Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1)([CH2:5][CH:6]([C:11](=[O:27])[NH:12][CH:13]([C:23](=[O:26])[NH:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][P:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1)([CH2:5][CH:6]([C:11](=[O:27])[NH:12][CH:13]([C:23](=[O:26])[NH:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(N)c1)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(NCc2ccccc2)c1)OC
Yield: 74.7 %

Procedure:
(3-Aminobenzyl){2-[2-(4-methoxyphenyl)-1-methylcarbamoyl ethylcarbamoyl]-4-methylpentyl}phosphinic acid methyl ester (prepared as described in Example 4/Step A) (150 mg, 0.30 mmole), benzaldehyde (38 mg, 0.36 mmole), sodium cyanoborohydride (23 mg, 0.357 mmole) and acetic acid (1 drop) in methanol were stirred at room temperature for 3 hours. The reaction was quenched with 1N hydrochloric acid (few ml's) and the reaction mixture concentrated. The residue was dissolved in ethyl acetate (20 ml) and washed with 1N hydrochloric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and dried with magnesium sulfate. Filtration and concentration gave the crude product which was purified by chromatography (3:97--methanol:methylene chloride) yielding 133 mg (75%) of (3-Benzylamino benzyl)-{2-[2-(4-methoxyphenyl)-1-methylcarbamoylethylcarbamoyl]-4-methylpentyl}phosphinic acid methyl ester as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1.[NH4+].[Cl-]>>[CH3:7][C:6]1[N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]2)[N:4]=[CH:3][C:2]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1[C@H]1CC[C@H](N)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@H](N)CC1
Reaction time: 1 h

Procedure:
To a solution of trans-4-(4-iodo-5-methyl-1H-pyrazol-1-yl)cyclohexanamine (170.0 mg, 0.5571 mmol) in THF (4 mL, 60 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (1.7 mL, 2.2 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.46 mL, 2.8 mmol), and allowed to stir at rt for 2 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound, and was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(I)c4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 606.2 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:8][C@@H:9]1[C@@H:26]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][C@@:24]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][C@H:17]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:18]2=[O:34])[CH2:10]1)(=[O:7])[CH:4]([CH3:6])[CH3:5].O>C(Cl)Cl.CO>[C:3]([O:8][C@@H:9]1[C@@H:26]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:25][C@@:24]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][C@H:17]([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[C@@H:18]2[OH:34])[CH2:10]1)(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C[C@@H]1N1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)C(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C[C@@H]1N1CCCCC1
Yield: 40.5 %

Procedure:
Sodium borohydride (16 g) was added to a stirred solution of 3α-isobutyroxy-2β,16β-dipiperidino-5α-androstan-17-one (51.6 g) in methylene dichloride (150 ml) and methanol (150 ml) and the reaction mixture was stirred for a further hour. Water was added, the product extracted with ether, and the extract washed well with water and dried. Concentration of the ether solution yielded 2β,16β-dipiperidino-5α-androstan-3α,17β-diol 3-isobutyrate (21 g) which was recrystallised from ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:12])[C:9]([OH:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>ClCCl.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:12][C:21](=[O:22])[NH:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(O)[C@H](O)c1ccccc1Cl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](C(=O)O)c1ccccc1Cl
Reaction time: 16 h
Yield: 88.2 %

Procedure:
1 g (5 mmol) of (R)-(2-chlorophenyl)hydroxyacetic acid are dissolved in 10 ml of dichloromethane, and 0.77 g (5 mmol) of 4-chlorophenyl isocyanate and 50 mg of dibutyltin dilaurate are added successively, and the mixture is stirred for 16 hours. Conventional work-up gives 1.5 g of (R)-(2-chlorophenyl)(4-chlorophenylcarbamoyloxy)acetic acid.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:22])([F:21])[S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:11][C:12]([S:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)([F:22])[F:21]
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: O=C(O)c1ccncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(SC(F)(F)F)cc1
Temperature: -78 °C
Yield: 10 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and 4-(trifluoromethylthio)aniline (68.5 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1 M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1 M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 11.4 mg (45 μmol; 10% yield) of pure desired product. LC-MS (method V): rt=3.09 min, m/z [M+H]+ 315.
Reaction SMILES: C1COCC1.I[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].C(N(CC)CC)C.[CH:21]#[C:22][CH2:23][CH2:24][CH3:25]>C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:21]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])#[C:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCC
Reactant: Nc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 mL THF were placed in the flask and degassed with argon. Then 2.3 g (10 mmol) 2-iodo-aniline, 0.72 g (1.0 mmol) PdCl2(PPh3)2 and 0.20 g (1.0 mmol) copper iodide were added and the flask was rinsed with argon. Then 4.2 mL (30 mmol) triethylamine and 1.5 mL (15 mmol) 1-pentyne were added. The reaction mixture was stirred for 3 h at RT, diluted with diethyl ether, filtered through kieselguhr and evaporated down.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][C:10]([N:13]([CH3:15])[CH3:14])=[N:11][CH:12]=1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[F-].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:7]1[CH:8]=[N:9][C:10]([N:13]([CH3:15])[CH3:14])=[N:11][CH:12]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CN(C)c1ncc(Br)cn1
Agent: [F-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C)C)nc1
Reaction time: 2 h
Yield: 74 %

Procedure:
n-Butyl lithium (1.5 M n-hexane solution; 6.06 ml, 9.09 mmol) was added dropwise to a solution of 5-bromo-2-dimethylaminopyrimidine (1.75 g, 8.66 mmol) in tetrahydrofuran (18 ml) at −78° C. under argon atmosphere in 15 min. The mixture was stirred at the same temperature for 2 hrs. and then tri-n-butyltin chloride (2.5 ml) was added dropwise thereto. The mixture was stirred at the same temperature for 0.5 hrs. and then at room temperature for 1 hr. To the reaction mixture were added 10% aqueous potassium fluoride (50 ml) and ethyl acetate (50 ml) in turn and the mixture was stirred at room temperature for 0.5 hrs. The organic layer was separated and washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on amine silica gel (Chromatolex (trademark) NH) (n-hexane) to give 5-tri-n-butylstannyl-2-dimethylaminopyrimidine (2.65 g, 74%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[F:30][C:31]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34]>ClCCl.C(N(CC)CC)C>[F:30][C:31]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:32]=1[CH2:33][NH:34][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1
Reactant: NCc1ccc(O)cc1F
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(O)cc1F)c1cccnc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(4-fluoro-phenoxy)-nicotinic acid (20.47 g) were added anhydrous dichloromethane (200 mL), dimethylformamide (2 mL), and oxalyl chloride (2.0 M in dichloromethane, 46.10 mL) were then added. The solution was cooled in a dry ice/acetone bath. Triethylamine (24.5 mL) and 2-fluoro-4-hydroxy-benzylamine hydrochloride (7.81 g) were then added. The solution was allowed to warm to ambient temperature and stir overnight. The reaction was then diluted with 200 mL dichloromethane and washed with 100 mL water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was then taken up in a solution of tetrahydrofuran (50 mL) and methanol (25 mL). Lithium hydroxide (5.26 g) in water (25 mL) were then added to the mixture, and the reaction was allowed to stir overnight at ambient temperature. The solution was then concentrated in vacuo. The resulting residue was taken up in 100 mL water, and acidified with conc. aq. HCl to pH 4. The aqueous layer was then extracted with ethyl acetate (3×300 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo. Recrystallization from methanol yielded pure title compound (9.75 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][O:17][S:33]([CH3:32])(=[O:35])=[O:34])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(COS(C)(=O)=O)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (1.0 g) in THF (10 mL) were successively added dropwise triethylamine (1.1 mL) and methanesulfonyl chloride (0.41 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (1.2 g).
Reaction SMILES: [CH2:1]([C:3]([CH2:7][CH2:8][CH:9]=[C:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[CH:4][CH2:5]O)[CH3:2].P(Br)(Br)[Br:16]>CCOCC>[Br:16][CH2:5][CH:4]=[C:3]([CH2:1][CH3:2])[CH2:7][CH2:8][CH:9]=[C:10]([CH2:13][CH3:14])[CH2:11][CH3:12]
Reactant: BrP(Br)Br
Reactant: CCC(=CCCC(=CCO)CC)CC
Solvent: CCOCC
Product: CCC(=CCCC(=CCBr)CC)CC
Reaction time: 2 h

Procedure:
3,7-Diethylnona-2,6-dien-1-ol (4.8 g.) is dissolved in 40 ml. of ether, cooled to -50° and 2.44 g. of phosphorus tribromide in 5 ml. of ether is added over 20 minutes. The reaction mixture is stirred for two hours, poured into ice and extracted with ether. The ethereal extracts are combined, washed with 10% sodium carbonate, water and saturated sodium chloride, dried over sodium sulfate and the solvent concentrated to yield 1-bromo-3,7-diethylnona-2,6-diene.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1Br.CCCCCC.C([Li])CCC.[C:24]([C:26]1[C:31]([O:32][Si](C)(C)C)=[CH:30][CH:29]=[CH:28][N:27]=1)#N.C([O:39]CC)C>>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[C:24]([C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:39]
Reactant: COCOc1ccc(C)cc1Br
Reactant: CCOCC
Reactant: C[Si](C)(C)Oc1cccnc1C#N
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1ccc(O)c(C(=O)c2ncccc2O)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-bromo-4-methylphenol methoxymethyl ether (9.49 g) in diethyl ether (170 ml) was cooled to -78° C. To the solution was added dropwise a 1.6M solution of n-butyl lithium hexane solution (30 ml) under argon atmosphere. The mixture was stirred for 45 minutes, to which was then added dropwise 2-cyano-3-trimethylsilyloxy pyridine (8.13 g) at -78° C. Then, the cooling bath was removed, and the mixture was stirred for 3 hours while warming up to room temperature. To the reaction mixture was added methanol (10 ml) to quench the reaction, then the solvent was distilled off under reduced pressure. To the residue were added methanol (100 ml), THF (25 ml) and 2N HCl (60 ml). The mixture was stirred overnight at room temperature, which was then heated for 2 hours under reflux. The reaction mixture was cooled by aeration, which was neutralized with an aqueous solution of sodium hydroxide, which was concentrated, followed by extraction with ethyl acetate. The extract was dried (anhydrous magnesium sulfate), then the solvent was distilled off, and the residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(2-hydroxy-5-methylbenzoyl)-3-hydroxypyridine (7.72 g) (Compound A-4), whose physical properties and spectrum data are shown in Table 1 and Table 3.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[NH3:12]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH2:12])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: N
Product: Cc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of methyl 6-methylnicotinate (13.9 g) and 28% aqueous ammonia (140 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 8.98 g, 72%). 1H-NMR (CDCl3) δ: 2.63 (3H, s), 5.60-6.20 (2H, brm), 7.25-7.28 (1H, m), 8.04-8.07 (1H, m), 8.90 (1H, d, J=2.1 Hz).
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[Br:15]N1C(=O)CCC1=O>CS(O)(=O)=O>[Br:15][C:2]1[C:1](=[O:14])[C:13]2[C:5](=[CH:4][CH:3]=1)[C:6]1[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=2
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CS(=O)(=O)O
Product: O=C1C(Br)=CC=C2C1=Cc1ccccc12
Temperature: 25 °C

Procedure:
Fluorenone (41 grams (g); 0.228 mol) was dissolved in 225 milliliters (ml) of methanesulfonic acid and treated portion wise at room temperature with solid N-bromosuccinimide (NBS) (38.55 g; 0.217 mol). The mixture became dark and warm, and the temperature was maintained below 60° C. by controlling the rate of NBS addition. Upon completion of the NBS addition, the mixture was allowed to cool to room temperature and was poured into 1 liter of ice water. The yellow solid that separated was collected by filtration, washed with copious quantities of water, air dried, and then recrystallized from about 1.5 liters of ethanol. The yield was 40 g (71%) and the product contained 5-10% of 2,7-dibromofluorenone as indicated by LC analysis. A small sample was purified by column chromatography, but in general the contaminated material was carried on in subsequent steps.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2.C(=O)([O-])[O-].[K+].[K+].[CH:21](I)([CH3:23])[CH3:22].CN(C=O)C>O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:21]([CH3:23])[CH3:22])[CH:9]=[C:8]2[C:3]=1[C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2
Reactant: Cc1cc(=S)c2c(O)cc(O)cc2o1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(=S)c2c(O)cc(OC(C)C)cc2o1
Yield: 88.3 %

Procedure:
6.88 g of 5,7-dihydroxy-2-methylthiochromone (30.35 mmol), 12.56 g of potassium carbonate (91.05 mmol), 6.07 ml of isopropyl iodide (60.70 mmol) and 150 ml DMF were stirred at 60° C. for 30 minutes. After addition of water, the reaction solution was extracted twice with ethyl acetate, and the organic layer was washed with saturated NaCl water and was then dried over sodium sulfate anhydride. The solvent was distilled off under reduced pressure, and the crude product was purified by flash column chromatography (hexane : ethyl acetate=4 : 1), to give 6.71 g of 5-hydroxy-7-isopropoxy-2-methylthiochromone (83% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1.C(O)C.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
tert-Butyl 3-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I25) (0.302 g, 0.508 mmol) was dissolved in EtOAc (12 mL) and absolute ethanol (8 mL) under an atmosphere of nitrogen. 10% Pd/C (0.250 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours after which the catalyst was removed by filtration through Celite and the solvent was removed in vacuo. The resulting solid was again dissolved in EtOAc (12 mL) and absolute ethanol (8 mL) under an atmosphere of nitrogen and 10% Pd/C (0.250 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 24 hours. The catalyst was removed by filtration through Celite, which was washed with EtOAc (7×10 mL) and the solvent was removed in vacuo to give a pale yellow viscous oil. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I26) (0.249 g, 82% yield) as a pale yellow viscous oil; 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 8.67 (s, 1H), 7.72-7.64 (m, 2H), 7.26-7.16 (m, 6H), 4.02-3.89 (m, 2H), 3.76 (s, 2H), 3.57 (s, 3H), 3.10-2.95 (m, 4H), 2.91-2.66 (m, 2H), 2.61-2.51 (m, 1H), 1.88 (d, J=11.8 Hz, 1H), 1.75-1.54 (m, 2H), 1.43 (m, 10H). LCMS Method C: rt 7.11 min; m/z 599.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:23])[C:10]2[C:5](=[CH:6][C:7]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:8](O)[CH:9]=2)[C:4]([F:22])([F:21])[O:3]1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.C1(C)C=CC=CC=1>[F:21][C:4]1([F:22])[C:5]2[C:10](=[CH:9][C:8]3[O:20][C:13]([C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)=[N:12][C:7]=3[CH:6]=2)[C:2]([F:23])([F:1])[O:3]1
Reactant: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: FC1(F)OC(F)(F)c2cc3oc(-c4ccncc4)nc3cc21
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
To a mixture of 1.34 g of N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide, 10 ml of tetrahydrofuran and 1.07 g of triphenylphosphine, 2.67 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. After 30 minutes, 1.07 g of triphenylphosphine was added, 2.67 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise thereto and stirred for further two hours. Water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and the resultant solid was recrystallized to give 0.14 g of 5,5,7,7-tetrafluoro-2-pyridin-4-yl-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 16”).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:20]=[CH:19][C:15]2=[N:16][S:17][N:18]=[C:14]2[CH:13]=1)C.Cl>O1CCCC1.[Li+].[OH-].O>[N:16]1[S:17][N:18]=[C:14]2[CH:13]=[C:12]([O:11][C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:21])=[O:3])[CH:20]=[CH:19][C:15]=12
Reactant: CCOC(=O)c1cccnc1Oc1ccc2nsnc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1Oc1ccc2nsnc2c1
Yield: 23.4 %

Procedure:
A solution of 2-(benzo[2,1,3]thiadiazol-5-yloxy)-nicotinic acid ethyl ester (0.74 g, 2.5 mmol) in tetrahydrofuran (2.78 ml) and 1 M LiOH (2.7 ml) was stirred over night. The mixture was diluted with water and then acidified to pH 1 with 2 N hydrochloric acid, and thereafter filtered to give a pale yellow solid (160 mg).