Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([OH:46])[CH2:43][CH2:42][NH:41][CH2:40][C:39]2([CH3:45])[CH3:44])=[CH:34][C:33]=1[O:47][CH3:48].CCN(C(C)C)C(C)C>ClCCl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([OH:46])[CH2:43][CH2:42][N:41]([C:13](=[O:15])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:10]([CH3:11])[CH3:12])[CH2:40][C:39]2([CH3:44])[CH3:45])=[CH:34][C:33]=1[O:47][CH3:48]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(C2(O)CCNCC2(C)C)ccc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C2(O)CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)CC2(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
N-Boc-D-valine (85 mg, 0.39 mmol), EDC (75 mg, 0.39 mmol), HOBt (53 mg, 0.39 mmol) was dissolved in dichloromethane (2 mL). 4-(4-Chloro-3-methoxyphenyl)-3,3-dimethylpiperidin-4-ol hydrochloride (100 mg, 0.33 mmol) was added followed by DIPEA (136 μL, 0.78 mmol) and the solution was stirred at rt for 10 min. The reaction was concentrated and the resulting oily residue was purified via column chromatography (10% to 50% EtOAc/heptane) to furnish tert-butyl (2R)-1-(4-(4-chloro-3-methoxyphenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (153 mg, 99% yield) MS found: (M-Boc)+=396.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:16])=[C:4]([Cl:15])[C:5]([Cl:14])=[C:6]([C:11]([OH:13])=[O:12])[C:7]=1[C:8]([OH:10])=[O:9].[Ag:17]>>[Ag:17].[Cl:1][C:2]1[C:3]([Cl:16])=[C:4]([Cl:15])[C:5]([Cl:14])=[C:6]([C:11]([O-:13])=[O:12])[C:7]=1[C:8]([O-:10])=[O:9].[Ag+2:17]
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Agent: [Ag]
Product: O=C([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)[O-]
Product: [Ag+2]

Procedure:
A photothermographic silver soap dispersion was prepared as described in U.S. Pat. No. 5,434,043. A second ligand, tetrachlorophthalic acid, capable of coordination with silver was then added and allowed to exchange with the dispersed silver salt to form a shell of silver tetrachlorophthalate on the original core. Photothermographic films were then constructed also as described in U.S. Pat. No. 5,434,043.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH:15]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16]1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[CH:15]1([C:19]([N:6]2[CH:7]([C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][CH:23]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:20])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)C1CCC1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=C(C1CCC1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
Cyclobutyl-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, cyclobutanecarboxylic acid chloride, and indole according to GP 2. Yield, 11%. 1H-NMR (DMSO-d6): δ=1.48-1.62 (m, 1H), 1.65-2.02 (m, 3H), 2.15-2.41 (m, 2H), 3.49-3.66 (m, 1H), 6.07 (s, br., 1H), 6.92-7.07 (m, 3H), 7.16 (t, J≈7.5 Hz, 1H), 7.19-7.30 (m, 3H), 7.35-7.42 (m, 1H), 7.43-7.52 (m, 2H), 7.68 (d, J=6.7 Hz, 1H), 7.92 (d, J=7.4 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H), 10.62 (s, 1H); (+)-ESI-MS: m/z=379 [M+H]+, 262 [M-indole+H]+, 180.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH:28]([C:30]1[S:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:23]1[CH:22]=[C:21]([C@@H:19]([OH:20])[CH2:18][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[S:34][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C=O)s2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 35 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (500 mg) in 1,2-dimethoxyethane (6 ml) was added 5-formyl-2-thiopheneboronic acid (206 mg), tetrakis(triphenylphosphine)palladium (63 mg) and aqueous solution of sodium carbonate (2M, 1.0 ml), and the mixture was stirred at 80° C. for 7 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-(5-formyl-2-thienyl)phenyl]ethyl]carbamate (187 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:20][CH2:19]4)[CH2:13][CH2:12]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:18]1([CH2:17][N:14]2[CH2:13][CH2:12][CH:11]([C:9]3[N:10]=[C:6]4[N:7]([C:2]([NH:31][CH2:32][CH2:33][NH:34][C:35]5[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=5)=[N:3][C:4]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])=[CH:5]4)[N:8]=3)[CH2:16][CH2:15]2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Clc1ccc(-c2cc3nc(C4CCN(CC5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(CC5CC5)CC4)nn23)nc1
Temperature: 130 °C

Procedure:
50 mg (0.10 mmol) of 5-chloro-2-[1-(cyclopropylmethyl)piperidin-4-yl]-7-(2,4-dichlorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 47A), 25 mg (0.12 mmol) of 6-[(2-aminoethyl)amino]-pyridin-3-carbonitrile hydrochloride (Example 2A) and 0.110 ml (0.6 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 22 mg (38% of theory) of the product as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:32][CH2:31]1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: OC1CCNCC1
Reactant: BrCCCCCCCCBr
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCCCCN3CCC(O)CC3)cc12

Procedure:
The compound was prepared by a method similar to Example 2 from 6-hydroxyflavone, 1,8-dibromooctane and 4-hydroxypiperidine: mp 57°-58° C.
Reaction SMILES: [CH3:1][O:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:6]=1[S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+]>CCOCC.O.O1CCCC1>[CH3:1][O:2][NH:3][S:13]([C:6]1[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:5]=1[Cl:4])(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CON
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CONS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g. of methoxy amine was dissolved in 100 ml. of H2O. Then, 14.0 g. of 2,4,5-trichlorobenzene sulfonyl chloride dissolved in 25 ml. of tetrahydrofuran was added under high speed mechanical stirring. Then, 8.8 g. of sodium hydroxide in a 50% solution + 10 ml. of water was dropped in at room temperature. An exothermic reaction took place and the temperature went up to 37.5° C. When the reaction subsided, it was stirred at room temperature for 2 hours and the solid was then filtered off and stirred into 150 ml. of ether for 1 hour. The solid was removed by filtration to yield 11.3 g. of product. The product was redissolved in ether. The ether was evaporated to yield 7.4 g. of product, m.p. 163°-166° C.
Reaction SMILES: [N+](C1N=C2N(C=1)CC(OCC1C=CC(OCC(N3CCC(=O)CC3)=O)=CC=1)CO2)([O-])=O.C([O:36][C:37](=[O:60])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][O:47][CH:48]2[CH2:53][O:52][C:51]3=[N:54][C:55]([N+:57]([O-:59])=[O:58])=[CH:56][N:50]3[CH2:49]2)=[CH:42][CH:41]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[N+:57]([C:55]1[N:54]=[C:51]2[N:50]([CH:56]=1)[CH2:49][CH:48]([O:47][CH2:46][C:43]1[CH:42]=[CH:41][C:40]([O:39][CH2:38][C:37]([OH:60])=[O:36])=[CH:45][CH:44]=1)[CH2:53][O:52]2)([O-:59])=[O:58]
Reactant: CC(C)(C)OC(=O)COc1ccc(COC2COc3nc([N+](=O)[O-])cn3C2)cc1
Agent: O=C1CCN(C(=O)COc2ccc(COC3COc4nc([N+](=O)[O-])cn4C3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(COC2COc3nc([N+](=O)[O-])cn3C2)cc1

Procedure:
1-{2-[4-(2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-phenoxy]-acetyl}-piperidin-4-one. A solution of [4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxylmethyl)-phenoxy]-acetic acid tert-butyl ester (130 mg, 0.32 mmol) in TFA (1.0 mL) and dichloromethane (2.0 mL) was stirred at room temperature for 1.5 h. Solvent was evaporated to give [4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-phenoxy]-acetic acid. To a solution of the above acid in dichloromethane (6.0 mL) under N2 was added diisopropylethylamine (0.20 mL), 4-piperidone hydrochloride monohydrate (98 mg, 0.64 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol), 1-hydrobenzotriazole (52 mg, 0.38 mmol). The mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane, washed with saturated NaHCO3 and 1 N HCl solution, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative TLC plates (5% MeOH in dichloromethane) to give the title product as oil (28.0 mg, 20%). ESI MS m/z 431 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 4.77 (s, 2H), 4.67-4.53 (m, 3H), 4.32 (d, J=12.0 Hz, 1H), 4.15-4.07 (m, 3H), 3.91-3.85 (m, 4H), 2.50-2.45 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18](=[CH2:23])[C:19]([O:21][CH3:22])=[O:20])=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18](=[CH2:23])[C:19]([O:21][CH3:22])=[O:20])=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: C=C(NC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)no1)C(=O)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C=C(NC(=O)c1cc(-c2ccc(N)cc2)no1)C(=O)OC
Temperature: 80 °C
Yield: 18.4 %

Procedure:
Methyl 2-(3-(4-nitrophenyl)isoxazole-5-carboxamido)acrylate (1.2 g, 3.78) was dissolved in EtOH (20 ml), THF (8 ml) and water (8 ml). Then ammonium chloride (601 mg, 11.34 mmol)) and iron (529 mg, 9.45) were added and refluxed at 80° C. for 1.5 hours. Reaction mixture was cooled and filtered through celite and solvent was removed under reduced pressure to get dark brown residue. Residue was taken in water and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and concentrated to get dark brown residue, which was purified by column chromatography using EtOAc and petroleum ether to yield 200 mg (18%) of the title compound. MS: ES (+): m/z 288 (M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 10.115 (s, 1H), 7.577 (d, 2H), 7.558 (s, 1H), 6.640 (d, 2H), 6.011 (s, 1H), 5.873 (s, 1H), 5.642 (s, 2H), 3.753 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1ccccn1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccn4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl)-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-chloromethylpyridine hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 81 mg (yield 82%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:34]=[CH:33][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:30]([NH2:32])=[O:31])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1>CN(C=O)C.CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:34]=[CH:33][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:30]([NH2:32])=[O:31])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: C=Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Yield: 46.9 %

Procedure:
A solution of 8-{[(2-chloropyridin-3-yl)carbonyl]amino}-1-(4-ethynylphenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (557 mg, 1.19 mmol) in DMF-DMSO (20 mL-1 mL) was treated at RT with H2 (5 psi) and Pd-CaSO4 (5%, 100 mg) for 12 min. The mixture was filtered through celite pad, concentrated and added water. The solid product was collected via filtration, washed with water and ether, and dried to give product (262 mg, 47%). 1H NMR was consistent with its structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].O.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9](=[O:10])[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:3][C:2]=1[C:26]#[N:27]
Reactant: CN(C)C=O
Reactant: O=C(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(Br)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 175 °C
Yield: 86 %

Procedure:
A mixture of (3-bromo-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone, prepared as described in Procedure 3 and 62, (2.0 g, 4.84 mmol), zinc cyanide (568 mg, 4.84 mmol) and tetrakis(triphenyphoshine)palladium (559 mg, 0.48 mmol) in DMF was heated at 175° C. under microwave irradiation for 10 minutes. The reaction mixture was allowed to cool to room temperature, poured into H2O and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by ISCO chromatography (12 g column, 0-20% EtOAc/hexane) to yield 2-fluoro-5-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzoyl)benzonitrile as a colorless oil (1.5 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (m, 2H), 7.41 (m, 3H), 7.27 (m, 1H), 5.97 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:9][C:7]2[C:6]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[CH:5][N:4]=[C:3]([CH2:2][OH:1])[CH:8]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cnc(CO)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 2-(hydroxymethyl)-5-(4-methoxybenzyloxy)pyridin-4(1H)-one (Intermediate 62, 3.48 g, 13.32 mmol) in DMF (100 mL) at room temperature was added 4-methoxybenzyl chloride (1.987 mL, 14.65 mmol) followed by potassium carbonate (2.273 mL, 39.96 mmol). The reaction mixture was stirred for 1 hour at room temperature then heated at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine. The ethyl acetate layer was concentrated to afford an oil. To the oil was added 1N HCl and a light brown solid crashed out. This was collected by filtration. The solid was taken up in ethyl acetate and washed with saturated sodium bicarbonate. The organics were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a brown solid (2.62 g, 52%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]1([CH3:18])[CH:12]=[CH:11][C:10]([S:13]([O:16]C)(=[O:15])=[O:14])=[CH:9][CH:8]=1>CC(C)=O>[C:7]1([CH3:18])[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1.[NH2:1][C:2]1[S:3][CH:4]=[CH:5][N+:6]=1[CH3:7]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1nccs1
Solvent: CC(C)=O
Product: C[n+]1ccsc1N
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a 200 ml three-necked flask were placed 2.0 g of 2-aminothiazole and 5.6 g of methyl p-toluenesulfonate, and the mixture was stirred at 120° C. for 4 hours. After the resulting mixture was cooled to 60° C., 100 ml of acetone was added and the mixture was stirred for 1 hour. The precipitates were filtered under reduced pressure, washed with acetone, and dried at room temperature under reduced pressure.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH3+:5].[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]=[S:18]>>[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]1[NH:5][CH2:4][CH2:3][S:18]1
Reactant: [NH3+]CCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NCCS1

Procedure:
2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine, which was reacted with 3-(chloromethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene according to Method D2a to give 2-(4-nitrophenylimino)-3-((6,6-dimethylbicyclo[3.1.1]hept-2-en-3-yl)methyl)-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].F[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[N:11][C:12]([CH3:18])=[N:13]2>CN(C)C=O>[CH3:18][C:12]1[N:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[CH:17][C:8]=2[O:3][CH2:2][CH2:1][OH:4])[N:13]=1
Reactant: OCCO
Reactant: Cc1ncc2c(F)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc2c(OCCO)cccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.4 %

Procedure:
To a solution of ethylene glycol (3.05 mL, 55.6 mmol) in N,N-dimethylformamide (50 mL) at room temperature was added sodium hydride (60% dispersion in oil, 0.30 g, 7.50 mmol) portion-wise. The reaction mixture was allowed to stir at room temperature for 30 minutes. A solution of 5-fluoro-2-methylquinazoline (2.22 g, 55.6 mmol) in N,N-dimethylformamide (5 mL) was added and the reaction mixture heated at 85° C. for 14 h. The mixture was allowed to cool to room temperature, quenched by the addition of water and concentrated in vacuo. Chromatography of the residue on SiO2 eluting with 40% ethyl acetate in dichloromethane to ethyl acetate gave the title compound as a yellow solid (0.39 g, 10%).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[C:7]([O-])(O)=O.[Na+].O.[F:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:22]1[C:23](=[O:50])[N:24]([CH2:40][C@@H:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][OH:43])[C:25](=[O:39])[N:26]([CH2:29][C:30]2[C:35](SC)=[CH:34][CH:33]=[CH:32][C:31]=2[F:38])[C:27]=1[CH3:28]>O.CC(C)=O>[F:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:22]1[C:23](=[O:50])[N:24]([CH2:40][C@@H:41]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:42][OH:43])[C:25](=[O:39])[N:26]([CH2:29][C:30]2[C:35]([S:3]([CH3:7])(=[O:5])=[O:2])=[CH:34][CH:33]=[CH:32][C:31]=2[F:38])[C:27]=1[CH3:28]
Reactant: O=S([O-])OO
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3SC)c(=O)n(C[C@H](CO)c3ccccc3)c2=O)c1F
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](CO)c3ccccc3)c2=O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Oxone (4.61 g, 7.5 mmol) was dissolved in water (20 mL) and saturated NaHCO3/H2O was added until the mixture was basic. A solution of 8c (1.35 g, 2.5 mmol) in acetone (20 mL) was added and the reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was filtered, and the filtrate was evaporated to give 8d (1.31 g, 92%). MS (CI) m/z 571.30 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:28][C@H:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1.CN1CCCC1=[O:41]>>[CH:15]([O-:14])=[O:41].[CH2:24]([N:3]1[C:2]([N:33]2[CH2:32][CH2:31][NH:30][C@@H:29]([CH3:28])[CH2:34]2)=[N:10][C:9]2[C:4]1=[N:5][C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)=[N:7][C:8]=2[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH:25]([CH3:27])[CH3:26]
Reactant: C[C@H]1CNCCN1
Reactant: CC(C)Cn1c(Cl)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CN1CCCC1=O
Product: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Product: O=C[O-]
Temperature: 120 °C
Reaction time: 4 h

Procedure:
N-Methylpyrrolidone (2 ml) was added to 5-(8-chloro-9-isobutyl-6-morpholin-4-yl-9H-purin-2-yl)pyrimidin-2-amine (200 mg, 0.51 mmol) and (2S)-2-methylpiperazine (412 mg, 4.1 mmol) and the resulting mixture was stirred at 120° C. for 4 hours. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give a formate of the title compound (192 mg) as a white solid.