Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:23]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>ClCCl>[O:21]=[C:19]1[NH:18][C:17](=[O:22])[CH:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[C:37]([NH:36][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:35][CH:34]=4)=[O:38])[CH:4]=3)=[CH:14][CH:13]=2)[S:20]1
Reactant: CNc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: CCCCCCOc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCOc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1
Yield: 68.6 %

Procedure:
0.67 g (2.14 mmol) of 5-(3′-methylaminobiphenyl-4-ylmethyl)thiazolidine-2,4-dione in 20 ml of dichloromethane is introduced into a 50 ml round-bottomed flask. 1 g (4.3 mmol) of 1-hexyloxy-4-isocyanatobenzene is added and the mixture is heated under reflux for 16 hours. The reaction medium is poured at room temperature over a 1 N HCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate. After evaporation of the solvents, the product obtained is purified by chromatography on silica gel (eluent: heptane/ethyl acetate=3/2). 0.78 g (68%) of 1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(4-hexyloxyphenyl)-1-methylurea is obtained in the form of a white powder having a melting point of 146–148° C.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH:28]=O>CN(C)C(=O)C>[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH:28]=[N:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CC(C)(C)CC=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)CC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 60 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3,3-dimethylbutanal (0.5 g, 5.0 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.072 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][N:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1.O>[O:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]3)=[CH:6][CH:7]=2)=[N:23]1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: Clc1noc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(C(F)(F)F)n(-c2ccc(Nc3noc4ccccc34)cc2)n1
Reaction time: 168 h
Yield: 18.7 %

Procedure:
To a stirred solution of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.20 g, 0.68 mmol) and 3-chlorobenzisoxazole (0.10 g, 0.65 mmol) in tetrahydrofuran (2.5 mL) under argon was added sodium bis-trimethylsilyl amide (1.0 M in tetrahydrofuran, 0.68 mL, 0.68 mmol). After seven days, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography (elution with ethyl acetate/hexanes) to give the above-named compound (0.050 g). m.p. 209-210° C. NMR (CDCl3, 400 MHz): δ 7.77 (d, 1H), 7.64 (m, 3H), 7.53 (d, 2H), 7.37 (m, 1H), 7.09 (s, 1H), 6.68 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Li+].Cl>C(O)C.O>[Cl:15][C:12]1[C:11]([Cl:16])=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Reaction time: 2 h
Yield: 60.6 %

Procedure:
4,5-Dichloro-1H-indole-2-carboxylic acid ethyl ester (0.5 g) was treated with 1 M lithium hydroxide in ethanol (3 mL) and heated, water bath, for 2 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethylacetate. The organic extracts were combined, dried over sodium sulfate and filtered, and solvent was evaporated to give 4,5-dichloro-1H-indole-2-carboxylic acid (0.27 g, 60%). This material was treated with -ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride (0.5 g), HOBT (0.4 g) and N,N-diisopropylethylamine (1 mL) in DMF (2 mL) and dichloromethane (2 mL) was treated with N-methylpiperazine (0.2 mL) stirred at ambient temperature for 18 h then diluted with water. The organic portion was separated, washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure, and the residue was purified via silica gel chromatography (3-8% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.15 g, 40%). 1H NMR (400 MHz, CDCl3): δ 10.2 (br.s, 1H), 7.25-7.16 (m, 2H), 6.75 (d, J=2 Hz, 1H), 3.92 (br.m, 4H), 2.47 (m, 4H), 2.30 (s, 3H). MS (electrospray): exact mass calculated for C14H15Cl2N3O, 311.06; m/z found, 312.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C[O:18][C:19](=O)[N:20]=[C:21](SC)[C:22]([C:36]1[CH:46]=[C:45]([O:47][CH3:48])[C:39]2[O:40][CH2:41][CH2:42][CH2:43][O:44][C:38]=2[CH:37]=1)=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[C:3]([N:8]2[C:19](=[O:18])[NH:20][C:21]([CH:22]([C:36]3[CH:46]=[C:45]([O:47][CH3:48])[C:39]4[O:40][CH2:41][CH2:42][CH2:43][O:44][C:38]=4[CH:37]=3)[NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:28][CH:29]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1F
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)OCCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3F)c(=O)[nH]2)cc2c1OCCCO2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 28 mg of (3-fluoropyridin-2-yl)hydrazine and 50 μl of triethylamine to a solution of 119 mg of {2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 2-(3-fluoropyridin-2-yl)-5-{(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11](=[CH:17][N:18](C)C)[C:12]2=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29]N)=[CH:25][CH:24]=1>C(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11]3[CH:17]=[N:18][N:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[C:12]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)C=C1C(=O)C2CC1CN(Cc1ccccc1)C2
Agent: Cl
Solvent: CCO
Product: Fc1ccc(-n2ncc3c2C2CC3CN(Cc3ccccc3)C2)cc1
Yield: 38.3 %

Procedure:
To a solution of 3-benzyl-7-dimethylaminomethylene-3-aza-bicyclo[3.2.1]octan-6-one (0.6 mmol) in ethanol (3 mL) was added (4-fluoro-phenyl)-hydrazine hydrochloride (0.7 mmol). The reaction mixture was heated at reflux overnight, cooled, concentrated and the residue was treated with dichloromethane and aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane and the organic layer was dried and stripped to provide an oil that was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes to yield product (0.23 mmol). 1H NMR (CDCl3, 400 MHz) δ 7.55 (m, 2H), 7.40 (s, 1H), 7.20–6.90 (m, 7H), 3.50 (br s, 2H), 3.25 (br s, 1H), 3.10 (br s, 1H), 2.95–2.6.
Reaction SMILES: [CH:1]([N:4]([CH:14]([CH3:16])[CH3:15])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[Li]CCCC.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][C:24]=1[O:31][CH3:32].[NH4+].[Cl-]>C1COCC1>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]([OH:28])[C:9]2[CH:10]=[CH:11][C:6]([C:5]([N:4]([CH:14]([CH3:16])[CH3:15])[CH:1]([CH3:3])[CH3:2])=[O:13])=[CH:7][CH:8]=2)=[CH:25][C:24]=1[O:31][CH3:32]
Reactant: CC(C)N(C(=O)c1ccc(I)cc1)C(C)C
Reactant: COc1cc(C=O)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C(C)C)cc2)ccc1F
Temperature: -78 °C
Yield: 60.3 %

Procedure:
N,N-Diisopropyl-4-iodobenzamide (6.0 g, 18 mmol) was dissolved in THF (200 mL) and cooled to −78° C. under nitrogen atmosphere. n-BuLi (14 mL, 1.3 M solution in hexane, 18 mmol) was added dropwise during 10 min at −65 to −78° C. 4-fluoro-3-methoxybenzaldehyde (2.8 g, 18 mmol) was added dropwise dissolved in THF (5 mL). NH4Cl (aq.) was added after 30 min. After concentration in vacuo, extraction with EtOAc/water, drying (MgSO4) and evaporation of the organic phase, the residue was purified by chromatography on silica (0-75% EtOAc/heptane) to yield the desired product (3.9 g, 60%). 1H NMR (CDCl3) δ 1.0-1.6 (m, 12H), 2.65 (d, J=4 Hz, 1H), 3.4-3.9 (m, 2H), 3.80 (s, 3H), 6.10 (d, J=4 Hz, 1H), 6.76 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 6.76 (m, 1H), 7.25, 7.40 (2d, J=7.5 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(C=O)c(-c2cccs2)c1
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)c(-c2cccs2)c1
Yield: 61 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-6-thiophen-2-yl-benzaldehyde (Ex-39A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 61% yield, mp 231° C. (dec.). 1H-NMR (DMSO-d6) δ 8.02 (d, 2H), 7.93 (d, 2H), 7.73 (m, 3H), 7.15 (t, 1H), 7.07 (d, 1H), 6.72 (d, 1H), 6.62 (d, 1H). MS m/z=394 ([M]+, 6%), 245 (100%). HRMS m/z: calc. 395.0953, found 395.0949.
Reaction SMILES: O[CH:2]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][CH:5]=1)[CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[Br:36][CH:2]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)c1cccc(NC(=O)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of N-[6-(1-hydroxyethyl)pyridin-2-yl]-2,2-dimethylpropanamide (1 g, 4.49 mmol, 1 eq.) in 20 ml of DCM was cooled to 0° C. and PPh3 (1.65 g, 6.29 mmol, 1.4 eq.) was added followed by N-Bromosuccinimide (0.96 g, 5.39 mmol, 1.2 eq.). The reaction was stirred at 0° C. for 1 h and at r.t. for 1 h. The solvent was removed and residue purified by chromatography on silica gel to give N-[6-(1-bromoethyl)pyridin-2-yl]-2,2-dimethylpropanamide (1.025 g, 79% yield) as a clear oil.
Reaction SMILES: S([O-])(=O)(=O)C.[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15](O)[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-:19]#[N:20].[Na+]>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15]([C:19]#[N:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC1CCN(Cc2ccccc2)C1
Temperature: 82.5 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
This transformation was carried out using the method described in C. Thomas et. al. reference 97. The mesylate of racemic 1-benzyl-pyrrolidin-3-ol (0.039 mol, 10 g), prepared as described above, sodium cyanide (0.24 mol, 15 g) and tetrabutylammonium cyanide (10 g, 0.037 mol) in 75 mL of DMSO was stirred at 80-85° C. for 16 h. The reaction mixture was partitioned between diethyl ether and sat. aq sodium bicarbonate. The aqueous layer was extracted twice with ether and the combined organic layer was washed successively with sodium bicarbonate, water, and sat aq. NaCl. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography over silica gel using a gradient of 20 to 30% ethyl acetate in hexane to afford 5.5 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C([N:18]=[C:19]=[S:20])(=O)C1C=CC=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:19]([NH2:18])=[S:20]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccccc1N
Solvent: CC(C)=O
Product: COc1ccccc1NC(N)=S
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To 50 ml of acetone were added 2.46 g of o-anisidine and 3.75 g of benzoyl isothiocyanate, and the mixture is stirred under reflux for 2 hours and, then, allowed to stand overnight in a refrigerator at 5° C. The resulting crystals were collected by filtration, washed with cold acetone and dried under reduced pressure. The crystals were added to 50 ml of 30% methylamine-methanol and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was washed with ethanol-ethyl acetate and dried under reduced pressure. The procedure provided 2.08 g of N-(o-methoxyphenyl)thiourea.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:17]([O-])=O)[C:8]([O:15][CH3:16])=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:12])=[O:13])[C:8]([O:15][CH3:16])=[C:7]([CH:6]=1)[NH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: COc1c(N)cc(C(C)(C)C)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 14.5 g 5-tert-butyl-1-methanesulphonyl-2-methoxy-3-nitro-benzene, 3.0 g 10% palladium on charcoal and 250 ml of methanol is shaken for 6 h at ambient temperature under a hydrogen atmosphere (50 psi). Then the catalyst is filtered off and the filtrate is evaporated to dryness.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:5]2[N:6]=[C:7]([N:14]3[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]3)[CH:2]=[C:3]([Cl:9])[N:4]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: CN1CCN(c2cc(Cl)nc(N3CCN(C)CC3)n2)CC1
Temperature: 0 °C

Procedure:
Trichloropyrimidine is added in portions to an ice cooled solution of N-methylpiperazine (40 g) in alcohol (200 ml). The mixture is then heated at 60° for 2 hr. The mixture is concentrated and chromatographed on silica gel with 2 to 5% methanol in methylene chloride to give 2,4-bis-[4-methylpiperazino]-6-chloropyrimidine. This material is heated at 130° in water (30 ml) with piperazine (32 g) in a Parr bomb for 20 hr. The product is partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give 2,4-bis[1-(4-methylpiperazino)]-6-piperazinopyrimidine. This triamine is stirred in acetonitrile (200 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (7.18 g) and potassium carbonate (2 g) for 20 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated and the organic phase is concentrated and chromatographed on silica gel (methylene chloride to 5% methanol and 0.5% ammonium hydroxide/methylene chloride) to give the free base corresponding to the title compound. The free base is dissolved in ethyl acetate and treated with methane sulfonic acid (2.22 g). The product is triturated with ether to give the title compound, bubbled at 110° without obvious decomp.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[F:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[F:25])[C:18](=O)[CH2:19]Br>>[F:14][C:15]1[CH:16]=[C:17]([C:18]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:19]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Product: COC(=O)c1cccc(-c2nc(-c3ccc(F)c(F)c3)cs2)c1
Yield: 70 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 3,4-difluorophenacyl bromide to obtain-methyl 3-[4-(3,4-difluorophenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 70%. Colorless prisms. Melting point: 147 to 148° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:12]1([C:11]#[C:10][CH2:9][CH2:8][NH2:7])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCC#Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC#Cc1ccccc1

Procedure:
A solution of (4-phenyl-but-3-ynyl)-carbamic acid tert-butyl ester (98 mg) was stirred for 0.5 h in 1:1 trifluoroacetic acid/dichloromethane (10 ml). The volatile materials were evaporated to give the crude 4-phenyl-but-3-ynylamine, which was used in subsequent transformations without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:9]([C:24]1[CH:37]=[CH:36][C:27]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])=[CH:26][CH:25]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[(4-chloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 8) and (4-bromo-phenoxy)-tert-butyl-dimethyl-silane in analogy to Example 1a): MS (ISP): 476.0 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:16][C:17]1[C:18](I)=[CH:19][C:20](=[O:36])[N:21]([CH2:23][CH2:24][C@@:25]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1.O>O1CCOCC1.[Pd]>[F:16][C:17]1[C:18]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][C:20](=[O:36])[N:21]([CH2:23][CH2:24][C@@:25]([CH3:35])([S:31]([CH3:34])(=[O:32])=[O:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Pd EnCat™ (95 mg, 0.037 mmol) was added to a mixture of potassium carbonate (312 mg, 2.26 mmoll), phenylboronic acid (131 mg, 1.07 mmol), and ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (319 mg, 0.716 mmol) in dioxane:water (10 ml, 4:1) in a 20 mL vial equipped with a stir bar. The reaction was heated to 90° C. and allowed to stir overnight at that temperature. The reaction was allowed to cool to RT, filtered and the catalyst was washed with methanol (10 ml) and dichloromethane (10 ml). The filtrate was concentrated to afford a crude solid. The crude was purified via flash chromatography using an Analogix SF15-12 column and an eluant of ethyl acetate in heptane (50-100%) and methanol in ethyl acetate (0-5%) to afford the title compound as a yellowish white solid (250 mg, 64.8%). LC-MS m/z 396.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.12 Hz, 3H) 1.62 (s, 3H) 2.15-2.32 (m, 1H) 2.53-2.66 (m, 1H) 3.16 (s, 3H) 3.89-4.06 (m, 2H) 4.07-4.26 (m, 2H) 6.50 (d, J=7.61 Hz, 0H) 7.20-8.12 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[C:11]([Si](C)(C)C)#[CH:12].[OH-].[Na+]>CCN(CC)CC.C(OCC)(=O)C.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>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[CH:12])[C:3]=1[C:4]#[N:5]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1c(N)cccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#Cc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 2-amino-6-bromobenzonitrile (1.25 g, 6.34 mmol) and ethynyltrimethylsilane (2.42 g, 12.7 mmol) in dry Et3N (15 mL) was added under N2 Cu(I) (60 mg), Pd(PPh3)4 (360 mg) and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with brine. The organic layer was evaporated and the residue was dissolved in methanol (20 mL), treated with 1M aqueous NaOH solution (1.05 equiv.) and stirred at room temperature for 1 hour. Methanol was evaporated off and the aqueous residue was extracted with CH2Cl2, dried over MgSO4, and purified over silica gel (ethyl acetate/hexanes 75/25) to furnish the desired product in 93% yield as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.54 (s, 1H), 6.24 (br s, 2H), 6.76 (dd, J=0.8, 7.6 Hz, 1H), 6.82 (dd, J=0.8, 8.4 Hz, 1H), 7.28 (dd, J=7.6, 8.4 Hz, 1H). MS 143 (MH+).