Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCc2ccccc2)cc1

Procedure:
A stirred mixture of 18.5 g. of phenethylbromide, 20.4 g. of p-hydroxyacetophenone, 17.3 g. of anhydrous potassium carbonate and 150 ml. of acetone was refluxed under argon for 22 hours. The reaction was then cooled and partitioned between ether and water. The ether layer was washed with water and then extracted with two 100 ml. portions of cold 1N sodium hydroxide. These extracts were combined, washed with water and brine, dried and evaporated to an oil. The oil was purified by chromatography, giving the desired intermediate as a light yellow oil.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][C:30]1[C:31]([NH2:37])=[N:32][CH:33]=[C:34]([CH3:36])[N:35]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:36][C:34]1[N:35]=[C:30]([CH3:29])[C:31]2[N:32]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:37]=2)[CH:33]=1
Reactant: Cc1cnc(N)c(C)n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)n1
Temperature: 130 °C

Procedure:
To a mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (770 mg, 1.61 mmol, 1.0 eq), 3,5-dimethylpyrazin-2-amine (CAS-Nr. 91678-81-8, 218 mg, 1.77 mmol, 1.1 eq) and diisopropylethylamine (0.28 mL, 1.61 mmol, 1.0 eq) in 10 mL isopropanol was added 3 Å molsieves. The reaction mixture was heated to reflux temperature for 2 h. No conversion was observed under these conditions (UPLC-MS). Therefore, the reaction mixture was heated to 130° C. for 1 h under microwave conditions (single mode microwave oven). The reaction mixture was filtered to remove the molsieve and the filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera, 25 g Snap cartridge, DCM→DCM/ethanol 95/5) to deliver 249 mg (31%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[N:30]([C@@:36]1([CH3:44])[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]1=[O:43])[C:29]2=[O:45].CC#N>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:24][CH2:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[N:30]([C@@:36]2([CH3:44])[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]2=[O:43])[C:29]3=[O:45])=[O:10])=[N:6][CH:7]=1
Reactant: C[C@]1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: O=C(O)c1ccc(Br)cn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@]1(N2C(=O)c3ccc(CNC(=O)c4ccc(Br)cn4)cc3C2=O)CCC(=O)NC1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of 5-bromopicolinic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 mL) was stirred under nitrogen at 40° C. for 2 hours. Then, 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) was added, and the mixture was stirred at this temperature for an additional 2 hours. The mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL). The organic phase was evaporated. The residue was chromatographed on silica gel using methylene chloride as the mobile phase. A pale red solid was obtained; this material was triturated in 10 mL of acetonitrile for 16 hours. The solid was filtered and washed with an additional 7 mL of acetonitrile. The product was dried under vacuum, providing 0.55 g (57% yield) as a white solid; mp 260-262° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 45/55 CH3CN/0.1% H3PO4, 3.61 (96.62%); 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 2.00-2.08 (m, 1H), 2.49-2.62 (m, 2H), 2.65-2.73 (m, 1H), 4.62 (d, J=6.3 Hz, 2H), 7.76-7.82 (m, 3H), 7.97 (dd, J=8.4 Hz, J=0.6 Hz, 1H), 8.26 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 8.81 (dd, J=2.3 Hz, J=0.6 Hz, 1H), 9.63 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ 21.0, 28.5, 29.1, 42.4, 58.7, 121.8, 123.1, 123.5, 123.9, 129.6, 131.3, 133.6, 140.5, 147.1, 148.5, 149.3, 163.5, 167.7, 167.8, 172.0, 172.1; Anal. Calcd for C21H17BrN4O5: C, 51.97; H, 3.53; N, 11.55. Found: C, 52.05; H, 3.44; N, 11.39.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=NC=N[CH:12]=1)(=[O:4])=[O:3].[CH:13]1([C:17]2[CH:22]=CC(CO)=C[CH:18]=2)[CH2:16][CH2:15][CH2:14]1>>[CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[CH:22][C:17]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:18][CH:12]=1)(=[O:4])=[O:3]
Reactant: OCc1ccc(C2CCC2)cc1
Reactant: CS(=O)(=O)OCc1cncnc1
Product: CS(=O)(=O)OCc1ccc(C2CCC2)cc1

Procedure:
4-Cyclobutylbenzyl methanesulfonate was prepared in a similar manner as used to prepare pyrimidin-5-ylmethyl methanesulfonate using (4-cyclobutylphenyl)methanol instead of pyrimidin-5-ylmethanol. The product was used directly in the next reaction without characterization.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN1CCCC1=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3
Reactant: C1CCNC1
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Solvent: CN1CCCC1=O
Product: CC1Cc2c(N3CCCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 33.8 %

Procedure:
7-Amino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.5 g) and pyrrolidine (0.7 g) are suspended in N-methylpyrrolidone (10 ml), and the mixture is heated at 110°-120° C. for 5 hours in a sealed tube. The reaction mixture is concentrated to dryness under reduced pressure, and to the residue is added ethyl acetate. The resulting crystals are separated by filtration and recrystallized from N,N-dimethylformamide to give 7-amino-8-fluoro-2-methyl-6-oxo-9-(1-pyrrolidinyl)-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.2 g) as yellow cubic crystals. m.p. 296°-299° C. (decomp.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][NH:10][S:26]([C:23]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of N-(2-Aminoethyl)carbamic acid tert-butyl ester (1.86 g, 11.5 mmol) and triethyl amine (3 mL) in CH2Cl2 (100 mL) at 0° C., was added (4-bromophenyl)chlorosulfone (2.93 g, 11.5 mmol). The mixture was stirred for 3 hours, before the solvent was removed. The residue was dissolved in EtOAc (150 mL), washed with sat. NaHCO3 (50 mL), sat. NaCl (50 mL), 1N HCl (50 mL), sat. NaCl (2×50 mL), dried over MgSO4, and evaporated to give 3.8 g of the title compound as a white solid in 100% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[C:10]=1[CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25](OCCC(C)C)=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[C:16]([N:15]1[C:11]2[C:10](=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=[CH:13][CH:12]=2)[C:19]([CH2:20][O:21][C:22](=[O:24])[CH3:23])=[N:25]1)(=[O:18])[CH3:17]
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1cccc(OCc2ccccc2)c1CCOC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1nn(C(C)=O)c2cccc(OCc3ccccc3)c12

Procedure:
This is obtained by nitrosation and subsequent ring closure by treating 2-(2-acetoxyethyl)-3-acetamidophenyl benzyl ether with isoamyl nitrite, sodium acetate and acetic anhydride in toluene at 80° C. It is obtained in the form of colorless crystals; m.p. 99°-100° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Product: COc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-methoxyphenyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 196°-199° C.) and piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(OCc2ccccc2)cc(C)c1C=O

Procedure:
In analogy to the procedure described in example 23 a], 4-hydroxy-2,6-dimethyl-benzaldehyde was reacted with benzyl bromide in the presence of potassium carbonate to yield 4-benzyloxy-2,6-dimethyl-benzaldehyde as orange liquid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[C:10]#[N:11].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1>CN(C=O)C>[I:16][C:13]1[CH:14]=[CH:15][C:8]([O:7][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: N#Cc1cc(I)ccc1O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(I)ccc1Oc1ccc(C(F)(F)F)cn1
Yield: 93.8 %

Procedure:
K2CO3 (91.0 g, 0.656 mol) was added to a solution of 2-hydroxy-5-iodo-benzonitrile (80.0 g, 0.328 mol) and 2-chloro-5-tri-fluoromethyl-pyridine (60.0 g, 0.328 mol) in DMF (500 ml) was added. The reaction mixture was refluxed overnight, filtered and concentrated. Purification via FC (PE/EtOAc=10/1) afforded the title product as a white solid (120 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([N:23]1[C:27]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:26][C:25]([CH:32]=O)=[N:24]1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([N:23]1[C:27]([CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:26][C:25]([CH2:32][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[N:24]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1C(C)(C)C
Yield: 74.5 %

Procedure:
Compound 52 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8][CH2:9][CH3:10])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[C:16]([F:21])[C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>>[F:11][C:12]1[CH:19]=[C:18]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH2:8][CH2:9][CH3:10])[C@@H:2]2[CH3:1])[CH:17]=[C:16]([F:21])[C:13]=1[C:14]#[N:15]
Reactant: CCC[C@]1(O)CCN[C@H]1C
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCC[C@]1(O)CCN(c2cc(F)c(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-propylpyrrolidin-3-ol 0.5 oxalate (250 mg), 2,4,6-trifluorobenzonitrile (414 mg) and lithium carbonate (195 mg), the title compound was obtained as colorless oil (yield: 233 mg, yield: 63%).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49]>>[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH:49][CH:18]1[CH2:19][CH2:20][N:15]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:26][CH:27]=3)[N:12]=2)[CH2:16][CH2:17]1
Reactant: CN(C)CCN
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
The titled compound was prepared by the procedure as outlined in example 118, by reacting 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) with N,N-dimethylethylenediamine (0.026 mL) and purified by HPLC and isolated as its tri-TFA salt; MS (ES+) 573.7 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2].S(Cl)(Cl)=O.Cl[CH2:18]Cl>>[CH3:18][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([CH3:12])[CH:5]=1
Reactant: ClCCl
Reactant: Cc1cc(C(=O)O)ccc1C#N
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C#N)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 4-cyano-3-methyl-benzoic acid from Example E2d (1.5 g, 9.3 mmol) and thionyl chloride (5 ml, 68.5 mmol) in dichloromethane (20 ml) was heated at re-flux for 2 h then solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (25 ml). Methanol (10 ml) was added and the solution was stirred at room temperature for 2 h then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield the title compound (1.6 g, 100%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[C:15]1([CH:21]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH:21](=[N:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CN
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-aminoacetate hydrochloride (15.00 g, 116.00 mmol, 1.0 eq) in CH2Cl2 (150 mL) was added Et3N (20 mL, 143.3 mmol, 1.2 eq) and PhCHO (14.6 mL, 143.3 mmol, 1.2 eq) in turn. The reaction mixture was stirred at room temperature overnight, and concentrated in vacuo. The residue was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo to afford the crude product methyl 2-(benzylideneamino)acetate, which was used for the next step without further purification. To a solution of methyl 2-(benzylideneamino)acetate in MeOH (200 mL) at −5° C. was added NaBH4 (2.80 g, 72.8 mmol, 0.55 eq) slowly. The reaction mixture was stirred at −5° C. for 2 h. The reaction mixture was then quenched with water and extracted with EtOAc (100 mL×3). The combined organic phases were washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) PE/EtOAc) to afford the title compound as colorless oil (21.30 g, 99%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2>C1COCC1.C(Cl)Cl>[N:1]1([CH:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCc1ccccc1C2N1CCNCC1
Reaction time: 8 h
Yield: 2915.9 %

Procedure:
Into a solution of partially dissolved piperazine (15.2 g, 0.17 mmol) in THF (130 mL) at more temperature was added dropwise a solution of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.3g, 10.3 mmol) in 20 mL THF. The reaction was allowed to stir overnight and then was diluted with CH2Cl2, washed once with 1.0N NaOH solution, once with brine and then dried (Mg SO4). It was then filtered and the solvent removed to give a residue which was flash chromatographed (5% MeOH saturated with NH3 in CH2Cl2) to give 1.38 g of a glassy solid of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([N:13]([CH2:18][CH2:19][C:20]([OH:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:22]([CH3:24])=[CH2:23])[C:14](=[O:17])OC)([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([N:13]2[CH2:18][CH2:19][C:20]([CH2:21][C:22]([CH3:24])=[CH2:23])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:31][C:14]2=[O:17])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: C=C(C)CC(O)(CCN(C(=O)OC)C(C)(C)C#Cc1ccc(F)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)C#Cc2ccc(F)cc2)C(=O)O1
Yield: 150.7 %

Procedure:
To a stirred solution of methyl 4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamate (35 mg, 0.03 mmol) in dry THF (2 mL) was added 60% NaH in oil (5 mg, 0.12 mmol). The mixture was heated at 60 C for 3 h, cooled, diluted with EtOAc (90 mL), washed with water (10 mL) and brine (10 mL), and dried over Na2SO4. Removal of the solvent left an oil (18 mg) which was purified by prep HPLC to afford 3-(4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (17.7 mg, 55%) as an oil. LC-MS Method 1 tR=2.22 min, m/z=392; 1H NMR (CDCl3) δ 1.63 (s, 3H), 1.66 (s, 3H), 1.81 (s, 3H), 2.24 (m, 1H), 2.37 (m, 1H), 2.58 (m, 2H), 3.06 (m, 1H), 3.64 (m, 1H), 4.64 (s, 1H), 4.83 (s, 1H), 6.98 (m, 2H), 7.25-7.40 (7H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]([CH3:27])([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:12][CH:11]=1)[CH:7]=[CH2:8])C.[OH-].[Na+].CO>O>[CH3:27][C:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:12][CH:11]=1)([CH:7]=[CH2:8])[CH2:5][C:4]([OH:28])=[O:3]
Reactant: C=CC(C)(CC(=O)OCC)Cc1ccc(OCCCNc2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CC(C)(CC(=O)O)Cc1ccc(OCCCNc2ccccn2)cc1
Yield: 62.3 %

Procedure:
A solution of the product of STEP 7 (0.26 g), 1 N sodium hydroxide in water (2 ml), and methanol (4 ml) was stirred overnight. Solvent was removed. The crude product was purified on a reverse phase HPLC using acetonitrile/water (0.5% TFA) gradient to give colorless oil (0.150 g). Anal. MS (APCI): m/z=355 (MH+), 1H NMR (500 MHz, CD3OD): δ1.09 (3H, s), 2.16 (2H, m), 2.25 (2H, q), 2.70 (2H, s), 3.59 (2H, t), 4.08 (2H, t), 4.85 (1H, d), 4.98 (1H, d), 5.92 (1H, dd), 6.81 (2H, d), 6.84 (1H, t), 7.07 (3H, m), 7.79 (1H, d), 7.86 (1H. t). Calcd. for C21H26N2O3+1.1 TFA: C, 58.07; H, 5.69; N, 5.84, Found: C, 57.87; H, 5.77; N, 5.70.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[O:24]=[C:25]1[CH2:29][S:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]([NH:38][S:39]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH2:32][CH2:31]2)=[N:26]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:29]4[S:28][C:27]([N:30]5[CH2:31][CH2:32][CH:33]([C:36]([NH:38][S:39]([N:42]6[CH2:46][CH2:45][CH2:44][CH2:43]6)(=[O:41])=[O:40])=[O:37])[CH2:34][CH2:35]5)=[N:26][C:25]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: O=C1CSC(N2CCC(C(=O)NS(=O)(=O)N3CCCC3)CC2)=N1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: O=C1N=C(N2CCC(C(=O)NS(=O)(=O)N3CCCC3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
Pyrrolidine-1-sulfonic acid (1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carbonyl)-amide was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and Pyrrolidine-1-sulfonic acid [1-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carbonyl]-amide following General Procedure E.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][CH2:26][CH2:25][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:14]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCCN1CCOCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.35 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.50 mmol of. 2-morpholin-4-yl-ethylamine LC/MS [1.74 min; 471 (M+1)].
Reaction SMILES: [C:1]([O:4]C(C)(C)C)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>O1CCCC1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH2:2][C:1]([OH:4])=[O:3])=[CH:20][CH:19]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(Br)cc1
Reaction time: 4 h

Procedure:
t-Butyl acetate (159 mL, 1180 mmol) was added to lithium diisopropylamide (941 mmol) in tetrahydrofuran at -78° C. followed by 4-bromobenzylbromide (200 g, 784 mmol). The bath temperature was kept at -15° C. for 4 hours whereupon the reaction was quenched with ammonium chloride. The mixture was extracted with diethyl ether and the organic layer was washed with dilute hydrochloric acid, water, and brine, drying with sodium sulfate to yield a pale oil. This was refluxed with trifluoroacetic acid (150 mL, 1960 mmol) for 1 hour. The trifluoroacetic acid was removed under vacuum and the residue was partitioned between diethyl ether and aqueous sodium hydroxide. The aqueous layer was acidified with concentrated hydrochloric acid at 0° C. and extracted with diethyl ether. This organic layer was washed with water and brine and was dried over sodium sulfate to obtain a white solid after removing solvent under vacuum, (167 g, 93%), 132-134° C. m.p.