Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[C:14]([F:13])([F:24])[F:25]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccccc1C(F)(F)F
Yield: 61.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-(trifluoromethyl)benzoyl chloride (80 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 63 mg of N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)-2-(trifluoromethyl)benzamide as a brown oil (Yield: 61%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([O:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:4].[CH3:15][O:16][C:17]([C:19]1[S:28][C:22]2[N:23]=[CH:24][N:25]=[C:26](Cl)[C:21]=2[C:20]=1[CH3:29])=[O:18]>>[CH3:29][C:20]1[C:21]2[C:26]([NH:12][C:11]3[C:6]([O:5][CH:3]([CH3:4])[C:2]([F:1])([F:13])[F:14])=[N:7][CH:8]=[CH:9][CH:10]=3)=[N:25][CH:24]=[N:23][C:22]=2[S:28][C:19]=1[C:17]([O:16][CH3:15])=[O:18]
Reactant: CC(Oc1ncccc1N)C(F)(F)F
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OC(C)C(F)(F)F)c2c1C
Temperature: 110 °C

Procedure:
Prepared analogously to example 1.1 by heating under microwave irradiation at 110° C. using 2-(1,1,1-trifluoropropan-2-yloxy)pyridin-3-amine and 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[CH2:10])[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].[C:11]([OH:14])(=[O:13])[CH3:12]>>[CH3:1][CH:2]([CH:9]=[CH2:10])[CH2:3][CH2:4][CH2:5][C:6]([O:14][C:11]([CH3:12])=[O:13])([CH3:8])[CH3:7]
Reactant: CC(=O)O
Reactant: C=CC(C)CCC=C(C)C
Product: C=CC(C)CCCC(C)(C)OC(C)=O

Procedure:
A process according to claim 8, wherein dihydromyrcene is reacted with acetic acid to produce dihydromyrcenyl acetate, which is then reacted with 4-tertiarybutylcyclohexanol to produce dihydromyrcenol and 4-tertiarybutylcyclohexyl acetate.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:7]=1[OH:17])[CH:4]=[CH2:5].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH2:20][CH2:21][CH2:22][O:17][C:7]1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:11][C:6]=1[CH2:3][CH:4]=[CH2:5])[CH3:24]
Reactant: C=CCc1cc(OCCCC)ccc1O
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(OCCCC)ccc1OCCCN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Sodium hydride (106 mg) was added to a solution of 2-allyl-4-butoxyphenol (500 mg) in toluene (40 ml). The reaction mixture was heated to reflux. A solution of 3-dimethylaminopropyl chloride (437 mg) in toluene (20 ml) was added to the refluxing reaction mixture and heating continued for a further 8 hours. The reaction mixture was cooled to ambient temperature, evaporated and the residue dissolved in water (10 ml). The resulting solution was extracted with ethyl acetate (4×15 ml). The ethyl acetate extracts were combined, dried (MgSO4) and evaporated to give an oil which was further purified by flash column chromatography on silica gel (Merck Art No 9385) using a 50:50:0.1 mixture of ethyl acetate, hexane and triethylamine as eluent to give N,N-dimethyl-3-(2-allyl-4-butoxyphenoxy)propylamine as yellow oil (556 mg); microanalysis, found: C, 74.5; H, 10.2; N, 4.8% C18H29NO2 requires: C, 74.2; H, 10.0; N, 4.8%; NMR([CD3 ]2SO): 0.91(3H,t), 1.42(2H,m), 1.65(2H,m), 1.82(2H,m), 2.15(6H,s), 2.38(2H,t), 3.27(2H,d), 3.88(4H,m), 5.2(2H,m), 5.92(1H,m), 6.7(2H,m) and 6.82(1H,m); m/z 292(M+H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH:14]=[N:15][OH:16].O>CN(C=O)C>[Cl:1][C:13]1([CH:14]=[N:15][OH:16])[CH:17]=[CH:18][CH:19]=[C:11]([O:10][CH3:9])[CH2:12]1
Reactant: COc1cccc(C=NO)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC1=CC=CC(Cl)(C=NO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-chlorosuccinimide (32.2 g, 241 mmol) was added to a solution of 3-methoxybenzaldehyde oxime (30.4 g, 201 mmol) in DMF (200 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred overnight at RT, mixed with water (250 ml) while being cooled with ice and the precipitate formed was removed by suction-filtration. The filtrate was extracted with ether (3×400 ml) and the combined organic phases were washed with water (300 ml) and sat. aq. NaCl solution (300 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethyl-3-methoxybenzene was obtained as a yellowish solid (32.86 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 113.2 %

Procedure:
To a solution of tert-butyl-1-piperazinecarboxylate (1.20 g) in acetonitrile (15 mL) was added ethyl 2-bromoisobutyrate (5.00 g) followed by potassium carbonate (0.975 g). The reaction mixture was heated at 80° C. for 12 hours, then cooled and partitioned between water and dichloromethane. The organic layer was washed with brine, dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=2[F:10])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: OC1(Cc2ccc(Cl)cc2F)CCN(Cc2ccccc2)CC1

Procedure:
A sample of 4-chloro-2-fluorobenzyl bromide is converted to its Grignard reagent which is reacted with N-benzyl-4-piperidone to provide 1-benzyl-4-(4-chloro-2-fluorobenzyl)-4-piperidinol in the manner described in Example 4A. This product is distilled at 175°-180° C., 0.18 mm, to provide an orange oil which is converted in ether to its hydrogen chloride salt. The salt is recrystallized four times from an ethyl alcohol-ether mixture to provide the purified salt, mp 211.5°-213° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:25][C:26]([CH:28]=[CH2:29])=[O:27].Cl>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[C:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH2:29][CH2:28][C:26](=[O:27])[CH:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(C)=O
Reactant: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1C=C2CCN(Cc3ccccc3)CC2(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1,3-Dibenzylpiperidin-4-one (3, Y═H, Z=benzyl (3.98 g, 13.96 mmol) was added to a solution of sodium methoxide (0.83 g, 15.36 mmol) in 80 mL of methanol and stirred at ambient temperature for 45 min. The contents were cooled to 0° C. and methylvinyl ketone (1.74 mL, 20.94 mmol) was added over 30 min. The contents were allowed to warm to ambient temperature and stir for 18 h. Concentrated HCl (1.55 mL) was added, the contents were stirred for a further 5 min and the solvents were evaporated to give a brown oil which was triturated in diethyl ether to give the title compound, 1.90 g. LC-MS: RT=2.26 min. (M+H)+ 332.
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[C@H:3]([NH:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:5].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[NH:49][C:48]([C@@H:50]3[CH2:54][CH2:53][CH2:52][N:51]3[C:55](=[O:66])[C@@H:56]([NH:60][C:61]3[S:62][CH:63]=[CH:64][N:65]=3)[CH:57]([CH3:59])[CH3:58])=[N:47][CH:46]=2)=[CH:41][CH:40]=1.C([O-])(O)=O.[Na+]>COCCOC.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>[C:19]1([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[N:49]=[C:48]([C@@H:50]4[CH2:54][CH2:53][CH2:52][N:51]4[C:55](=[O:66])[C@@H:56]([NH:60][C:61]4[S:62][CH:63]=[CH:64][N:65]=4)[CH:57]([CH3:59])[CH3:58])[NH:47][CH:46]=3)=[CH:41][CH:40]=2)[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C@@H:7]3[CH2:8][CH2:9][CH2:10][N:6]3[C:4](=[O:5])[C@@H:3]([NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH:2]([CH3:37])[CH3:1])[NH:15][CH:14]=2)=[CH:17][CH:18]=1
Reactant: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
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: O
Solvent: COCCOC
Product: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](Nc5nccs5)C(C)C)n4)cc3)cc2)c[nH]1
Temperature: 80 °C
Yield: 1.7 %

Procedure:
A mixture of (S)-3-methyl-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-(thiazol-2-ylamino)butan-1-one (275 mg, 0.527 mmol), (S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-2-(thiazol-2-ylamino)butan-1-one (250 mg, 0.527 mmol), NaHCO3 (133 mg, 1.582 mmol) and Pd(Ph3P)4 (60.9 mg, 0.053 mmol) in DME (3 mL) and Water (1 mL) was degassed by passing a stream of N2 through the mixture. The vessel was sealed and the reaction was heated at 80° C. overnight. The reaction mixture was diluted with H2O and extracted with EtOAc containing ca. 5% MeOH (×3). The combined org layers were concentrated, dissolved in MeOH and loaded onto an MCX cartridge. The cartridge was washed with MeOH and then NH3 in MeOH (2M). The appropriate fractions were concentrated in vacuo and the residue was purified by prep HPLC (CH3CN—H2O—NH4OAc). The material was purified by column chromatography (biotage) eluting with 0 to 20% MeOH in EtOAc. Further purification by prep HPLC (CH3CN—H2O—NH4OAc) followed by lyophilization afforded the title compound as a colorless solid (6.9 mg, 2%).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][C:20]=12.O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22]([N:8]3[C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11][O:10][C:9]3=[O:12])=[N:21][C:20]=12
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: Clc1ccn2ncc(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC[C@H](c2ccccc2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
To a solution of (S)-4-phenyloxazolidin-2-one (0.737 g, 4.517 mmol) in DMF was added sodium hydride (0.189 g, 4.73 mmol) and the reaction stirred at ambient temperature for 45 minutes. 3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (1.00 g, 4.302 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction mixture was poured into water and the water layer extracted with ether. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using 2% EtOAc/DCM as the eluent to yield (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (1.233 g, 3.433 mmol, 79.80% yield).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[F:36][C:37]1([F:41])[CH2:40][NH:39][CH2:38]1>C(#N)C>[Cl:24][C:18]1[CH:19]=[C:20]([N:39]2[CH2:40][C:37]([F:41])([F:36])[CH2:38]2)[CH:21]=[CH:22][C:17]=1[S:14]([C@H:12]1[CH2:11][N:10]([C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)[C@H:9]([C:7]([NH:6][C:3]2([C:1]#[N:2])[CH2:5][CH2:4]2)=[O:8])[CH2:13]1)(=[O:16])=[O:15]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 385b) was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 90° C. for 48 h to give the title compound as off-white foam. MS (ESI): m/z=579.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C(C)(C)C)=O)=[CH:4][C:3]=1[S:16]([CH3:19])(=[O:18])=[O:17].C(O)(C(F)(F)F)=O.[NH2:27][C:28]1[N:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:40]([N:37]1[CH2:36][CH2:35][N:34]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:4]=3)=[N:33][CH:32]=2)[CH2:39][CH2:38]1)(=[O:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)Cc1cnc(Cl)c(S(C)(=O)=O)c1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(S(C)(=O)=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2-(6-chloro-5-(methylsulfonyl)pyridin-3-yl)acetate 197-5 (40 mg, 0.13 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(6-chloro-5-(methylsulfonyl)pyridin-3-yl)acetic acid 197-6, was dissolved in DMF (2 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (35 mg, 0.16 mmol) and DIEA (114 uL, 0.65 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (75 mg, 0.20 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was purified by silica gel flash chromatography and eluted with 5% MeOH in CH2Cl2 to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-(methylsulfonyl)pyridin-3-yl)acetamide 197-7. MS m/z 452.1 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1>O1CCCC1.O>[CH2:9]([S:10][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccnc1Br
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccnc1SCc1ccccc1
Reaction time: 0.25 h
Yield: 222.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.44 g) in tetrahydrofuran (45 mL) was added dropwise phenylmethanethiol (465 mg) at room temperature and the mixture was stirred for 15 min. 2-Bromo-3-methylpyridine (2.0 g) was added to the reaction mixture, and the mixture was stirred at 60° C. for 1.5 hr. The reaction mixture was diluted with water, and concentrated under reduced pressure. The residual aqueous layer was extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-hexane-ethyl acetate=97:3) to give the title compound as a gray oil (yield 1.79 g, 72%).
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH2:8])[CH:6]=[CH2:7].[CH3:9][C:10]1[N:15]=[C:14](SC)[NH:13][C:12](=[O:18])[C:11]=1[CH2:19][CH2:20][CH3:21]>O>[CH2:5]([NH:8][C:14]1[NH:13][C:12](=[O:18])[C:11]([CH2:19][CH2:20][CH3:21])=[C:10]([CH3:9])[N:15]=1)[CH:6]=[CH2:7]
Reactant: CCCc1c(C)nc(SC)[nH]c1=O
Reactant: C=CCN
Solvent: O
Solvent: CC(=O)O
Product: C=CCNc1nc(C)c(CCC)c(=O)[nH]1
Temperature: 130 °C

Procedure:
A mixture of allylamine acetate (12 g) and 6-methyl-2-methylthio-5-propylpyrimid-4(3H)-one (6 g) was heated at 130° C for 45 minutes. The mixture was cooled and water was added. The precipitated product was collected, washed with water, dried and recrystallised from petroleum (b.p. 80°-100° C) giving 2-allylamino-6-methyl-5-propylpyrimid-4(3H)-one (formula VII, R1 = CH3, R = C3H7, R6 = H, R7 = CH2CH=CH2) having a melting point of 152°-153° C.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:17].BrBr>C(O)(=O)C>[BrH:17].[CH2:2]([N:9]1[CH2:15][CH2:14][CH:13]([Br:17])[C:12](=[O:16])[CH2:11][CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Agent: Br
Agent: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CCN(Cc2ccccc2)CCC1Br

Procedure:
175 g of (0.732 mol) 1-benzylhexahydroazepin-4-one hydrochloride IV are dissolved in 500 mL acetic acid. Upon addition of 100 mL of a saturated solution (30%) of hydrobromic acid in acetic acid, 37 mL (0.732 mol) of bromine are added dropwise at room temperature and with efficient stirring, whereby the brown color of bromine disappears.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16](#[N:19])[CH:17]=[CH2:18].C1(CNCC2CCCCC2)CCCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.CCCCCC.O1CCOCC1>[C:16]([CH:17]=[CH:18][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13])#[N:19]
Reactant: C=CC#N
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(C=CC#N)c(C(=O)OC)c1
Temperature: 80 °C

Procedure:
A microwave vial was charged with dimethyl 4-bromoisophthalate (Example 88A, 500 mg, 1.83 mmol), acrylonitrile (117 mg, 2.20 mmol), N,N-dicyclohexylmethylamine (429 mg, 2.20 mmol), tri-tert-butylphosphine (0.11 mL, 0.11 mmol, 1.0 M in toluene), tris(dibenzylideneacetone)dipalladium(0) (50.3 mg, 0.055 mmol), and 1,4-dioxane (1.4 mL) under nitrogen. The reaction mixture was heated to 80° C. in an oil bath for 4 hours. Reaction was complete as indicated by thin layer chromatography (40% ethyl acetate/hexane). The reaction mixture was cooled to room temperature and diluted with ethyl acetate. Filtration removed HBr salts. The filtrate was concentrated. The residue was triturated with ethyl acetate/hexane (1:6) to provide dimethyl 4-(2-cyanovinyl)isophthalate as a mixture of trans and cis isomers (ratio 5.5:1) which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH3:24])[C:12]([F:23])=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:25])[C:8]([C:26]([O:28]CC)=[O:27])=[CH:7]1.[OH-].[Li+].O.Cl>CO>[CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH3:24])[C:12]([F:23])=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:25])[C:8]([C:26]([OH:28])=[O:27])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC[C@H]3CO)c(F)c(C)c2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)c(F)c(N4CCC[C@H]4CO)nc32)c(OC)c1

Procedure:
A mixture of EXAMPLE 3A (312 mg) and 1M lithium hydroxide (1.9 mL) in methanol (6 mL) at 25° C. was stirred for 24 hours, treated with water (100 mL), adjusted to pH 3 with 1M hydrochloric acid, and filtered.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>COCCOC.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:30][C:31]1[CH:36]=[CH:35][C:34]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=[CH:10]3)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of ethyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthalenecarboxylate (0.3 g, 0.861 mmol), tetrakis(triphenylphosphine) palladium (0) (0.04 g, 0.0345 mmol), 2 M Na2CO3 (4 mL) and 4-hydroxyphenyl boronic acid (0.143 g, 1.03 mmol) in ethylene glycol dimethyl ether (5 mL) was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water and EtOAc. The EtOAc layer was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as oil. The crude material was purified by flash chromatography over SiO2 with a Hex:EtOAc (0 to 50% EtOAc) gradient to afford 0.23 g (92%) of the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1 H), 8.76 (d, J=9.0 Hz, 1 H), 8.20 (m, 2 H), 8.07 (d, J=7 Hz, 1H), 7.93 (m, 1 H), 7.66 (d, J =9 Hz, 2 H), 7.58 (t, J=8 Hz, 1 H), 6.88 (d, J=9 Hz, 2 H), 4.42-4.37 (m, 2 H), 1.37 (t, J =7 Hz, 3 H).