Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([O:13][CH:14]1[CH2:17][N:16]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:15]1)[C:4]1[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=1[Cl:2]
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Yield: 44 %

Procedure:
A solution of 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) (0.29 mmol), tert-butyl isocyanate (0.29 mmol) and triethylamine (0.58 mmol) in dichloromethane (3 mL) was shaken at room temperature overnight, quenched with water, filtered through a PTFE phase separator cartridge and reduced in vacuo to yield a colourless gum (52 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([CH3:16])[C:13](=S)[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH3:26].CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:12]=[C:13]([NH2:26])[C:14]([CH3:16])=[N:15]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(Br)cc32)NC1=S
Reactant: N
Solvent: CO
Solvent: CN(C)C=O
Product: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(Br)cc32)N=C1N
Temperature: 100 °C
Yield: 30 %

Procedure:
6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione (Example 49 Step 2), directly from the previous step was dissolved in dry DMF (4 mL) in a microwave vial. Ammonia, 7M in MeOH (18 mL, 126 mmol) was added. The vial was sealed and the reaction was heated at 100° C. for 60 min in a microwave reactor (fixed hold time). The mixture was concentrated and the residue was dissolved in ammonia (7M in MeOH, 18 mL, 126 mmol) and heated at 120° C. for 30 min in a microwave reactor. This cycle was repeated three more times. After evaporation of the solvent, the remaining product was subjected to flash chromatography (0-7% of MeOH(NH3) in DCM) to give the title compound as a mixture of isomers (1.29 g, 30% yield over two steps): MS (ES+) m/z 406 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:18][C@@H:17]3O[C@@:16]3([CH2:20]O)[C@@H:7]2[C@H:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[O:9][CH:10]=1)=[O:4].C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:18][CH:17]=[C:16]([CH2:20][Cl:33])[C@@H:7]2[C@H:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[O:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@@]3(CO)[C@H]12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CCl)[C@H]12
Yield: 24 %

Procedure:
2.0 g of (1S,4aS,6S,7R,7aR)-6,7-epoxy-7 -(hydroxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydrocyclopenta [c] pyrane-4-carboxylic acid methylester described in Example 19 were dissolved in dichloromethane followed by addition of 2.5 ml of triethylamine and 1.4 ml of methanesulfonylchloride while stirring and cooling with ice. After stirring for 12 hours at the same temperature, the reaction mixture was extracted with ethyl-acetate. After washing the organic phase with saturated aqueous sodium bicarbonate and brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a pale yellow oil from the hexane-ether eluate in the form of (1S,4aS,7aR)-7-(chloromethyl)-1-(methylcarbamoyloxy )-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (770 mg, yield: 24%). The physicochemical properties of this compound are described below.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:51]=[CH:50][C:29]2[N:30]3[C:34]([CH2:35][NH:36][CH2:37][C:28]=2[CH:27]=1)=[N:33][N:32]=[C:31]3[CH:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[CH2:40][CH2:39]1.C(N(CC)CC)C.[CH3:59][N:60]([CH2:62][C:63](O)=[O:64])[CH3:61]>CN(C)C(=O)C>[Cl:25][C:26]1[CH:51]=[CH:50][C:29]2[N:30]3[C:34]([CH2:35][N:36]([C:63](=[O:64])[CH2:62][N:60]([CH3:61])[CH3:59])[CH2:37][C:28]=2[CH:27]=1)=[N:33][N:32]=[C:31]3[CH:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[CH2:42][CH2:43]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 50 °C
Yield: 57.8 %

Procedure:
A solution of HBTU (152 mg, 0.38 mmol) in N,N-dimethylacetamide (1.9 ml) was added to a solution of the amine of example 4 (97 mg, 0.26 mmol), triethylamine (1.5 μl, cat.) and dimethylamino-acetic acid (36 mg, 0.26 mmol) in N,N-dimethylacetamide (2.5 ml) and heated to 50° C. for 2 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was partitioned between dichloromethane (10 ml) and 2M aqueous sodium hydroxide solution (10 ml). The organic phase was dried over magnesium sulphate before being evaporated under reduced pressure and purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (7:1:93) as eluant to afford the title compound (70 mg) as a brown foam.
Reaction SMILES: Cl.O.O.Cl[Sn]Cl.[Cl:7][C:8]1[C:33]([N+:34]([O-])=O)=[CH:32][C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C@@H:15]3[C@H:20]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18][CH2:17][N:16]3[C:10]=2[CH:9]=1>C(O)C>[NH2:34][C:33]1[C:8]([Cl:7])=[CH:9][C:10]2[N:16]3[CH2:17][CH2:18][CH2:19][C@@H:20]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[C@H:15]3[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=3[O:12][C:11]=2[CH:32]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)c([N+](=O)[O-])cc3Oc3ccccc3[C@H]12)C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc2c(cc1Cl)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Temperature: 60 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
80 μL 36% HCl and SnCl2.2H2O (600 mg, 2.66 mmol) were added trans-N-(7-chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (215 mg, 0.49 mmol) in 10 mL of ethanol. The resulting mixture was stirred at 60° C. for 18 h. After cooling the mixture was evaporated and dissolved in ethyl acetate. Aq. sodium bicarbonate was added to the solution (Sn salts were formed) followed by decalite and the mixture was filtered. The filtrate was extracted with ethyl acetate and the organic layer was washed with brine, dried (Na2SO4) and evaporated to give the title compound (194 mg, 82%). Data: (m/z)=413 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([NH2:5])=[O:4].N[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC1C=CC(Cl)=CC=1Cl.CNC>>[C:8]1([NH:5][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1
Reactant: CN(C)C(N)=O
Agent: CNC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CN(C)C(=O)Nc1ccccc1
Temperature: 205 °C
Reaction time: 5.5 h

Procedure:
3.35 g (0.038 mol) of N,N-dimethylurea and 2.33 g (0.025 mol) of aniline were added with stirring into 28 ml of 1,2,4-trichlorobenzene. The reaction mixture was slowly heated to 205° C., dimethylamine being passed in from 60° C. After 5.5 hours, 11.8 g (0.27 mol) of dimethylamine had been passed in and the reaction was complete. The reaction mixture was cooled to room temperature, whereupon a precipitate deposited. The precipitate was filtered off, washed with 1,2,4-trichlorobenzene, dried and then boiled in water. The aqueous mixture was cooled, and the precipitate was filtered off with suction and dried. 3.3 g of N-phenyl-N',N'-dimethylurea, i.e. 81% of theory, having a melting point of 130° to 133° C. were obtained in this way.
Reaction SMILES: [Br:1][C:2]1[S:18][C:5]2[N:6]([CH2:16][CH3:17])[CH:7]=[C:8]([C:11]([O:13]CC)=O)[C:9](=[O:10])[C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:18][C:5]2[N:6]([CH2:16][CH3:17])[CH:7]=[C:8]([C:11]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:13])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cn(CC)c2sc(Br)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)sc21
Temperature: 190 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of ethyl 2-bromo-7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (Eur. J. Med. Chem. 1987, 22, 139) (0.500 g) and 4-chlorobenzylamine (1.84 mL) is stirred at 190° C. for 1 h. The reaction is then allowed to cool to rt and is diluted with toluene. The resulting precipitate is filtered off and washed with toluene followed by hexanes to yield a tan solid. This material is recrystallized from acetic acid/water then ethanol to yield 0.379 g (59%) of the title compound as a white, crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:22].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>ClCCl>[Cl:30][CH2:31][C:32]([NH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:11][CH2:12]2)=[CH:4][C:3]=1[F:22])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)c(F)c2)CC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)CCl)c(F)c2)CC1
Yield: 64 %

Procedure:
tert-Butyl 4-(4-amino-3-fluoro phenoxy)piperidine-1-carboxylate (7.54 g, 0.024 moles) was dissolved in dichloromethane (100 mL) and added triethylamine (3.6 g, 0.036 moles) at room temperature. To the resulting mass, a solution of chloro acetyl chloride (2.9 g, 0.026 moles) in dichloromethane (15 mL) was added drop wise at room temperature. After completion of the reaction, the organic mass was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate:hexane, 1:5) to afford the title compound 5.94 g (Yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.Cl.[NH2:21][OH:22].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([C:8](=[N:21][OH:22])[NH2:9])[CH:7]=1
Reactant: NO
Reactant: COC(=O)[C@@H]1CCC[C@@H]1Nc1ncc(C#N)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)[C@@H]1CCC[C@@H]1Nc1ncc(C(N)=NO)cc1Cl
Yield: 100 %

Procedure:
A solution of cis-methyl 2-(3-chloro-5-cyanopyridin-2-ylamino)cyclopentanecarboxylate (0.154 g; 0.55 mmol), hydroxylamine hydrochloride (0.057 g; 0.82 mmol) and DIEA (0.143 mL; 0.82 mmol) in EtOH (2 mL) was stirred at ambient temperature for 42 hours. The solvent was evaporated in vacuo and the residue dissolved in DCM/water. The mixture was passed through a hydrophobic frit and the solvent evaporated in vacuo to afford the title product (0.172 g; quantitative). 1H NMR (CDCl3, 400 MHz) δ 8.25 (1H, d, J=2 Hz), 7.74 (1H, d, J=2 Hz), 5.74 (1H, d, J=8.4 Hz), 4.77-4.70 (3H, m), 3.61 (3H, s), 3.19-3.14 (1H, m), 2.14-1.70 (6H, m).
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:13].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:3]1[S:4][C:5]2[C:10]([C:11](=[O:12])[C:2]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: OB(O)c1ccccc1
Reactant: Cc1sc2ccccc2c(=O)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc2ccccc2c(=O)c1-c1ccccc1
Yield: 93 %

Procedure:
The compound (1.0 mmol, 302 mg) obtained in (1) above, dichlorobis(triphenylphosphine)palladium (0.03 mmol, 21 mg), phenylboronic acid (1.3 mmol, 159 mg) and potassium carbonate (4.0 mmol, 552 mg) were dissolved in degassed dimethylformamide (3.2 mL) and water (0.8 mL), and the solution was stirred under a nitrogen atmosphere at 80° C. for 4 hours. After the disappearance of the starting materials was confirmed by thin-layer chromatography, water was poured into the reaction solution to terminate the reaction. The organic substances were extracted with ethyl acetate, the obtained organic layer was dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the title compound (0.93 mmol, 237 mg) was obtained in a 93% yield.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[CH:11]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Isopropoxyaniline (24.2 g) was dissolved in acetic acid (300 mL), and a mixture of bromine (8.25 mL) and acetic acid (80 mL) was added dropwise. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. Water was added to residue, and the mixture was extracted with diethylether. The extract was washed successively with aqueous sodium thiosulfate solution and brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-bromo-4-isopropoxyaniline (10.2 g) as a black brown oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC(C)=O.C(=O)=O.[NH3:19]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH2:19])[CH:7]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C=O
Solvent: CC(C)=O
Product: Nc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
2,4-Difluoronitrobenzene (1.0 eq) was placed in a dry round-bottomed flask equipped with a dry ice condenser charged with acetone/dry ice. Ammonia was condensed into the flask and the resulting solution was stirred at reflux for 7 hours. A yellow precipitate was formed within 1 hours. After 7 hours, the condenser was removed and the liquid ammonia was allowed to evaporate over several hours. The crude product was purified by flash chromatography on silica gel (85:15 hexanes:EtOAc, product at Rf=0.32, contaminant at Rf=0.51). GC/MS m/z 156.1 (M+), Rf 11.16 minutes.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:10])=[CH:28][CH:27]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)NCCCCc1cccnc1
Yield: 93.8 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (15 g) and 3-pyridinebutanamine (5,53 g) in tetrahydrofuran (60 mL) was stirred for 1.5 hours at room temperature and was worked up in the usual manner. The crude amide was crystallized from ethyl acetate-hexane (2×) to give 14.45 g of (E)-5,5-bis(4-fluorophenyl)-N-[4-(3-pyridinyl) butyl]-2,4-pentadienamide mp 155°-156° C. Anal. Calculated for C26H24F2N2O: C, 74.62; H, 5.78; F, 9.08; N, 6.69 Found: C, 74.55; H, 5.87; F, 9.33; N, 6.60.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.CC[O:18]CC.CCOC(C)=O>CC(O)=O.[Pd]>[C:1]1([C:7]2[CH:12]=[N+:11]([O-:18])[C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2ccccc2)cn1
Reactant: CCOCC
Agent: [Pd]
Agent: OO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2)c[n+]1[O-]
Temperature: 70 °C

Procedure:
To a solution of 100 g 5-phenyl-2-picoline in 170 mL of glacial HOAc was added 30% H2O2 and the resulting solution was heated at 70° C. overnight. After the reaction mixture was cooled to room temperature, 1 g of 10% Pd/C was added to destroy excess of H2O2. The reaction mixture was then filtered on celite, washed with toluene and the filtrate was evaporated to dryness affording a yellow solid residue. The crude material was swished with a mixture of Et2O/EtOAc (10:1) and filtered to afford the pure title product as a white solid, m.p.: 91° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].Cl[C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1.O>O1CCCC1>[CH2:1]([O:4][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[C:2]#[CH:3]
Reactant: C#CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of propargyl alcohol (420 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 530 mg (98%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Chloro-3-iodobenzene (10.0 g, 41.9 mmol) was dissolved in 100 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). The desired product was obtained as a light yellow oil (7.38 g, purity ˜70%, yield ˜59%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].C(N(CC)CC)C.[CH:13]([NH2:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:13]([NH:26][C:3](=[O:4])[CH2:2][Br:1])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Product: O=C(CBr)NC(c1ccccc1)c1ccccc1
Yield: 19.4 %

Procedure:
A solution of 2.91 g (14.39 mmol) of bromoacetyl bromide in 40 ml was cooled to 0° C. and 2.1 ml (14.39 mmol) of triethylamine and 2.64 g (14.39 mmol) of benzhydrylamine were successively added. The reaction solution was then evaporated to dryness under reduced pressure, and the resulting residue was purified on silica gel with EA as mobile phase. The product crystallized from the product fractions was filtered off with suction, washed with a little cold diethyl ether and dried under reduced pressure, resulting in 0.85 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl>>[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: ClCCOCCCl
Product: N#Cc1ccnc(-c2cn(CCOCCCl)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and bis(2-chloroethyl)ether according to the procedure for the preparation of Example 43, part A. [M+H] Calc'd for C13H13ClN4O, 278. Found, 277, 279.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:78][N:79]([CH3:84])[CH2:80][CH2:81][CH2:82][NH2:83]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:83][CH2:82][CH2:81][CH2:80][N:79]([CH3:84])[CH3:78])=[O:28])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: CN(C)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 652.4 %

Procedure:
To a mixture of 0.125 g (0.257 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 9 mL of dimethylformamide was added 0.0521 g (0.386 mmole) of 1-hydroxybenzotriazole, 0.146 g (0.385 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.140 g (1.081 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0393 g (0.385 mmole) of 3-(dimethylamino)-propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.955 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-trifluoromethyl-benzamide (I-209) as a white solid.