Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@:11]([CH2:16][S:17][CH3:18])([OH:15])[CH2:10]2)[C:5]([F:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][N:27]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:24]2=[N:25][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.O.CCOC(C)=O.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>[Cl:20][C:21]1[CH:22]=[C:23]2[C:29]([C:2]3[N:7]=[C:6]([NH:8][C@H:9]4[CH2:14][CH2:13][CH2:12][C@@:11]([CH2:16][S:17][CH3:18])([OH:15])[CH2:10]4)[C:5]([F:19])=[CH:4][N:3]=3)=[CH:28][N:27]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[C:24]2=[N:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CSC[C@@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
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: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSC[C@@]1(O)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 140 °C

Procedure:
To a solution of (1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-(methylthiomethyl)cyclohexanol, 49d, (0.09 g, 0.28 mmol) in CH3CN (4 mL) was added 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.14 g, 0.33 mmol) followed by aqueous Na2CO3 (0.42 mL of 2 M solution, 0.83 mmol). The reaction was degassed with nitrogen for 15 min and tetrakis triphenylphosphinepalladium(0) (0.02 g, 0.01 mmol) was added. The reaction was heated to 140° C. via microwave irradiation for 20 minutes. The mixture was cooled to room temperature and was diluted with water/EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes gradient).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)CO>[CH2:11]([O:18][C:19]1[C:20]([NH:25][C:9]2[S:10][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: S=C=Nc1cccnc1Cl
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: OCCO
Product: c1ccc(COc2cccnc2Nc2nc3cccnc3s2)cc1
Temperature: 120 °C

Procedure:
A mixture of 2-chloro-3-isothiocyanatopyridine (0.342 g, 2.00 mmol) and 3-(benzyloxy)pyridin-2-amine (0.401 g, 2.00 mmol) in ethylene glycol (2 mL) was heated at 120° C. for 3 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated. The residue was purified by MPLC eluting with 4:1 hexane:ethyl acetate to afford the title compound as a wax. The wax was triturated with 10:1 hexanes:dichloromethane (11 mL), filtered, and dried to afford N-(3-(benzyloxy)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine (0.095 g, 14.2% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 5.30 (s, 2H), 7.03 (m, 1H), 7.32-7.43 (m, 4H), 7.50 (d, 1H), 7.60 (d, 2H), 7.93-7.97 (m, 2H), 8.35 (d, 1H), 10.71 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH:10](OCC)=[O:11]>C(OCC)C>[CH3:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][CH:10]=[O:11])[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC=O
Reactant: C#Cc1cccc(C)c1
Solvent: CCOCC
Product: Cc1cccc(C#CC=O)c1
Temperature: -70 °C
Yield: 47 %

Procedure:
1.56 g of 3-ethynyltoluene was dissolved in 20 ml of ethyl ether, and with stirring at -70° C., 8.5 ml of 1.5M n-butyllithium-hexane solution and 1.2 ml of ethyl formate were added. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice water, and the organic layer was separated. The solvent was evaporated to give 900 mg (yield 47%) of 3-(3-methylphenyl)-2-propynaldehyde as a colorless oil.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][C:53]=1[F:54].CO.[CH2:60]([N:67]1[CH2:71][CH:70]=[C:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O>[CH2:60]([N:67]1[CH2:71][C@H:70]([C:50]2[CH:51]=[CH:52][C:53]([F:54])=[C:48]([Cl:47])[CH:49]=2)[C@@H:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 60 °C
Yield: 22 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (31 mg, 0.05 eq.), (R)-BINAP (76 mg, 0.05 eq.) and 3-chloro-4-fluoro-phenylboronic acid (850 mg, 2.0 eq.). 60 mL of MeOH and 6.0 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone. The reaction mixture was heated at 60° C. for 2 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 180 mg (22%) of the title product as a light yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=1>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[C:17]2[C:22]([O:23][CH2:24][CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: CCOc1cccnc1Br
Solvent: ClCCl
Product: CCOc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of N-(1-benzylpiperidin-4-yl)-N-methylamine (XXVII, 4.80 g) and 2-bromo-3-ethoxypyridine (XXVIIIa, 2.3805 g) is placed in a metal, screw cap reaction vessel using dichloromethane as the transfer solvent. Reduced pressure is applied to the vessel with heating at 50° to 60° for 45 min to remove dichloromethane. The vessel is then sealed and heated at 160 to 165° for 2 days. After cooling, the resulting solids are dissolved in dichloromethane and washed with water and saline. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure to give the product, which is chromatographed (silica gel; eluting with ethyl acetate/hexane (30/70) followed by ethyl acetate/hexane (50/50)), to give N-(1-benzylpiperidin-4-yl)-N-(3-ethoxypyridin-2-yl)-methylamine (XXVIII, Chart G); MS (m/z) 325; IR (neat) 1462, 1211, 1481, 1589 and 1450 cm-1.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@:38]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:95]=[C:96]1[CH:100]=[CH:99][C:98](=[O:101])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH2:110])=[O:108]>CN(C=O)C>[O:101]=[C:98]1[CH:99]=[CH:100][C:96](=[O:95])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH:110][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@:38]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:108]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CCOC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C)C[C@@H]1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN2C(=O)C=CC2=O)C(C)C)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mg (12 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S,2R)-1-(ethoxycarbonyl)-2-phenylcyclopropyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 3 ml of DMF and then admixed with 8.9 mg (23 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 10 μl of N,N-diisopropylethylamine and with 12 mg (47 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT for 1 h. This was followed by concentration under high vacuum and purification of the remaining residue by means of preparative HPLC. Thus, 5.8 mg (37% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1ccccc1F
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccccc1F

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(2-fluorophenyl)acetate hydrochloride (prepared from 2-fluorophenylglycine (Fluka) and ethanol using General Procedure H), the title compound was prepared as a solid (mp=153-170° C.). The reaction was monitored by tlc (Rf=0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[H][H].[NH2:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[C:12](=[CH:13][C:14](=[O:28])[C:15](Cl)=[C:16]1CCCCC)[O:11]2.NC1C=C2C(=CC=1)N=C1C(=CC(=O)C=C1CCCCC)O2>O.CN(C)C=O.O1CCCC1.[Pd].C(O)(=O)C>[CH:21]1[C:8]([NH2:7])=[CH:9][C:10]2[O:11][C:12]3[C:17](=[N:18][C:19]=2[CH:20]=1)[CH:16]=[CH:15][C:14](=[O:28])[CH:13]=3
Reactant: [H][H]
Reactant: CCCCCc1c2nc3ccc(N)cc3oc-2cc(=O)c1Cl
Agent: [Pd]
Agent: CCCCCc1cc(=O)cc2oc3cc(N)ccc3nc1-2
Agent: [BH4-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc2nc3ccc(=O)cc-3oc2c1

Procedure:
Acetic acid (30%, 200 cm3) from a 2-necked flask was added, dropwise, while stirring, to a solution consisting of approximately 5 g of sodium borohydride and 200 mg of sodium hydroxide dissolved in 200 cm3 of water. Hydrogen gas was passed through a 3-necked flask in which the mixture of 7-amino-2-chloro-1-pentylphenoxazin-3-one and 7-amino-1-pentylphenoxazin-3-one (0.564 g) was dissolved in anhydrous dimethylformamide (15 cm3 by heating and then cooling) and the solution was diluted with anhydrous tetrahydrofuran (THF) (15 cm3). A Pd/C catalyst (5%, 200 mg) was added to the solution. The solution was sparged gently with hydrogen gas and this was continued for a long time after the apparent reduction (approximately 1 h). The reduction was demonstrated by the solution turning from a purple color to a grayish-green color. A solution of resorufamine was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:15]=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Sc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2ccccc2Cl)ccn1
Yield: 94.7 %

Procedure:
Using the method of Example 3, Step A, 2-chlorobenzenethiol (912 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to afford 2-chloro-4-(2-chlorophenylthio)pyridine (1.53 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.36 (t, 1H), 6.89 (s, 1H), 6.84 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[C:37]([Cl:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Cl:48][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1Cl
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3-chloro-4-(2-propoxyethoxy)phenyl borate (164 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration and recrystallized from ethanol to give colorless crystals of 7-[3-chloro-4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 74) (255 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(F)cc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 1-(bromomethyl)-2,4-difluorobenzene (0.70 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.82 g, 50%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][N:21]([CH3:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:25]3[CH2:26][CH2:27][CH:22]([N:21]([CH3:28])[CH3:20])[CH2:23][CH2:24]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CN(C)C1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N(C)C)CC3)c(F)c21
Yield: 36.6 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.43 g), 4-dimethylaminopiperidine (2.1 g), and pyridine (3 ml) was refluxed for 6 hours. The mixture was evaporated to dryness. The residue was treated with water and extracted with dichloromethane. The organic layer was washed with water, dried, and evaporated. The solid was recrystallized from ethyl acetate and gave 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-dimethylamino-1-piperidinyl)-4-oxoquinoline-3-carboxylic acid (0.22 g), mp 210°-211° C.
Reaction SMILES: C(C1C=CC(C2C=C(C(F)(F)F)SC=2CO)=CC=1)C.OC1C=CC(CCC(OCC)=O)=C(C)C=1C.[CH2:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[S:46][C:45]=2[CH2:53][O:54][C:55]2[CH:60]=[CH:59][C:58]([CH2:61][CH2:62][C:63]([O:65]CC)=[O:64])=[C:57]([CH3:68])[C:56]=2[CH3:69])=[CH:40][CH:39]=1)[CH3:37]>>[CH2:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:48]=[C:47]([C:49]([F:51])([F:52])[F:50])[S:46][C:45]=2[CH2:53][O:54][C:55]2[CH:60]=[CH:59][C:58]([CH2:61][CH2:62][C:63]([OH:65])=[O:64])=[C:57]([CH3:68])[C:56]=2[CH3:69])=[CH:40][CH:39]=1)[CH3:37]
Reactant: CCOC(=O)CCc1ccc(OCc2sc(C(F)(F)F)cc2-c2ccc(CC)cc2)c(C)c1C
Agent: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: CCc1ccc(-c2cc(C(F)(F)F)sc2CO)cc1
Product: CCc1ccc(-c2cc(C(F)(F)F)sc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 208 by coupling of (3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methanol and ethyl 3-(4-hydroxy-2,3-dimethyl phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.35 (d, J=6.0 Hz, 2H), 7.28 (d, J=6.0 Hz, 2H), 6.95 (d, J=5.3 Hz, 1H), 6.65 (d, J=5.3 Hz, 1H), 5.15 (s, 2H), 2.96 (t, J=5.5 Hz, 2H), 2.68 (q, J=5.5 Hz, 2H), 2.60 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 2.18 (s, 3H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]([S:4]([N:7]1[CH2:10][C:9]2([CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11]2)[CH2:8]1)(=[O:6])=[O:5])([CH3:3])[CH3:2]>CC(O)=O.C(Cl)Cl.[Pd]>[CH:1]([S:4]([N:7]1[CH2:8][C:9]2([CH2:14][CH2:13][NH:12][CH2:11]2)[CH2:10]1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)N1CC2(CCN(C(=O)OCc3ccccc3)C2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CC2(CCNC2)C1
Reaction time: 1.5 h

Procedure:
A solution of benzyl 2-isopropylsulfonyl-2,6-diazaspiro[3.4]octane-6-carboxylate (230 mg, 0.65 mmol) in AcOH (2 mL) was treated with Pd (7.0 mg, 0.06 mmol) (10% on activated carbon) and stirred under an atmosphere of hydrogen for 1.5 h. The reaction mixture was diluted with DCM, filtered and washed with 1N HCl and brine. The organic layer was dried over Na2SO4, filtered and concentrated to obtain 2-isopropylsulfonyl-2,6-diazaspiro[3.4]octane in quantitative yield. LC/MS m/z 219.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](Cl)=[O:26])(=[O:21])[CH3:20]>O1CCCC1>[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6])=[O:26])(=[O:21])[CH3:20]
Reactant: CCc1cc(N)cc(C(=O)O)c1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)C(CSC(C)=O)Cc2ccccc2)cc(C(=O)O)c1
Yield: 62.2 %

Procedure:
3-Amino-5-ethylbenzoic acid (2.1 g) is dissolved in a 33% aqueous solution of tetrahydrofuran (30 ml) containing sodium carbonate (1.3 g), and to the mixture is added dropwise a solution of 2-acetylthiomethyl-3-phenylpropionyl chloride (3.0 g) in tetrahydrofuran (20 ml) with stirring under ice cooling, and the mixture is stirred at room temperature for one hour. Tetrahydrofuran is distilled off under reduced pressure, and the residue is extracted with ethyl acetate (100 ml). The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then ethyl acetate is distilled off under reduced pressure. The residue is dissolved in methanol and purified by a medium pressure column chromatography with CHP-20P (eluant, water-methanol). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (2.8 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C[CH2:28][N:29](C(C)C)C(C)C.CN>C1COCC1>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:29][CH3:28])[CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Temperature: 100 °C

Procedure:
In a 350 mL sealed tube fitted with stirring bar were combined at 0° C. 4-(4-benzyloxy-phenoxy)-2-chloro-pyridine (Step a, 2.11 g, 6.79 mmol), DMSO (10 mL), DIEA (1.3 mL, 7.47 mmol), and CH3NH2 (4.1 mL of a 2 N solution in THF, 8.15 mmol). The reaction was heated to 100° C. for 7 days. During that period, an additional amount of CH3NH2 solution was added on four separate days (for a total of 70 mL). The reaction was cooled to RT and diluted into 1N NaOH and Et2O after evaporating off THF. After separation of the layers, the organic layer was washed 3× with 1 N NaOH then with brine. The crude residue was eluted on a silica gel column with a hexanes/EtOAc gradient to yield the title compound.