Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:28]([F:31])([F:30])[F:29])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:7][CH:6]=1>C(I)CCC.[Ag]=O>[CH2:28]([O:1][CH:2]([C:28]([F:30])([F:31])[F:29])[CH:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(O)C(F)(F)F)cc2)nc1
Agent: O=[Ag]
Solvent: CCCCI
Product: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(OCCCC)C(F)(F)F)cc2)nc1
Reaction time: 96 h
Yield: 173.7 %

Procedure:
1.0 g of (-)-2-(4-(3-hydroxy-4,4,4-trifluoro-1-butenyl)phenyl)-5-decyloxypyrimidine was dissolved in 5 ml of butyl iodide. The solution was added with 3 g of silver oxide and stirred at 25°-30° C. for 4 days. The reaction mixture was cleared of silver oxide by filtration and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 0.98 g of (-)-2-(4-(3-butoxy-4,4,4-trifluoro-1-butenyl)phenyl)-5-decyloxypyrimidine.
Reaction SMILES: [NH:1]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1.[CH2:29]([N:32]([CH2:49][CH:50]=[CH2:51])[C:33]1[N:38]=[C:37](Cl)[N:36]=[C:35]([NH:40][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[N:34]=1)[CH:30]=[CH2:31].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:25][C:23]1([CH3:26])[CH2:24][CH:19]([N:1]([C:37]2[N:38]=[C:33]([N:32]([CH2:49][CH:50]=[CH2:51])[CH2:29][CH:30]=[CH2:31])[N:34]=[C:35]([NH:40][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[N:36]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:37]2[N:38]=[C:33]([N:32]([CH2:49][CH:50]=[CH2:51])[CH2:29][CH:30]=[CH2:31])[N:34]=[C:35]([NH:40][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[N:36]=2)[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]2)[CH2:20][C:21]([CH3:28])([CH3:27])[NH:22]1
Reactant: C=CCN(CC=C)c1nc(Cl)nc(NC(C)(C)CC(C)(C)C)n1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: C=CCN(CC=C)c1nc(NC(C)(C)CC(C)(C)C)nc(N(CCCCCCN(c2nc(NC(C)(C)CC(C)(C)C)nc(N(CC=C)CC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1
Yield: 19.2 %

Procedure:
A stirred solution of 4,4'(hexamethylenediimino)bis(2,2,6,6-tetramethylpiperidine) (9.5 grams; 0.024 mole), 2-diallylamino-4-chloro-6-t-octylamino-1,3,5-triazine (16.0 grams; 0.048 mole), and powdered sodium hydroxide (2.0 grams; 0.05 mole) in xylene (150 mls) is heated at reflux for 24 hours while removing by-product water by means of a trap. The resulting mixture is then filtered and the filtrate is heated to evaporate the solvent and obtain a light tan oil which solidifies on triturating with petroleum ether. The solid is then recovered and dried to obtain 4.6 grams of the desired product, mp 113115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)c1cccc(OC)c1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccc(OC)c1C
Temperature: 60 °C
Yield: 83.8 %

Procedure:
To a solution ethyl 3-(3-methoxy-2-methylphenyl)-3-oxopropanoate (137.2 g, 595 mmol, from Step A) in ethyl alcohol (924 mL), 10% Pd—C (13.7 g) was added and 3 atm of hydrogen were applied. The mixture was heated to 60° C. for 20 hr, cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (2% EtOAc/hexanes) on SiO2 to afford 110.8 g of the title compound as a pale yellow liquid: 1H NMR (500 MHZ, CDCl3) δ 1.25 (t, 3H, J=7.1 Hz), 2.19 (s, 3H), 2.55 (t, 2H, J=8.0 Hz), 2.95 (t, 2H, J=8.0 Hz), 3.82 (s, 3H), 4.14 (q, 2H, J=7.1 Hz), 6.73 (d, 1H, J=8.2 Hz), 6.78 (d, 1H, J=7.6 Hz), 7.10 (d, 1H, J=7.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][C:10]1([CH3:13])[CH2:12][O:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:9][C:10]([OH:11])([CH3:13])[CH3:12])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(Br)ccc1=O
Temperature: 100 °C
Yield: 75.5 %

Procedure:
A mixture of 5-bromopyridin-2(1H)-one (600 mg, 3.5 mmol), 2,2-dimethyloxirane (750 mg, 10.4 mmol) and K2CO3 (960 mg, 6.9 mmol) in DMF (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (80 mL), washed with water, brine, and dried over MgSO4. The organic layer was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10 to 50% EtOAc/hexane) to give Compound 244a (650 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=2.6 Hz, 1H), 7.40 (dd, J=9.6, 2.8 Hz, 1H), 6.54 (d, J=9.7 Hz, 1H), 3.99 (s, 2H), 3.57-3.39 (s, 1H), 1.27 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.Cl[CH2:11][C:12](=O)[CH3:13].[OH-:15].[Na+].Cl>>[CH3:13][C:12]1[C:11]([OH:15])=[CH:8][C:3]2[C:2](=[CH:7][CH:6]=[N:5][CH:4]=2)[N:1]=1
Reactant: [OH-]
Reactant: CC(=O)CCl
Reactant: Nc1ccncc1C=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2ccncc2cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
4-Amino-pyridine-3-carbaldehyde (1.0 g) and chloroacetone (0.7 g) were suspended in a 5 N aqueous sodium hydroxide solution (5 ml), and the suspension was allowed to stand in a sealed tube for 3 days. The reaction solution was neutralized with 10% hydrochloric acid, and the precipitated crystal was then collected by filtration. Isopropanol was added to the collected crystal, and the mixture was heated under reflux. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation. Hexane was added to the residue, and the precipitated crystal was collected by filtration and was washed with hexane to give 2-methyl-[1,6]naphthyridin-3-ol (0.60 g, yield 46%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:22]#[N:23])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)C.OCCC(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1>>[OH:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:22]#[N:23])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)CC(c1ccc2c(C#N)c[nH]c2c1)c1ccccn1
Agent: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Product: N#Cc1c[nH]c2cc(C(CCO)c3ccccn3)ccc12

Procedure:
6-(3-Hydroxy-1-pyridin-2-yl-propyl)-1H-indole-3-carbonitrile CLXXII was prepared from 3-(3-cyano-1H-indol-6-yl)-3-pyridin-2-yl-propionic acid ethyl ester using the procedure described for preparation of 4-(3-Hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LX (Example 14).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:17]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]#[N:38])=[CH:27][CH:26]=2)[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:52]=[N+:53]=[N-:54])(CCCC)CCCC)CCC>CC1C=CC=CC=1C>[CH2:1]([O:8][C:9]([C:11]1([N:17]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:54][N:53]=[N:52][N:38]=3)=[CH:29][CH:30]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C1(C(=O)OCc2ccccc2)CCCCC1
Solvent: Cc1ccccc1C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C1(C(=O)OCc2ccccc2)CCCCC1

Procedure:
A mixture of 3.3 g (6.5 mmol) of N-(1-benzyloxycarbonylcyclohexyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-N-pentanoyl-amine, 4.1 g (12.3 mmol) of tributyltin azide and 30 ml of o-xylene is heated to reflux for 44 hours. Working-up of the mixture in a manner analogous to that described in Example 23 yields the N-(1-benzyloxycarbonylcyclohexyl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in the form of light-brown crystals melting between 189° and 190° (from ethyl acetate/diethyl ether).
Reaction SMILES: [O-]CC.[Na+].[Na].[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Br[CH2:15][CH:16]([CH3:19])[CH2:17][Cl:18]>C(O)C>[Cl:18][CH2:17][CH:16]([CH3:19])[CH2:15][O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(CCl)CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(CCl)COc1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
To a stirred sodium ethoxide solution, prepared starting from 3.5 parts of sodium in 24 parts of ethanol, were added 16.8 parts of 4-fluorophenol. After stirring for 15 minutes, there was added dropwise a solution of 77 parts of 1-bromo-3-chloro-2-methylpropane in 72 parts of ethanol at room temperature. Upon completion, stirring was continued for 20 hours at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated. The residue was taken up in 2,2'-oxybispropane. The organic phase was washed with water and with alkaline water 5%, dried, filtered and evaporated. The residue was distilled, yielding 11.6 parts of 1-(3-chloro-2-methylpropoxy)-4-fluorobenzene; bp. 126° C. (water-jet) (intermediate 82).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[O:23][C:22](=O)[NH:21][N:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].Cl.[NH2:26][CH2:27][C:28]#[N:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[O:23][C:22]([NH:29][CH2:28][C:27]#[N:26])=[N:21][N:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccnc(-c2c[nH]c3ccc(-c4n[nH]c(=O)o4)cc23)n1
Reactant: N#CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccnc(-c2c[nH]c3ccc(-c4nnc(NCC#N)o4)cc23)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a solution of 5-(3-(4-isopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (350 mg, in about 60% pure) in DMF (4 mL) at RT was sequentially added 2-aminoacetonitrile hydrochloride (302 mg, 3.27 mmol) (Alfa Aesar), diisopropylethylamine (0.79 mL, 4.57 mmol) and BOP (530 mg, 1.20 mmol) (Aldrich). After the reaction was stirred at RT for 18 h, it was diluted with H2O (10 mL) and extracted with EtOAc (3×25 mL). The aqueous layer was discarded. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified on a silica gel column eluting with 25-100% EtOAc in Hex to give 2-(5-(3-(4-isopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-ylamino)-acetonitrile (45 mg) as a brown amorphous solid. MS (ESI, pos. ion) m/z: 360.0 (M+1). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br.), 9.16 (1H, s), 8.69 (1H, d, J=5.1 Hz), 8.49 (1H, t, J=5.7 Hz), 8.33 (1H, m), 7.73 (1H, d, J=8.2 Hz), 7.62 (1H, d, J=8.6 Hz), 7.16 (1H, d, J=5.1 Hz), 4.43 (2H, d, J=5.7 Hz), 3.06 (1H, dt, J=13.7, 6.8 Hz), 1.37 (6H, d, J=6.8 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH:28]([C@@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)([CH3:30])[CH3:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[C@H:31]([CH:28]([CH3:30])[CH3:29])[CH2:35][O:34][C:33]4=[O:36])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 61 and (R)-4-isopropyloxazolidin-2-one (155 mg), the title compound (20 mg) was obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:38]=2)[C:33]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[N:32]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:36]3[CH:35]=[C:34]4[C:39](=[CH:38][CH:37]=3)[N:31]([CH3:30])[N:32]=[C:33]4[C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cn1nc(-c2cccnc2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3cccnc3)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75 mg, 0.15 mmol), 1-methyl-3-(pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (60.4 mg, 0.18 mmol), Pd(PPh3)4 (17.4 mg, 15 μmol), and K2CO3 (62.2 mg, 0.45 mmol). De-gassed dioxane (1.6 mL) and water (0.4 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 70% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.67 (d, J=3.6 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J=7.7 Hz, 1H), 8.19 (dd, J=8.8, 1.0 Hz, 1H), 7.87 (s, 1H), 7.60-7.45 (m, 6H), 5.17 (s, 1H), 4.34-4.08 (m, 5H), 2.61 (s, 3H), 1.25 (t, J=7.1 Hz, 3H), 0.99 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH:4][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1c(F)cc(F)cc1Br
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1c(F)cc(F)cc1Br
Reaction time: 5 h
Yield: 91.7 %

Procedure:
2-Bromo-4,6-difluoroaniline (10.4 g, Aldrich) was dissolved in dichloromethane (75 ml) and treated with pyridine (4.63 g) in an ice bath. 4-Dimethylaminopyridine (0.61 g) was then added and the mixture was allowed to warn to room temperature. After dropwise addition of pivaloyl chloride (7.23 g, BDH), the reaction was stirred for 5 hours. On completion, the mixture was added to diethyl ether (250 ml), washed twice with 2M HCI (250 ml) and the resulting organic layer was treated with saturated NaHCO3 (2×250 ml). The organic layer was washed with water (250 ml), and dried over MgSO4. Removal of the solvent from the filtrate gave the crude title product as a white solid (13.40 g).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](=[O:35])[NH:27][C:26]1=[O:36]>C(O)C>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH:8]2[CH2:9][CH2:10][N:11]([CH2:22][CH2:23][CH2:24][N:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28](=[O:35])[NH:27][C:26]3=[O:36])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: O=c1[nH]c(=O)n(CCCCl)c2ccccc12
Solvent: CCO
Product: O=c1[nH]c(=O)n(CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)c2ccccc12

Procedure:
2.7 g (0.01 mole) of 4-(diphenylhydroxymethyl) piperidine, 1.2 g (0.005 mole) of 1-(3-chloropropyl)-2,4(1H,3H)-quinazolinedione in 75 ml of ethanol are heated at reflux temperature for 7 h.
Reaction SMILES: FC1C=C(C=CC=1SC#N)N.[C:12]([NH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29][C:30](C3C=CC=CC=3)(C3C=CC=CC=3)[C:31]3C=CC=CC=3)=[C:25]([F:49])[CH:24]=2)[CH2:18]1)(=[O:14])[CH3:13].BrCC[Cl:53]>CN1CCCC1=O>[C:12]([NH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH2:30][CH2:31][Cl:53])=[C:25]([F:49])[CH:24]=2)[CH2:18]1)(=[O:14])[CH3:13]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Reactant: ClCCBr
Agent: N#CSc1ccc(N)cc1F
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(SCCCl)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
Prepared according to the General Procedure for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-ones (Example 6) from 5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)thio-3′-fluorophenyl]-oxazolidine-2-one with 1-bromo-2-chloroethane (0.055 g, 0.38 mmol) in N-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t. for 2 h. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.047 g (72%). MS (m/z): 347 [M+H]+.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=[O:11].[H-].[Na+].I[CH3:15].O>CN(C)C=O>[CH3:15][N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=[O:11]
Reactant: CI
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2sccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.60 (21.3 mmol) 1H-Thieno(3,2-d)(1,3)oxazine-2,4-dione were dissolved in dried dimethylformamide and cooled to 0° C. 664 mg (27.7 mmol) sodium hydride was slowly added (Argon) and the mixture was stirred for 30 min at 0° C. and 30 min at room temperature. After cooling again to 0° C. 3.93 g (1.73 ml, 27.7 mmol) iodomethane were added. After stirring for 1 h at room temperature 200 ml water were added. The residue was filtrated and washed with water and ethyl ether.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.[C:12]([O-:15])([O-])=[O:13].[Na+].[Na+]>C1COCC1.O>[O:11]=[C:8]1[CH2:9][CH2:10][C:5]2([CH2:1][N:2]([C:12]([O:15][C:5]([CH3:6])([CH3:1])[CH3:4])=[O:13])[CH2:3][CH2:4]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CCNC2)CC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.9 %

Procedure:
To a solution of 2-azaspiro[4.5]decan-8-one (10 g, 65.26 mmol) in a mixture of THF and H2O (3/1 (v/v), 200 mL) were added (Boc)20 (28.48 g, 130.53 mmol) and Na2CO3 (13.83 g, 130.53 mmol). The reaction mixture was stirred at rt for 2 h, then quenched with H2O (200 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (500 mL), dried over Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the product as colorless oil (9 g, 54.5%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[NH:13][C:12]2=[O:22])=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>CN(C)C=O>[O:21]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[CH:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:4][CH:5]=2)[C:12](=[O:22])[NH:13]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NC(=O)c2ccccc2C1=CNc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCc1ccc(NC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
To a suspension of 4-[(4-Hydroxymethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (294 mg, 1 mmol) in N,N-dimethylformamide (10 mL) is added methanesulfonyl chloride (0.77 mL, 10 mmol) and triethylamine (2.79 mL, 20 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. The crude product, methanesulfonic acid 4-[(1,3-dioxo-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-benzyl ester (304 mg), thus obtained is used as such for the next reaction.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][CH:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nccc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nccc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2yloxymethyl)-pyrazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M73) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (109 mg).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:3])[CH3:2].CI.[C:26](=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]([N:4]([CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH3:26])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2=C(CC(C)NC(C)C)C(=O)NCCC2)cc1
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COc1ccc(C2=C(CC(C)N(C)C(C)C)C(=O)NCCC2)cc1

Procedure:
The mixture of 8.23 g of 3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 2.25 ml of methyl iodide, 3.59 g of potassium carbonate and 100 ml of absolute ethanol is refluxed for five hours and evaporated. The residue is suspended in 100 ml of water and the suspension extracted with diethyl ether. The extract is dried, evaporated and the residue crystallized from ethanol-water to yield the 3-[2-(N-isopropyl-N-methylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 86°-88°.