in Example 36-1 in dimethyl sulfoxide (10 mL), molecular sieves 4A (1.0 g) and trimethyl(trifluoromethyl)silane (1.09 mL, 7.39 mmol) were added, and then the mixture was stirred at room temperature for 3 hours. Ethyl acetate (80 mL) was added to the reaction solution, and insoluble matter was removed by filtration through celite. The filtrate was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous hydrochloric acid solution (3 mL) and methanol (12 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=80/20→40/60) to obtain 392 mg of the title compound (yield: 91%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([N:21]([CH3:22])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.35 g, 1.04 mmol) in THF (6 ml) was added 1-bromomethyl-4-trifluoromethyl-benzene (0.27 g, 1.15 mmol) and Et3N (0.148 ml, 1.45 mmol). The reaction mixture was stirred overnight at RT and concentrated under vacuo. The product purified by flash chromatography (SiO2, EtOAc/Heptane 1:4) to afford 130 mg (29%) of the title compound as a colorless oil. ES-MS m/e: 492.9 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[N:4]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)CN(S(=O)(=O)c2ccccn2)c2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21

Procedure:
100 mg (0.27 mmol) of 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione were initially charged in 1 ml of pyridine, and 88 mg (0.41 mmol) of 2-pyridylsulphonyl chloride hydrochloride were added. For workup, the mixture was concentrated fully and the residue purified by flash chromatography (100 g of silica gel/95:5 CH2Cl1:CH30H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:27](=[O:28])[CH2:26][Cl:25])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)CCl)C1O
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 μl (0.935 m mol) of triethylamine and 20 ml of methylene chloride was added with 74 μl (0.935 m mol) of chloroacetyl chloride with stirring at the room temperature, followed by further stirring for 30 minutes. After the completion of the reaction, the precipitated crystals were separated by filtration to obtain 201 mg (yield: 76%) of the intended compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:29]([CH3:32])([CH3:31])[OH:30])[CH:5]=[C:6]([O:27][CH3:28])[C:7]=1[O:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[N:12]=[C:11]([CH3:26])[N:10]=1>C(O)C.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([C:29]([CH3:32])([CH3:31])[OH:30])[CH:5]=[C:6]([O:27][CH3:28])[C:7]=1[O:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[N:12]=[C:11]([CH3:26])[N:10]=1
Reactant: CCCC(CCC)Nc1nc(C)nc(Oc2c(Br)cc(C(C)(C)O)cc2OC)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: CCCC(CCC)Nc1nc(C)nc(Oc2c(Br)cc(C(C)(C)O)cc2OC)c1N
Reaction time: 18 h

Procedure:
Platinum black, (5%,0.25 g) was added to a solution of 3-bromo-5-methoxy-α,α-dimethyl-4-[[2-methyl-5-nitro-6-[(1-propylbutyl)amino]-4-pyrimidinyl]oxy]benzenemethanol (0.80 g) in 50 mL of ethanol. The mixture was hydrogenated at a pressure of 41 psi for 18 hours. The mixture was filtered through celite and the filtrate was stripped under reduced pressure. The residue was taken up in 1 N NaOH and extracted with methylene chloride. The combined methylene chloride extracts were dried over MgSO4 and the filtrate was stripped under reduced pressure to yield the title compound, mp 114-116° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:24]([C:23]3[CH:26]=[CH:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:29][C:22]=3[CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: Cc1cc(N2CCOCC2)ccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1cc(N2CCOCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 34.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 2-Methyl-4-morpholin-4-yl-benzaldehyde (38.4 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 28.37 mg (35%) of the title compound. (300 MHz, DMSO-d6) 12.83 (s, 1H), 7.91 (s, 1H), 7.72 (m, 2H), 7.21 (s, 1H), 7.00 (d, J=9 Hz, 1H), 6.90 (s, 2H), 6.33 (s, 1H), 6.26 (s, 1H), 5.18 (t, J=17 Hz, 9 Hz, 1H), 3.75 (s, 4H), 3.22 (s, 4H), 2.86 (s, 1H), 2.75 (s, 1H), 2.59 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz). MS=479 (M+H), HPLC: 2.42 min. (G Method)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([CH:12]=O)=[CH:10][CH:9]=[CH:8][CH:7]=1.[Mg+2].[Br-].[Br-]>>[CH:8]1[CH:9]=[CH:10][C:11]([CH:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:7]=1
Reactant: O=Cc1ccccc1-c1ccc[nH]1
Agent: [Br-]
Agent: [Mg+2]
Product: c1ccc(C(c2ccc[nH]2)c2ccc[nH]2)cc1

Procedure:
In the survey of various acid catalysts for the pyrrole-benzaldehyde condensation, MgBr2 gave a good yield of 5-phenyldipyrromethane with little N-confused 5-phenyldipyrromethane and 5,10-diphenyltripyrrane. This observation prompted us to study the effect of MgBr2 on the pyrrole-mesitaldehyde condensation. Four reactions were carried out with 0.1, 0.3, 0.5 or 1.0 equiv of MgBr2 using a 100:1 ratio of pyrrole:mesitaldehyde at room temperature. For the reaction with 0.5 equiv of MgBr2, GC analysis showed 82.9% of 5-mesityldipyrromethane and 0.9% of unreacted mesitaldehyde. Among the acids surveyed, the use of 0.5 equiv of MgBr2 appeared superior for the synthesis of 5-mesityldipyrromethane.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH:26]=[N+]=[N-])[N:17]=[CH:16]2)[C@@H:6]1[F:30])(=[O:3])[CH3:2].[ClH:31]>ClCCl.C(OCC)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH2:26][Cl:31])[N:17]=[CH:16]2)[C@@H:6]1[F:30])(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Yield: 81 %

Procedure:
The compound (20) (21.8 mg) obtained in item (9) above was dissolved in dichloromethane (1 ml), and to the resulting solution was added a 1.25M hydrogen chloride solution (0.05 ml) in diethylether at 5° C., and the mixture so obtained was allowed to stand at that temperature overnight. The resulting reaction solution was washed with water and the organic layer obtained was dried over anhydrous sodium sulfate and concentrated to give the titled compound (21) (18.0 mg) as a syrup. Yield: 81%.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:21]([CH3:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([F:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[C:18]([C:17]1[CH:20]=[C:21]([CH3:22])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:3][C:4]=3[F:25])=[O:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)#[N:19]
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2F)CC1
Yield: 81.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(4-bromo-2-fluorobenzoyl)piperazin-1-yl]-5-methylnicotinonitrile (215 mg) described in Preparation Example 134 and oxazolidin-2-one (70 mg), the title compound (178 mg) was obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32]>C(OCC)(=O)C.CO.[Pd]>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([CH:24]([CH3:26])[CH3:25])[C@@H:12]32)[C:3]1([CH3:32])[CH3:33]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 18 h

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (4 g, 8.76 mmol) and 10% Pd/C (1.398 g, 1.314 mmol) in ethyl acetate (80 mL) and MeOH (30 mL) was connected to Parr Shaker and shaked for 18 h under 45 psi at room temperature. LCMS indicated the formation of desired product. The reaction mixture was filtered through celite and the filtrates were concentrated under reduced pressure to give the title compound as white solid (3 g, 75%). LCMS: m/e 457.27 (M−H)−, 2.40 min (method 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.N.C([N:15](CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH2:15])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1cnc(Br)cc1Br
Agent: N
Solvent: C1CCOC1
Product: Nc1cc(Br)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 50 h
Yield: 95 %

Procedure:
Under nitrogen, to a solution of 2,4-dibromo-5-nitropyridine in THF (150 mL), was added ammonia (2.0M in MeOH), followed with triethylamine (5 mL). This mixture was then stirred at rt for 50 h. The reaction mixture was concentrated, taken up in EtOAC, filtered through a silica gel pad, and then concentrated in vacuo to afford the title compound (3.67 g, 95%). MS (ES+) m/e 218 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=O)=[CH:11][CH:10]=1.[C:19]([CH2:21][C:22]([NH2:24])=[O:23])#[N:20].O=O>CS(C)=O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][NH:24][C:22](=[O:23])[C:21]=2[C:19]#[N:20])=[CH:11][CH:10]=1
Reactant: N#CCC(N)=O
Reactant: COc1ccc(/C=C/C=O)cc1
Agent: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2cc[nH]c(=O)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A mixture of potassium tert-butoxide (5.54 g, 49.3 mmol) in DMSO (20 mL) was added to a mixture of (E)-3-(4-methoxyphenyl)acrylaldehyde (2.0 g, 12.33 mmol) and 2-cyanoacetamide (1.140 g, 13.56 mmol) in DMSO (30 mL) dropwise under an oxygen balloon with a water bath cooling outside. After completion of addition, the mixture was stirred under oxygen for 1 h at room temperature, quenched with water (100 mL) and adjusted to pH 5-6 with careful addition of 1 N HCl. A brown precipitate was formed, collected by filtration, washed with water (2×50 mL), dried under vacuum to give 4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.0 g, 36% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.69 (1H, δ, J=6.60 Hz), 7.62 (2H, δ, J=8.80 Hz), 7.11 (2H, δ, J=8.80 Hz), 639 (1H, δ, J=6.60 Hz), 3.87 (3H, s); MS (ES+) m/z: 227 (M+H); LC retention time: 2.532 min (analytical HPLC Method A).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].O>ClCCl>[CH2:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)=[O:18])[CH3:21]
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
To a suspension of 30 g (0.15 mol) of 3-piperidin-4-yl-1H-indole and 28 mL (0.2 mol) in 185 mL of anhydrous dichloromethane, 17 mL (0.18 mol) of ethyl chloroformate was added dropwise keeping the temperature of the reaction below 20° C. After 2 h at room temperature, the crude mixture was poured into 100 mL of water. The organic layer was separated and dried with sodium sulfate. After filtration, the solvent was removed under reduced pressure affording 39 g (95% of yield) of the expected product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 3-nitrobenzaldehyde (1) (200 g, 1.32 mol) in methanol (1000 mL) at 0° C. under N2 atmosphere was slowly added NaBH4 (25 g, 0.66 mol) and then the reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was re-cooled to 0° C. and quenched with ice-water, methanol was removed under reduced pressure and the residue was extracted with CH2Cl2 (5×200 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to furnish compound 2 (190.7 g, 93%) as liquid which was taken as such for next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.[CH3:21][N:22]([CH3:33])[C:23]1[CH:28]=[CH:27][C:26](OB(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:21][N:22]([CH3:33])[C:23]1[CH:28]=[CH:27][C:26]([C:16]2[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH2:6][C:7]3[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=3)[CH:15]=2)=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(OB(O)O)cc1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccc(N(C)C)cc2)c1OC
Temperature: 0 °C
Yield: 88.5 %

Procedure:
376 mg of 5-(3,4-dimethoxy-5-iodo-benzyl)-pyrimidine-2,4-diamine and 400 mg of 4-dimethylamino-phenylboric acid (Example 3a)) are treated with 40 ml of dioxan and 2.4 ml of a 2M potassium carbonate solution and 24 mg of tetrakis-tri-phenylphosphine-palladium. The mixture is heated at reflux under argon for 14 hrs. Subsequently, it is poured on to ice-water, extracted with methylene chloride, dried over magnesium sulphate and chromatographed on silica gel with methylenechloride/methanol 98:2. 327 mg (91%) of 5-(4'-dimethylamino-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a yellowish solid. M.p. 230°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][NH:1]2)[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: OC[C@@H]1CCCN1
Product: N#Cc1c(N)cccc1OC[C@@H]1CCCN1

Procedure:
Prepared as in Example 24d from (S)-pyrrolidin-2-ylmethanol and 2-amino-6-fluorobenzonitrile as brown solid (51%). MS 218 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:17]12[C:23](=[O:24])[O:22][C:20](=[O:21])[CH:18]1[CH2:19]2.Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH:7]1([C:1]2[CH:2]=[CH:3][C:4]([C:23]([C@H:17]3[CH2:19][C@H:18]3[C:20]([OH:22])=[O:21])=[O:24])=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: O=C1OC(=O)C2CC12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccc(C2CCCCC2)cc1)[C@H]1C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
14.3 g (89.2 millimoles) of cyclohexylbenzene are added dropwise to 23.7 g (0.18 mole) of anhydrous aluminum chloride in 50 ml of nitrobenzene at 10°-15° C., whilst stirring. 10.0 g (89.2 millimoles) of 1,2-cyclopropanedicarboxylic acid anhydride are then added, a little at a time, at the same temperature and thereafter the mixture is stirred for 20 hours at room temperature, followed by 1 hour at 50° C. The solution is introduced into a mixture of 500 g of ice and 50 ml of concentrated hydrochloric acid. The nitrobenzene is removed by steam distillation and the solid which has precipitated is filtered off at 10° C. and dissolved in aqueous sodium carbonate solution. The solution is filtered and the filtrate is acidified with concentrated hydrochloric acid. The solid which precipitates is filtered off, washed with water and dried under reduced pressure at 50° C. 19.9 g (82% of theory) of cis-2-(p-cyclohexylbenzoyl)-cyclopropanecarboxylic acid are obtained as almost colorless crystals of melting point 162°-163° C. after recrystallization from methanol.
Reaction SMILES: C(N(CC)CC)C.[NH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:9].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1C=CC=CC=1>[CH3:14][C:13]([CH3:16])([O:12][C:10]([NH:8][NH:9][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:11])[CH3:15]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)CBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Triethylamine (13.94 ml., 0.1 mol.) was added to a solution of hydrazine carboxylic acid, 1,1-dimethylethyl ester (13.216 g., 0.1 mole) in benzene (100 ml.), followed by the addition of ethyl bromoacetate (11.09 ml., 0.1 mol.). The reaction mixture was refluxed (oil bath, 95°-100° C.) for 14 hours, after which triethylamine (1.4 ml., 0.01 mol.) was added followed by ethyl bromoacetate (1.1 ml., 0.01 mole). After refluxing for an additional 8 hours, triethylamine (2 ml., 0.015 mol.) and ethyl bromoacetate (1.4 ml., 0.013 mole) were added. The mixture was allowed to reflux for another 14 hours (total 36 hours). After cooling to room temperature, the reaction mixture was filtered and the solid triethylamine, hydrochloride salt was washed with ethyl acetate/hexane (1:1). The combined filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried (sodium sulfate) and filtered. The filtrate was concentrated in vacuo to afford 19.38 g. of crude product as a yellow syrup which was used for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=2[C:13]=1[O:14][CH3:15].Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=3[C:13]=2[O:14][CH3:15])=[N:18][CH:19]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(N)ccc2c1CCC(=O)CC2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CCC(=O)CC2

Procedure:
The title compound was prepared from 2-amino-1-methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 179. Product was prepared as a white solid (18 mg, 30%). LCMS (m/e) 468 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, 1H, J=8.1 Hz), 7.96 (s, 1H), 7.93 (d, 1H, J=7.1), 7.82 (s, 1H), 7.81 (d, 1H), 7.281 (s, 1H), 7.04 (d, 1H, J=8.2 Hz), 6.35 (m, 1H), 6.29 (m, 1H), 4.03 (m, 1H), 3.67 (s, 3H), 3.29 (s, 2H), 2.95 (m, 2H), 2.89 (m, 4H), 2.67 (m, 1H), 2.53 (m, 2H), 2.09 (d, 1H, J=9 Hz), 1.40 (d, 1H, J=9 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(#N)C>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)=[CH:28][CH:27]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-chlorobenzylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a gradient of 40% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=385.