Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[CH:5]=O.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[C:23]=1[NH2:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[C:23]=3[N:29]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1
Reactant: CN1CCN(CCCOc2ccc(C=O)cc2F)CC1
Reactant: Cc1cccc(N)c1N
Product: Cc1cccc2[nH]c(-c3ccc(OCCCN4CCN(C)CC4)c(F)c3)nc12
Yield: 100 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (94 mg, 0.34 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine (42 mg, 0.34 mmol, 1.0 equiv), and Na2S2O5 (84 mg, 0.44 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 130 mg (100%) of the title compound. MS (electrospray): mass calculated for C22H27FN4O, 382.22; m/z found, 383.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.86-7.78 (m, 2H), 7.40-7.37 (m, 1H), 7.12-6.97 (m, 3H), 3.99 (t, J=6.1 Hz, 2H), 3.00-2.30 (m, 13H), 2.25 (s, 3H), 1.94-1.90 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:33][CH2:32][C:26]4([C:30](=[O:31])[NH:29][CH2:28][CH2:27]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]3([C:30](=[O:31])[NH:29][CH2:28][CH2:27]3)[CH2:32][CH2:33]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC3(CCNC3=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CCNC4=O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 8-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-2,8-diazaspiro[4.5]decan-1-one were reacted to give 379. LCMS m/z 258.6 (2M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.CC(C)([O-])C.[K+].C1(C)C=C(C)C=C(C)[C:17]=1[S:24]([O:27][NH2:28])(=[O:26])=[O:25].CS(O)(=O)=O>CO.ClCCl>[CH3:17][S:24]([OH:27])(=[O:26])=[O:25].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][NH2:28])=[C:4]([I:9])[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Oc1ccc(Br)cc1I
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: NOc1ccc(Br)cc1I
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
To a solution of product of step A (10.0 g, 33.4 mmol) in methanol (100 mL) at 0° C. was added potassium tert-butoxide (2.59 g, 23.1 mmol) portionwise and the mixture stirred for 40 min. The reaction mixture was concentrated in vacuo, and suspended in dichloromethane. To the suspension was added a solution of O-(mesitylsulfonyl)hydroxylamine (5.53 g, 33.4 mmol) in dichloromethane at 0° C. and the reaction stirred for 1 h. The mixture was then washed with cold 5% KOH solution and dried over anhydrous sodium sulfate. The organic layer was treated with methanesulfonic acid (1.75 mL, 26.72 mmol) then concentrated in vacuo to give crude O-(4-bromo-2-iodophenyl)hydroxylamine methanesulfonic acid salt (8.0 g, 58%) as a brown solid. CAUTION: This compound has potential to be shock sensitive and may be susceptible to decomposition. It should be handled with care and used directly without storage.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([C:29]4[CH:30]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:32]=[CH:33][CH:34]=4)[OH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CCO.[OH-].[Na+]>C1COCC1>[C:31]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:32]=[CH:33][CH:34]=[C:29]([CH:27]([OH:28])[C:22]2[C:23]([CH3:26])=[N:24][O:25][C:21]=2[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[CH:30]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(-c5ccccc5)c4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C(O)c1cccc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-{4′-[4-(biphenyl-3-yl-hydroxy-methyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (1 equivalent) was dissolved in THF then EtOH and NaOH (3N aq., 3 equivalents) was added and the reaction stirred at 60° C. overnight. The reaction was worked up and purified via preparatory HPLC (0.1% TFA/H2O/ACN).
Reaction SMILES: C(Cl)CCl.[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:15]([F:17])[F:16].[C:27]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36](O)=[O:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([CH:14]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]([F:17])[F:16])=[C:7]([CH:12]=1)[CH2:6][NH:5][C:36](=[O:37])[C@@H:35]1[CH2:39][CH2:40][CH2:41][N:34]1[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CN)C(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Yield: 50.9 %

Procedure:
EDC (0.171 g, 1.25 mmol) was added to a stirred mixture of N-{1-[2-(aminomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.314 g, 0.96 mmol), N-BOC-L-proline (0.207 g, 0.96 mmol) and HOAT (0.171, 1.25 mmol) in DMF (2.0 mL). After 18 h the mixture was partitioned between EtOAc and water. The organic layer was washed with 1M citric acid, saturated aqueous NaHCO3 and brine, dried (Na2SO4) and reduced in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 10-50% ethyl acetate/hexanes gradient) to give N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (0.256 g) as a foam; LC-MS m/z=524.3.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:14][CH2:13][CH2:12][O:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: COCCN
Product: COCCNCc1cccc(Br)n1
Yield: 93.7 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 18, Step C, using 6-bromo-pyridine-2-carbaldehyde (0.275 g, 1.48 mmol) and 2-methoxy-ethylamine (0.111 g, 1.48 mmol). The crude product was purified (SiO2: 0-5% MeOH/DCM) to yield the title compound (0.34 g, 94%).
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C@H:9]3[CH2:14][S:13](=[O:15])[CH:12]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=4[F:24])[C@@H:11]([NH:25]C(=O)OC(C)(C)C)[CH2:10]3)[CH2:6][C:5]=12.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C@H:9]3[CH2:14][S:13](=[O:15])[CH:12]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=4[F:24])[C@@H:11]([NH2:25])[CH2:10]3)[CH2:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3c[nH]nc3C2)CS(=O)C1c1cc(F)cc(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2Cc3c[nH]nc3C2)CS(=O)C1c1cc(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
tert-Butyl N-[(3S,5R)-5-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)-1-oxo-2-(2,3,5-trifluorophenyl)thian-3-yl]carbamate was dissolved in a mixture of TFA (0.02 mL) and methylene chloride (0.2 mL). After stirring at RT for 105 min, the solvents were evaporated and the residue was freeze-dried from a mixture of benzene and ethanol to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12]SC2=O)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH2:21][CH2:20]1>CN(C)C=O>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[CH:12][C:13]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)=[O:14])[CH2:21][CH2:20]1
Reactant: O=C1CSC(=O)N1c1ccc(C(F)(F)F)cc1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccccc2C=CC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame-dried 3-neck round bottom flask equipped with a magnetic stir bar, sodium hydride (50 mg, 1.25 mmol of a 60% oil dispersion) was washed with hexane and covered with 6.0 mL of anhydrous dimethylformamide (DMF). To this was added a solution of 3-(4-trifluoromethylphenyl)-thiazolidine-2,4-dione (240 mg, 0.92 mmol) and 2-(4-methylpiperazin-1-yl)benzaldehyde (170 mg, 0.84 mmol) in 2 mL of DMF. After stirring at room temperature overnight the mixture was heated to reflux for 4 hours and cooled. The solvent was removed in vacuo and the residue partitioned between saturated aqueous ammonium chloride and chloroform. The organic layer was washed with saturated NaCl, dried and filtered. The residue was absorbed onto silica gel (640 mg) and flash chromatographed on a 4×0.75 in column eluting with ethyl acetate: hexanes (3:1) followed by 100% ethyl acetate. The crude product oil was dissolved in hot EtOAc and allowed to cool to deposit 30 mg of yellow crystals which were filtered and dried, m.p. 207-209° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=C(C2C=CC=CC=2)C(C2C=CC=CC=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([C:49]([C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH3:60])[CH:54]=2)=O)=O)[CH:46]=[CH:47][CH:48]=1>>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([C:49]2[C:51]([C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH3:60])[CH:54]=3)=[N:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([C:8]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:11]5[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=5[N:9]=4)[CH:20]=3)[N:25]=2)[CH:46]=[CH:47][CH:48]=1
Reactant: COc1cccc(C(=O)C(=O)c2cccc(OC)c2)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1
Product: COc1cccc(-c2nc3ccc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)cc3nc2-c2cccc(OC)c2)c1

Procedure:
Prepared as described for Compound 406 using 3,3′-dimethoxybenzil in place of benzil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:7][C:6]=2[CH:11]=1
Reactant: ClCCN1CCOCC1
Reactant: Sc1nc2cc(Cl)ccc2s1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ccc2sc(SCCN3CCOCC3)nc2c1
Temperature: 25 °C
Yield: 67 %

Procedure:
Dissolved in 5 ml of N,N-dimethylformamide was 1.00 g (5.0 mmol) of 5-chloro-2-mercaptobenzothiazole, and 0.26 g (10.8 mmol) of hydrogenated sodium were added to the solution, which was stirred at room temperature. One hour later, 0.93 g (5.0 mmol) of a hydrochloride of 2-chloroethylmorpholine were added to the suspension, which was then stirred for 2 hours at 80° C. The solution was diluted with 100 ml of chloroform, followed by addition of 100 ml of a 5% saline solution and washing. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 1.05 g of white crystalline powders (67% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:15])[CH2:13]Br)[CH3:10]>CC(C)=O>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([NH:1][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:15])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(N)cc1
Solvent: CC(C)=O
Product: CCOC(=O)CNc1ccc(C)cc1
Yield: 35.9 %

Procedure:
The compound was prepared according to general procedure E. To a solution of p-toluidine (4.7 mmol) in dry acetone (20 ml), ethylbromoacetate (4.7 mmol) was added. The mixture was refluxed for 3 hours. After cooling, the solvent was removed under reduced pressure. The residue was chromatogaphed on a silica gel column (dichloromethane/ethyl acetate 9/1 as eluent) to give 326 mg of ethyl 2-(p-tolylamino)acetate (yield 36%). 1H NMR (500 MHz, CDCl3): δ 1.29 (t, J=7.4 Hz, 3H), 2.28 (s, 3H), 3.90 (s, 2H), 4.26 (q, J=7.4 Hz, 2H), 6.58 (d, J=8.2 Hz, 2H), 7.05 (d, J=8.2, 2H) 13C NMR (126 MHz, CDCl3): δ 15.6, 21.8, 47.7, 62.5, 114.8, 131.2, 146.3, 172.8. MS (ESI): m/z 193.9 [M+H]+
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)=[O:2].[H][H]>C(O)C.[Pd]>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2]
Reactant: [H][H]
Reactant: O=CNNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NNC=O)cc1

Procedure:
1-Formyl-2-(4-nitrophenyl)hydrazine (10.2 g, 0.056 mole) and 10% palladium/charcoal (catalytic amount) were suspended in ethanol (500 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a white crystalline powder. Yield 7.1 g (84%), m.p. 122°-125° C.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[Br-].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:22](=O)[CH3:23]>C1(C)C=CC=CC=1.C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:22]([CH3:23])=[CH2:1]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
KHMDS(1 eq) in toluene is added dropwise over 5 minutes to a stirred suspension of triphenylphosphinemethyl bromide(1.2 eq) in THF at −78° C. under nitrogen. After complete addition solution is allowed to warm to room temperature for 5 minutes then cooled a second time to −78° C. 1-(2-fluoro-5-nitrophenyl)ethanone(1 eq) in THF is then added via cannulla into the cold suspension over 10 minutes. Resulting mixture is then allowed to warm to room temperature and stirred for 1 h. Solvent is then removed under reduced pressure, cyclohexane is then added and mixture heated briefly to reflux, cooled to room temperature, filtered and filtrate concentrated. Crude product is purified using flash chromatography(85% Hex:15% EtoAc) on silica to afford 1-fluoro-4-nitro-2-(prop-1-en-2-yl)benzene.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])(O)=O.[Na+].[CH3:19][C:20](N(C)C)=O.C(I)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(=O)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCI
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a dry 100 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet were added 3.00 g of 2-fluoro-4-nitrobenzoic acid, 3.00 g of NaHCO3, and 20 mL of anhydrous dimethylacetamide. The suspension was treated with 3.50 mL of ethyl iodide and stirred at RT under N2 for 18 h. The reaction mixture was filtered to remove solids and the filtrate concentrated in vacuo to give an orange residue which was dissolved in 100 mL of CH2Cl2. The solution was washed with saturated aqueous NaHCO3 (3×50 mL), water (1×60 mL), and dried over anhydrous Na2SO4. Removal of drying agent by filtration and passage through a silica gel plug (3×5 cm) gave a light yellow solution which was concentrated in vacuo to afford 3.10 g (90%) of ethyl 2-fluoro-4-nitrobenzoate as a light yellow crystalline solid, m.p. 70-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[C-]#N.[CH2:16]([NH:20][CH3:21])[CH2:17][CH2:18][CH3:19]>C1C=CC=CC=1>[CH2:16]([N:20]([CH3:21])[C:9]([NH:8][C:5]([CH3:7])([CH3:6])[C:4]1[CH:11]=[CH:12][CH:13]=[C:2]([Cl:1])[CH:3]=1)=[O:10])[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)(N=C=O)c1cccc(Cl)c1
Reactant: CCCCNC
Agent: [C-]#N
Solvent: c1ccccc1
Product: CCCCN(C)C(=O)NC(C)(C)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 88.7 %

Procedure:
3.9 g of m-chloro-α,α-dimethylbenzyl isocyanate prepared from the corresponding cyanide in the same way as in Synthesis Example 1, was added to a solution of 1.8 g of N-n-butyl-N-methylamine in 20 ml of benzene and the mixture vigorously stirred. After allowing the mixture to stand overnight, the reaction solution was washed with a 2N aqueous hydrochloric acid solution, a 2N aqueous sodium hydroxide solution and water in that order, and the organic layer was dried over sodium sulfate. The layer was concentrated by evaporating off the solvent to obtain crystals, which were recrystallized from n-hexane to obtain 5.0 g of the title compound as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[NH:13][C:12](=O)[C:11]([CH3:16])([CH3:15])[S:10](=[O:18])(=[O:17])[CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[NH:13][C:12](=[S:30])[C:11]([CH3:16])([CH3:15])[S:10](=[O:18])(=[O:17])[CH2:9]2)[CH:7]=1
Reactant: CC1(C)C(=O)N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)C(=S)N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 89.1 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1λ6-thiomorpholin-3-one (1.4 g, 3.84 mmol, Eq: 1.00) in dioxane (29.5 ml) was added Lawesson's reagent (3.10 g, 7.68 mmol, Eq: 2.00). The reaction mixture was stirred at 80° C. for 10 hours. The reaction mixture was poured into sat. NaHCO3-solution and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give a light yellow oil. The residue was chromatographed on 20 g silica gel with ethyl acetate in heptane to give (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1λ6-thiomorpholin-3-thione (1.3 g, 3.42 mmol, 88.9% yield) as a light yellow foam. MS (ISP): m/z=380.0 [M+H]+ and 382.3 [M+2+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=1)=[O:16])[CH2:6][CH2:5]2
Reactant: NCc1ccccn1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCc1ccccn1)O2
Yield: 85.5 %

Procedure:
Following the amide coupling procedure described in protocol A, 499 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.99 mmol), 370 mg CDI (2.28 mmol) and 324 mg 2-picolylamine (3.0 mmol), produced 579 mg of 6-hydroxy-2,5,7,8-tetramethyl-N-(pyridin-2-ylmethyl)chroman-2-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29](Br)[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:46]([O:48][CH2:49][CH3:50])=[CH2:47])CCC>C1(C)C=CC=CC=1.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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:46]([O:48][CH2:49][CH3:50])=[CH2:47])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Yield: 99.7 %

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.412 g, 0.673 mmol), tetrakis(triphenylphosphine)palladium (0.093 g, 0.081 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (0.379 g, 1.05 mmol) were dissolved in toluene (3 mL) and slowly brought to reflux for 1 hour. The solvent was evaporated and the solid was redissolved in dichloromethane (8 mL) and purified by silica gel chromatography to give 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.405 g, 99.0%). 1H NMR δ(400 MHz, CDCl3) 8.73 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J=2.9 Hz, 1H), 7.18 (m, 1H), 5.90 (m, 1H), 4.52 (d, J=2.4 Hz, 1H), 4.18 (d, J=2.4 Hz, 1H), 3.93 (q, J=7.1 Hz, 2H), 3.80 (m, 2H), 3.38 (m, 2H), 3.26 (s, 2H), 2.41 (s, 3H), 2.35 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.64 (m, 2H), 1.49 (s, 9H), 1.45 (s, 6H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[C:4]=2[CH:3]=1.N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:10]1[C:4]2[CH:3]=[C:2]([I:1])[CH:13]=[CH:12][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CON
Reactant: O=C1CCCCc2ccc(I)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCCCc2ccc(I)cc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a stirred suspension of 3-iodo-6,7,8,9-tetrahydrobenzocylohepten-5-one prepared as described in example P3a (0.806 g; 2.82 mmol) in methanol (5.7 ml) was added pyridine (0.7 ml; 9.02 mmol) followed by a portion wise addition of methoxyamine hydrochloride (0.754 g; 9.02 mmol). The reaction mixture was stirred at 20° C. for 16 h under nitrogen. The solvent was removed in vacuo to afford 0.86 g (97% of theory) of crude 3-iodo-6,7,8,9-tetrahydrobenzocylohepten-5-one-O-methyl-oxime E/Z-mixture as a brown oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35](O)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH2:16][N:17]([C:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[C:26]5[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:38])[F:39])=[CH:24][CH:25]=5)=[O:36])[CH2:18][CH:19]4[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: O=C(c1ccccc1-c1ccc(C(F)(F)F)cc1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 4′-trifluoromethyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for C30H53F3N4O, 514.56; m/z found 515.3 [M+H]+.