Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1.NN.CCOCC>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](Oc2cc(N3CCOCC3)cc3nccnc23)CC1
Agent: NN
Solvent: CO
Solvent: CCOCC
Product: N[C@H]1CC[C@@H](Oc2cc(N3CCOCC3)cc3nccnc23)CC1
Reaction time: 0.5 h

Procedure:
As shown in step 9-iii of Scheme 9, to a suspension of 2-[(cis)-4-(7-morpholinoquinoxalin-5-yl)oxycyclohexyl]isoindoline-1,3-dione (2.3 g, 5.02 mmol) in MeOH (25 mL) was added hydrazine (321 mg, 315 μL, 10.0 mmol) and the reaction mixture stirred for 18 hours at RT, over which time the initial suspension became homogenenous followed by the appearance of a precipitate. Et2O (30 mL) was added and the reaction mixture stirred an additional 30 minutes. The precipitates were filtered off, the filtrate concentrated under reduced pressure, the residue treated with DCM (30 mL), and any remaining solids removed by filtration. The filtrate was concentrated under reduced pressure to provide (cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexanamine (compound 1030), which was used as is in subsequent reactions: 1H-NMR (300 MHz, CDCl3) δ 8.69 (d, J=1.9 Hz, 1H), 8.62 (d, J=1.9 Hz, 1H), 6.95 (d, J=2.5 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 5.00-4.67 (m, 3H), 4.03-3.81 (m, 4H), 3.49 (s, 1H), 3.43-3.25 (m, 4H), 2.88 (q, J=6.2 Hz, 2H), 2.36-1.96 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:6][CH:5]=1)=[O:3].[BH4-].[Na+]>C(O)C>[OH:3][CH:2]([C:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:6][CH:5]=1)[CH3:1]
Reactant: CC(=O)c1csc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1csc2ccccc12
Temperature: 20 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To a solution of 3-acetyl thianaphthene (2.024 g, 11.5 mmol) in ethanol (15 mL) was added sodium borohydride (0.434 g, 11.5 mmol). The mixture was stirred at 20° C. for 4 hours then evaporated, diluted with brine and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and evaporated to give the intermediate title compound as a clear oil (1.924 g, 94%) which was used as is in subsequent reactions. FDMS m/e=178 (M+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:25]([C:26]2[CH2:30][CH:29]([CH2:31]Cl)[O:28][N:27]=2)=[C:24]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:23]=[CH:22][C:9]=1[C:10]([C:12]1[CH:13]=[N:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])=[O:11].Cl>CS(C)=O>[CH3:7][C:8]1[C:25]([C:26]2[CH:30]3[CH:29]([CH2:31]3)[O:28][N:27]=2)=[C:24]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:23]=[CH:22][C:9]=1[C:10]([C:12]1[CH:13]=[N:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])=[O:11]
Reactant: Cc1c(C(=O)c2cnn(C(C)(C)C)c2O)ccc(S(C)(=O)=O)c1C1=NOC(CCl)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(C(=O)c2cnn(C(C)(C)C)c2O)ccc(S(C)(=O)=O)c1C1=NOC2CC12
Reaction time: 8 h

Procedure:
At room temperature, 0.17 g (1.50 mmol) of potassium tert-butoxide was added to a solution of 0.23 g (0.51 mmol) of 4-[2-methyl-3-(5-chloromethyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-tert-butyl-1H-pyrazole in 2.5 ml of dimethyl sulfoxide, and the mixture was stirred overnight. The mixture was then stirred into 300 ml of 3% strength aqueous hydrochloric acid, the aqueous phase was extracted three times with in each case 200 ml of ethyl acetate and the combined organic phases were washed four times with in each case 50 ml of water, dried over sodium sulfate and concentrated under reduced pressure. This gave 0.12 g (57%) of the title compound in the form of a brown solid of melting point 69-74° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[O:18][C:17](=[O:19])[C:16]([C:20](=[O:23])[CH2:21][CH3:22])=[C:15]([OH:24])[CH:14]=1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CC(O)=O.C1COCC1.O>[OH:24][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[O:18][C:17](=[O:19])[C:16]=1[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)c1c(O)cc(CCCCO[Si](C)(C)C(C)(C)C)oc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(=O)c1c(O)cc(CCCCO)oc1=O

Procedure:
6-(4-((t-Butyldimethylsilyl)oxy)butyl)-4-hydroxy-3-propionyl-2H-pyran-2-one (XIV; 5 g; 14.1 mmol) in 150 ml AcOH/THF/water (3/1/1, v/v/v) was stirred at 28° C. for 18 h. The reaction mixture was neutralized with saturated NaHCO3, extracted with 3×150 ml EtOAc, dried with Na2SO4, and evaporated to an oil. The product was purified via silica chromatography (40% EtOAc in hexanes).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH2:15]=[C:16]([CH2:19][OH:20])[CH2:17][OH:18]>>[OH:18][CH2:17][C:16](=[CH2:15])[CH2:19][O:20][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7]
Reactant: C=C(CO)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: C=C(CO)COc1cccc([N+](=O)[O-])c1C#N
Yield: 55 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and 2-methylenepropane-1,3-diol in 55% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.93 (dd, J=8.4 Hz, J=0.8 Hz, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.73 (dd, J=7.6 Hz, J=0.8 Hz, 1H), 5.23-5.29 (m, 2H), 5.03 (t, J=5.6 Hz, 1H), 4.85 (s, 2H), 4.06 (d, J=5.2 Hz, 2H). |ΠατAππ1009—Λ1|ZZMΠTAΓ|
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:16]([Cl:15])=[O:18])[CH:12]=[CH:13][CH:14]=1
Reactant: Fc1cccc(Nc2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N(c1ccccc1)c1cccc(F)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 3 liter three-neck mechanically stirred flask under N2 containing a solution of 3-fluoro-N-phenylaniline (86 g, 460 mmol) in 1.2 L dichloromethane was cooled in an ice bath to 0° C., and then triphosgene (150 g, 505 mmol) was added. A solution of pyridine (52 mL, 640 mmol) in dichloromethane (200 mL) was added in a dropwise fashion. Initial addition resulted in a temperature spike to 25° C. after the first 10 mL had been added over 10 min. The addition was paused, and the reaction mixture was stirred for 1 h while cooling to 5° C. Addition of the pyridine solution was again commenced at a rate of 5 mL/min, at which a reaction temperature of 5-10° C. was maintained. After addition was complete (about 1 h), the reaction had proceeded to completion, and was quenched by the slow addition of ice water (500 g). Gas formation from the quench was controlled by adjusting the stirring speed, as decomposition was largely a function of the mixing of the two immiscible layers. Gas effluent was passed through a 20% sodium hydroxide trap, until all gas evolution had ceased (about 3 h). The aqueous layer was removed, and was then extracted with an additional 300 mL of dichloromethane. The organic extracts were combined, dried over MgSO4, and the solvent was removed. Clean product was readily isolated as a viscous, pink oil, which gradually formed a pale pink solid upon seeding with crystals. LCMS m/z (%)=250.0 [M+H]+; 1H NMR (CDCl3, 400 MHz) δ 7.00-7.07 (m, 1H), 7.10 (d, J=9.6 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.35 (d, J=7.7 Hz, 2H), 7.35-7.41 (m, 2H), 7.42-7.48 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C@H:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:25](=O)(ON1C(=O)CCC1=O)[O:26]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:25]1=[O:26]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1F)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2F)C1=O)C(C)(C)C
Yield: 101.1 %

Procedure:
A solution of Example 135A (183 mg, 0.54 mmol) and disuccinimidyl carbonate (0.165 g, 0.645 mmol) in dichloromethane (3 mL) was treated with triethylamine (90 uL, 0.645 mmol) at 25° C. for 16 h. The mixture was partitioned between 10% sodium carbonate and dichloromethane. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to give the crude title compound (199 mg, crude yield).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]>CO.[Rh]>[C:1]([OH:11])(=[O:10])[C@H:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[OH:3]
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: [Rh]
Solvent: CO
Product: O=C(O)[C@@H](O)C1CCCCC1

Procedure:
(S)(+)-Mandelic acid (76.0 g) was dissolved in 440 ml methanol containing 5 ml glacial acetic acid. The phenyl ring was entirely reduced in the presence of 5 gm. of 5% rhodium-on-alumina catalyst under 100 psi H2 pressure in 10 hrs. Following filtration of the solution through Celite® (diatomaceous earth) to remove the catalyst, the methanol was removed via a rotary evaporator. The resulting white solid was dissolved in 1 liter (l) of hot diethyl ether and filtered while hot. The volume of the solution was reduced to 400 ml and 250 ml cyclohexane was added. The ether was then removed and the resultant cyclohexane solution was stored several hours under refrigeration. White crystals of the desired product formed and were collected via filtration. The solid was dried overnight in vacuo at 40° C. Seventy-one grams of (S)(+)-hexahydromandelic acid were obtained for a 90% yield: m.p. 128°-129° C. (lit., 129° C.) and [α]D23 =+23.5° (1, HOAc) (lit. [α]D23 =+25.5 (1.1, HOAc) for the (R) (+) isomer.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1O[CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13].ClC1C2C(=CC=CC=2)C=CC=1[S:35]CCNCC1SC=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[S:35][CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13]
Reactant: Clc1c(SCCNCc2cccs2)ccc2ccccc12
Reactant: O=S(=O)(CCNCc1ccco1)c1ccc2ccccc2c1Cl
Product: O=S(=O)(CCNCc1cccs1)c1ccc2ccccc2c1Cl
Yield: 68 %

Procedure:
Prepared as described for compound 25 from 2-[(1-chloronaphthalen-2-yl)sulfanyl]-N-(thiophen-2-ylmethyl)ethanamine in 68% yield as yellow solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[NH:8][C:9](=O)[C:10]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:13][C:11]=2[N:12]=1)[CH:2]([CH3:4])[CH3:3].N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:38]>C(Cl)(Cl)Cl>[Cl:38][C:9]1[C:10]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:13][C:11]=2[N:12]=[C:7]([CH2:6][O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[N:8]=1
Reactant: CC(C)COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: CC(C)COCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Reflux a mixture of 2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one (0.510 g, 1.35 mmol), 2,6-lutidine (0.62 mL), and POCl3 (0.50 mL) in CHCl3 (10 mL) for 16 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine as yellow viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)cn1
Product: COc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 50.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g) and (4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.35 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH:3]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:25])=[CH:22][CH:21]=1)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:9][CH:10]=1.C1COCC1.[OH-].[Na+]>CO>[CH3:1][C:2]([CH3:36])([CH3:35])[CH:3]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:22][CH:21]=1)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A 20 drams vial was charged with methyl (±)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido)propanoate (92 mg, 0.18 mmol), THF (1.8 mL) and MeOH (1.8 mL). NaOH 1M aq. (0.9 mL) was then added in one portion and the resulting mixture stirred for 30 minutes at room temperature. Organic solvents removed under reduced pressure and 5 mL of water added to the vial. Under magnetic stirring, citric acid solution (10%, aq.) added dropwise to reach ca. pH 3. The solid formed was recovered with a büchner funnel, washed with water and dried under high vacuum to provide (±)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido)propanoic acid as a white solid (76.9 mg, 86.0%). 1H NMR (400 MHz, DMSO-d6) δ 0.98 (s, 9H) 2.44-2.48 (m, 2H) 3.38-3.47 (m, 2H) 4.33 (d, J=8.22 Hz, 1H) 6.54 (d, J=8.41 Hz, 1H) 7.17 (dd, J=8.90, 2.84 Hz, 1H) 7.44 (d, J=8.22 Hz, 2H) 7.55 (d, J=9.00 Hz, 1H) 7.74 (d, J=8.41 Hz, 2H) 7.84 (d, J=2.54 Hz, 1H) 8.08 (s, 1H) 8.44 (t, J=5.28 Hz, 1H) 8.84 (s, 1H) 12.18 (br. s., 1H); MS (M+1): 490.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:22]=1[CH2:23]O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:47])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:22]=1[CH2:23][F:47])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CO)c1OCc1cccc(C#N)c1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CF)c1OCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of [5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (106) (51.1 g, 0.10 mol) in dry dichloromethane (700 mL) was slowly added bis(2-methoxyethyl)aminosulfur trifluoride (39.7 g, 0.18 mol) at 0° C. under nitrogen atmosphere. The reaction was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a gradient mixture of dichloromethane:acetone (1:0 to 18:1) as an eluant to give [5-(3-cyano-benzyloxy)-4-fluoromethyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (107) (41.3 g, 80% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:9]=[CH:8][C:7]([PH:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)[CH3:2].[BH3:25].O1CCCC1>O1CCCC1>[CH2:20]([N:17]([CH2:18][CH3:19])[C:14]1[CH:13]=[CH:12][C:11]([PH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:23][CH3:24])[CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1)[CH3:21].[BH3:25]
Reactant: CCN(CC)c1ccc([PH](=O)c2ccc(N(CC)CC)cc2)cc1
Agent: B
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(Pc2ccc(N(CC)CC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
Under a nitrogen stream, to a solution of bis(4-diethylaminophenyl)phosphine oxide (3.76 g, 10 mmoL) synthesized in Example 10 in tetrahydrofuran (35 mL) was added borane-tetrahydrofuran solution (35 mL, 3.3 equivalents) at 25° C. to 30° C. over 2 hr. Then, silica gel (6.3 g, 9.7 equivalents) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. Then, silica gel was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from n-hexane/ethyl acetate (1/1) to give the title compound (1.8 g, white crystals). yield 49%. melting point 108.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:18]=1)=[O:22]
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NCC(F)(F)F)s1
Yield: 79 %

Procedure:
As described for example 22b, 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (72 mg, 79%) which was obtained as an off white solid MS: m/e=397.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:1][C:2]2[C:3]([C:8]([O:10][CH2:18][C:17]3[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=3)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C(O)c1ncccc1O
Agent: [H-]
Agent: [Na+]
Product: O=C(OCc1ccc(Cl)cc1)c1ncccc1OCc1ccc(Cl)cc1

Procedure:
8.4 g (60 mmol) of 3-hydroxypyridine-2-carboxylic acid were alkylated (3 h, 110° C.) with 5.2 g (approximately 130 mmol, 60%) of sodium hydride and 19.3 g (120 mmol) of 4-chlorobenzyl chloride in N,N-dlmethylacetamide in analogy with Example 30a). After concentration in vacuo and extraction with Na bicarbonate solution, the residue was purified on silica gel using heptane/ethyl acetate (1:1), and 14.8 g of the product were crystallized from appropriate fractions using diisopropyl ether, m.p. 92°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:11]O)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O=S(Cl)[Cl:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:11][Cl:15])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COc1ccnc(CO)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccnc(CCl)c1OC
Temperature: 25 °C
Yield: 162.6 %

Procedure:
3,4-Dimethoxy-2-hydroxymethylpyridine (0.34 g, 0.002 mol) was dissolved in CH2Cl2 (8 ml). SOCl2 (0.27 g, 0.00227 mol) in CH2Cl2 (2 ml) was added under stirring at room temperature. After 10 min the mixture was neutralized with NaHCO3 (5 ml). The phases were separated, the CH2Cl2 phase was washed with NaCl-solution, dried over Na2SO4 and evaporated giving the desired product (0.61 g, 88%).
Reaction SMILES: [F:1][C:2]1[C:20]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15](N)=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[OH2:28]>>[F:1][C:2]1[C:20]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:28])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(N)=O)cn4C)CC1
Reactant: O
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CC1
Temperature: 20 °C

Procedure:
7-Fluoro-8-(4-methyl-1-piperazinyl)-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Application Example 2, but starting with 0.3 g of 7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxamide. After cooling to approximately 20° C., the reaction mixture is treated with 50 cm3 of water; the insoluble matter is drained and washed with twice 10 cm3 of water.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[N+:13]([O-])=O.N#N>C(O)C.[Pd]>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][NH:4][C:5]1[C:6]([NH2:13])=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COc1ccc(NCC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: COc1ccc(NCC(C)(C)C)c(N)c1

Procedure:
N-(2,2-Dimethylpropyl)-4-methoxy-2-nitroaniline (3) (15.3 g, 64.2 mmol, 1.0 equiv.) was dissolved in ethanol (200 ml). After purging the reaction mixture with N2, 10% palladium on carbon (13.67 g, 12.84 mmol, 0.2 equiv.) was added. The mixture was sparged under an atmosphere of hydrogen (1 atm) at room temperature. When LCMS showed completion of the hydrogenation, the mixture was filtered through Celite filter. The Pd/C residue was washed thoroughly with MeOH. The filtrate was then concentrated in vacuo to give N1-(2,2-dimethylpropyl)-4-methoxybenzene-1,2-diamine (4) as a dark red oil. LRMS m/z (M+H) 209.0 found, 209.2 required.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([NH2:32])[CH2:30][CH3:31]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:32][CH2:29][CH2:30][CH3:31])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: CCCN
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NCCC)C1(C)C

Procedure:
The product from Example 173 and propylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.83 (t, J=7.3 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.26-1.43 (m, 5H), 1.56 (s, 9H), 1.56-1.67 (m, 3H), 1.96-2.09 (m, 1H), 2.62-2.69 (m, 3H), 2.72-2.95 (m, 2H), 3.06-3.17 (m, 1H), 7.53-7.57 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 436 (M+H)+. Anal. calcd. for C24H41N3O2S: C, 66.16; H, 9.49; N, 9.65. Found: C, 65.76; H, 9.51; N, 9.68.