Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:38][CH:39]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1
Yield: 91.5 %

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (61 mg) was reacted with 50 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 63.4 mg of 208. MS (Q1) 484.3 (M)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]1O)=[S:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=[S:4]
Reactant: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(C)(C)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=S)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 49.4 %

Procedure:
A mixture of 7.0 g of N,2,2-trimethyl-3,4-dihydro-3-hydroxy-6-nitro-2H-1-benzopyran-4-carbothioamide, 3.0 g of p-toluenesulfonic acid monohydrate, and 300 ml of toluene was heated at reflux for 1 hour. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH2Cl2). Recrystallizatlon from a mixed solvent of CH2Cl2, diethyl ether, and hexane gave 3.25 g of N,2,2-trimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(F)cccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cccc(F)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[S:24]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25]1.CON(C)[C:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[O:36]>C1COCC1>[C:35]([C:25]1[S:24][CH:28]=[CH:27][C:26]=1[C:29]([OH:31])=[O:30])(=[O:36])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1
Reactant: CON(C)C(=O)c1ccncc1
Reactant: O=C(O)c1ccsc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccsc1C(=O)c1ccncc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To a solution of diisopropylamine (5.2 g, 51.5 mmol) in anhydrous THF (40 mL) at −30° C. was added n-BuLi (23.2 mL, 56.2 mmol, 2.5M in THF) dropwise. The mixture was stirred at the same temperature for 0.5 h, then cooled to −78° C. and HMPA (0.8 g, 4.7 mmol) was added slowly. Then a solution of thiophene-3-carboxylic acid (3.0 g, 23.4 mmol) in anhydrous THF (50 mL) was added slowly. The mixture was stirred at the same temperature for 1 h, N-methoxy-N-methyl-4-pyridinecarboxamide (5.0 g, 46.9 mmol) was added drop wise into the stirring mixture at −78° C. The reaction mixture was stirred for another 1 h at room temperature and was then quenched with H2O (10 mL). The aqueous layer was acidified with 5% aq. HCl to pH 1-2, the precipitate was collected by filtration. The filter cake wash with DCM and the filtrate was extracted with DCM (3×200 mL). The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was washed with DCM to give the title product (2.2 g, yield 40%) as a white solid.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:7]=1)=O.[OH-].[Li+]>C1COCC1.O>[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1

Procedure:
A solution of 2,2,2-trifluoro-N-(3-{3-[2-(3-fluoro-phenylamino)-pyrimidin-4-yl]-pyrazolo[1,5-a]pyridin-2-yl}-phenyl)-acetamide (2.15 g, 4.4 mmol) and lithium hydroxide (277 mg, 6.6 mmol) in THF (44 mL) and water (10 mL) was stirred for 16 h. The reaction was extracted with DCM. The combined organic phases were dried over MgSO4 and purified through silica gel to give the title compound as a white solid. 1H NMR (400 MHz, d6-DMSO): δ 9.75 (s, 1H), 8.78 (d, J=6.8 Hz, 1H), 8.52 (d, J=9.2 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 7.80 (d, J=12.4 Hz, 1H), 7.47-7.43 (m, 2H), 7.29-7.23 (m, 1H), 7.12-7.06 (m, 2H), 6.77 (s, 1H), 6.71 (dt, J=8.4 and 2.4 Hz, 1H), 6.66-6.62 (m, 2H), 6.54 (d, J=5.6 Hz, 1H), 5.21 (s, 2H) ppm. HRMS calculated C23H17FN6 [M+H]+ 397.1577 found 397.1558.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=3)[C:12]2=[O:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=3)[C:12]2=[O:24])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2CCN(c3ccc(CO)cc3)C2=O)cc1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC(C)(C)c1ccc(N2CCN(c3ccc(C=O)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-tert-butylphenyl)-3-(4-(hydroxymethyl)phenyl)imidazolidin-2-one (100 mg, 0.31 mmol), 4-methylmorpholine N-oxide (72 mg, 0.62 mmol), and 4 A molecular sieves (100 mg) in 10 ml of acetonitrile was treated with tetrapropylammonium perruthnate and the resulting mixture was stirred at room temperature for 3 hours. The solids were filtered and the filtrated was concentrated. The residue was purified on ISCO system (2% methanol in dichloromethane) to give a pure product as a white crystalline (72 mg, 73%): 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.81 (d, 2H), 7.79 (d, 2H), 7.50 (d, 2H), 7.40 (d, 2H), 4.03 (s, 4H), 1.33 (s, 9H). MS (ESI) m/z: Calculated: 322.17; Observed: 323.1 (M++1).
Reaction SMILES: C1(CO[C:9](=O)[N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29](=[O:31])[CH3:30])[C@@H:24]([CH3:32])[CH2:23][C@H:22]4[NH:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=3)=[CH:15][CH:14]=2)C)C=CC=CC=1.[ClH:42]>C(O)C.CO.[Pd]>[ClH:42].[C:29]([N:25]1[C:26]2[C:21](=[CH:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([CH2:12][NH:10][CH3:9])=[CH:18][CH:17]=3)=[CH:28][CH:27]=2)[C@H:22]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=2)[CH2:23][C@@H:24]1[CH3:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN(C)C(=O)OCc4ccccc4)cc3)cc2[C@H](Nc2ccc(F)cn2)C[C@@H]1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CNCc1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(F)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
A mixture of phenylmethyl[(4-{(2S,4R)-1-acetyl-4-[(5-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}phenyl)methyl]methylcarbamate (for a preparation see intermediate 79) (55 mg, 0.100 mmol) and palladium (10% w/w on charcoal, 50% wet, 6.35 mg, 0.060 mmol) in ethanol (9 mL) was stirred under hydrogen (1 bar) at room temperature for 17 h then filtered through celite. The insoluble material was rinsed with ethanol (20 mL) and the combined filtrate and washings were concentrated in vacuo. Purification of the residue with MDAP (modifier: ammonium bicarbonate) gave a white solid which was dissolved in MeOH (0.4 mL), then treated with HCl (1.25M in MeOH, 38.3 μL, 0.0478 mmol). The resulting mixture was concentrated in vacuo to give (2S,4R)-1-acetyl-N-(5-fluoro-2-pyridinyl)-2-methyl-6-{4-[(methylamino)methyl]phenyl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (23 mg, 48%) as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>ClCCl.C(OCC)(=O)C>[CH3:1][N:2]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH2:3]
Reactant: CNN
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of methylhydrazine 7.13 ml (150 mmol) and triethylamine 16.7 ml (120 mmol), ethyl 2-bromoacetate 16.7 g (100 mmol) in dichloromethane 50 ml was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 300 ml and washed with brine 200 ml. The organic phase was dried over magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 10.2 g (77%).
Reaction SMILES: [C:1]([C:4](=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].Cl.[C:33]([NH2:36])(=[NH:35])[CH3:34].C([O-])(=O)C.[Na+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CN(C=O)C>[Cl:31][C:26]1[CH:25]=[C:24]([C:23]2[C:4]([C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:6])=[C:1]([CH3:2])[N:36]=[C:33]([CH3:34])[N:35]=2)[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: CC(=O)C(=Cc1ccc(Cl)c(Cl)c1)C(=O)NCCC(c1ccccc1)c1ccccc1
Reactant: CC(=N)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)NCCC(c2ccccc2)c2ccccc2)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
120 mg (0.265 mmol) of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3,3-diphenylpropyl) acrylamide was dissolved in 5 ml of DMF. 37.6 mg (0.398 mmol) of acetamidine hydrochloride and 26.1 mg of (0.318 mmol) of sodium acetate were added thereto and stirred at 100° C. overnight. After the solvent was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of toluene. 120 mg (0.530 mmol) of DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone; hereinafter abbreviated as DDQ) was added thereto and stirred at 100° C. overnight. After filtration of insoluble matters and evaporation of the solvent under reduced pressure, the filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[NH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[O:39][N:38]=[C:37]([CH2:40]Cl)[N:36]=2)[CH:34]=1>C(#N)C>[Br:28][C:29]1[CH:34]=[C:33]([C:35]2[O:39][N:38]=[C:37]([CH2:40][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:1])([F:20])[F:21])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[C:6]3[CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:36]=2)[CH:32]=[N:31][CH:30]=1
Reactant: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1C(F)(F)F
Reactant: ClCc1noc(-c2cncc(Br)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CCC(F)(F)F)n2Cc2noc(-c3cncc(Br)c3)n2)c1C(F)(F)F
Yield: 22.8 %

Procedure:
To a solution of 4-(trifluoromethyl)-2-(3,3,3-trifluoropropyl)-1H-indole-5-carbonitrile (Example 302A) (0.200 g, 0.653 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (0.851 g, 0.2.612 mmol) and 3-bromo-5-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]pyridine (0.269 g, 0.979 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.081 g, 23% yield): MS (ES) m/z 544 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](F)([C:17]([F:20])([F:19])[F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([CH3:22])[C:4]=1[NH2:23])[CH3:2].[OH-:24].[K+]>C(#N)C.O>[NH2:23][C:4]1[C:5]([CH3:22])=[CH:6][C:7]([C:9]([OH:24])([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Reactant: [OH-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(C(O)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Temperature: 70 °C
Reaction time: 48 h
Yield: 59.8 %

Procedure:
To a solution of 2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methyl-phenylamine (prepared as descriebed in WO 2008/074427) (3.88 g, 11 mmol) in a mixture of acetonitrile (320 ml) and water (80 ml) was added potassium hydroxide (46.2 g, 827 mmol). The reaction mixture was stirred at 70° C. for 2 days. The reaction mixture was diluted with water (200 ml) and the mixture extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3) to give 2-(4-amino-3-ethyl-5-methylphenyl)-1,1,1,3,3,4,4,4-octafluorobutan-2-ol (2.31 g, 60% yield). LC-MS (Method 1): RT=1.87, [M−H]−=352.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH3:23])[NH:7][N:6]=1)=[O:4].[OH-].[K+]>>[CH2:21]([O:20][C:18]([C:9]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:5]([C:3]([OH:4])=[O:2])=[N:6][NH:7][C:8]=1[CH3:23])=[O:19])[CH3:22]
Reactant: CCOC(=O)C1=C(C)NN=C(C(=O)OC)C1c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C1=C(C)NN=C(C(=O)O)C1c1cccc(Cl)c1

Procedure:
0.1 mol of 4-(3-chlorophenyl)-1,4-dihydro-6-methyl-pyridazine-3,5-dicarboxylic acid 5-ethyl 3-methyl ester is saponified with 0.105 mol of KOH analogously to Example 28 to give 4-(3-chlorophenyl)-1,4-dihydro-6-methyl-pyridazine-3,5-dicarboxylic acid 5-ethyl ester. Melting point 182° C. (ethanol).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:20]=[C:21](N)[N:22]=[C:16]4[C:15]=3[CH2:24][CH2:25][CH3:26])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[NH4+].[OH-].[BrH:33]>O>[Br:33][C:21]1[N:22]=[C:16]2[N:17]([CH:18]=[N:19][C:14]([CH2:13][N:9]3[CH:10]=[CH:11][N:12]=[C:8]3[C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:15]2[CH2:24][CH2:25][CH3:26])[N:20]=1
Reactant: Br
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(N)nc12
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(Br)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 174 (788 mg, 2.24 mmol) in aqueous HBr (48%, 8 ml) cooled to 0° C. is added dropwise a solution of NaNO2 (232 mg, 3.36 mmol) in water (2 ml). The mixture is stirred at 0° C. for 30 minutes and CuBr (482 mg, 3.36 mmol) is added in 3 portions. The mixture is stirred at 0° C. for 30 minutes then allowed to warm to room temperature in 2 hours. Concentrated NH4OH is added dropwise to the solution until the pH≧7. The mixture is then extracted with EtOAc (3×15 ml) and the combined extracts are washed with brine (15 ml), dried (Na2SO4) and evaporated. The brown solid obtained it washed with ether (4 ml) then hexane (6 ml), which gives 175 as a light brown solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:22]([O:21][C:19]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([C:26]#[N:27])[N:3]=2)[CH2:13][CH2:14]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1Br
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1sc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1C#N

Procedure:
A solution of ethyl 4-bromo-2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1,3-thiazole-5-carboxylate (Intermediate 222) (1.3 g, 2.9 mmol), Zn(CN)2 (250 mg, 2.2 mmol), tris(dibenzylidineaceetone)dipalladium(0) (125 mg, 0.13 mmol) and 1,1′-bis(diphenylphosphino) ferrocene (151 mg, 13 mmol) in 20 ml DMF under argon was heated at 130° C. for 1 hour in a microwave reactor. Solvent was removed and the residue was taken up in EtOAc and washed with water and brine. Drying (MgSO4) and removal of solvent gave an oil that was chromatographed on silica gel (DCM followed by gradient elution to 5% MeOH in DCM) to give 1.9 g of product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].BrBr.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12]([NH:29][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)=[N:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCc1ccc(F)cc1
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(Cl)c(Cl)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1N=C(NCc2ccc(F)cc2)C(c2ccccc2)N1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
To a stirred solution of 1-(3,4-dichloro-phenyl)-5-phenyl-1,3-dihydro-imidazol-2-one (1 equiv., 0.33 mmol, 100 mg) in chloroform (5 mL) was added dropwise Br2 (1.1 equiv., 0.36 mmol, 19 μL) in chloroform (2 mL) at 0° C. under nitrogen. After 10 min, 4-fluorobenzylamine (10 equiv., 3.28 mmol, 372 μL) was added in situ at 0° C. The reaction mixture was allowed to warm up to room temperature and heated at reflux overnight. After evaporation of solvent, the residue was purified by column chromatography (SiO2, n-heptane/ethyl acetate: 0-100%) affording the title compound as a white solid (32 mg, 23%). δH NMR (DMSO, 300 MHz) 8.83 (1H, br, s, NH), 7.91 (1H, d, J=2.4 Hz, H arom), 7.46-7.08 (11H, m, H arom), 6.16 (1H, s, C5H), 4.44 (2H, s, CH2Ph); m/z (EI) 431.0 (12%), 430.0 (74), 429.1 (26), 428.0 (100, M+H+).
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.COCCOC.C(=O)([O-])O.[Na+].[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24][N:23]=1>Br.O>[F:31][C:28]([F:29])([F:30])[C:26]1[N:25]=[CH:24][N:23]2[CH:8]=[CH:9][N:21]=[C:22]2[CH:27]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1cc(C(F)(F)F)ncn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1cc2nccn2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.4 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (2.09 ml, 13.5 mmol) in concentrated hydrobromic acid (0.68 ml) and water (0.68 ml) was heated at reflux under nitrogen for 20 min. The solution was allowed to cool to room temperature, ethylene glycol dimethyl ether (5 ml) was added and the solution was neutralised to pH 7 with solid sodium hydrogen carbonate. The mixture was filtered and the solid was washed with more ethylene glycol dimethyl ether (7 ml). To the combined filtrates was added 4-amino-6-trifluoromethylpyrimidine (2.00 g, 12.3 mmol) and the mixture was stirred at 65° C. for 18 h. After allowing to cool, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give 2.426 g of 7-trifluoromethylimidazo[1,2-c]pyrimidine: 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.86 (1H, s), 7.96 (1H, s), 9.13 (1H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[O:21]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[O:21]1[CH2:25][CH2:24][CH:23]([C:26]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:27])[CH2:22]1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Reactant: O=C(O)C1CCOC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)C1CCOC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 92 mg 3-tetrahydrofuranecarboxylic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. 1.09 g of the residue are purified by silica gel flash chromatography. 110 mg of the title compound are obtained after drying as colorless foam.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[C:6]([O:11]C)(=O)[C:7]([CH3:9])=[O:8].C(O)(=O)C>O>[OH:8][C:7]1([CH3:9])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:6]1=[O:11]
Reactant: COC(=O)C(C)=O
Reactant: CNC(N)=O
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)NC(=O)C1(C)O
Yield: 31.5 %

Procedure:
155 g of N-methylurea were added to 214 g of methyl pyruvate in a 3 1 eggplant type flask. 800 ml of acetic acid and 200 ml of water were added to dissolve them and the solution was refluxed for 2.5 hours. Then, the reaction mixture was evaporated to dryness and acetic acid was removed by azeotropic distillation with toluene. The obtained crude product was purified by chromatography on silica gel (ethyl acetate and 5% methanol/chloroform) to give 95 g of 5-hydroxy-1,5-dimethylhydantoin (compound 10).
Reaction SMILES: C([Cl:9])(=O)C1C=CC=CC=1.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]([CH2:40][CH3:41])=[CH:34][CH2:35][CH2:36][CH:37](O)[CH3:38]>>[Cl:9][CH:37]([CH2:36][CH2:35][CH:34]=[C:33]([CH3:32])[CH2:40][CH3:41])[CH3:38]
Reactant: CCC(C)=CCCC(C)O
Reactant: O=C(Cl)c1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: CCC(C)=CCCC(C)Cl

Procedure:
Triphenylphosphite benzoylchloride (10 g.) is mixed with 1.9 g. of 6-methyl-5-octen-2-ol and kept at room temperature overnight. The crude product is washed with 2N sodium hydroxide and water and dried to yield 2-chloro-6-methyl-5-octene.