Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][CH2:39][C:40]#[N:41])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:42]>CS(C)=O>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][CH2:39][C:40]([NH:2][OH:3])=[NH:41])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:42]
Reactant: Cc1cc(F)ccc1-c1nc(NCCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NO
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NCCC(=N)NO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 45 %

Procedure:
Under Ar, a soln of hydroxylamine hydrochloride (119 mg, 1.72 mmol) and triethylamine (0.26 mL, 1.89 mmol) in 5 mL of DMSO was stirred at room temperature for 5 min, the product of Example 206, 3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-propionitrile (150 mg, 0.34 mmol) was added. The resulting mixture was heated to 80° for 16 h. Preparative hplc, followed by recrystallization from ethanol and hexane, gave the desired product 80 mg (45%). LC-MS: 469.2 (MH+, m/z), 1.52 (Rt, min).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([NH2:10])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:10][C:7]2[C:6]([CH3:11])=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1cc(C(C)C)cnc1N
Solvent: c1ccncc1
Product: Cc1cc(C(C)C)cnc1NS(=O)(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
5-isopropyl-3-methylpyridin-2-amine (142 mg, 0.945 mmol) and 4-fluorobenzene-1-sulfonyl chloride (221 mg, 1.13 mmol) were dissolved in pyridine (3 mL) and left to stand overnight. Another 1 eq of 4-fluorobenzene-1-sulfonyl chloride was added to the mixture and the reaction left to stand for a further 6 hours. The reaction was concentrated in vacuo and the crude product extracted to the organic phase of an acidic work up between ethyl acetate and 5% citric acid. The organic phase was then passed through a hydrophobic frit, concentrated in vacuo and purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient). The relevant fractions were then combined and evaporated to give the title compound (127 mg). LCMS (2 min, formic) Rt 1.03 min, m/z (ES+) 309 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: OB(O)c1ccccc1Cl
Product: COC(=O)c1ccnc(-c2ccccc2Cl)c1

Procedure:
500 mg (2.31 mmol) of methyl 2-bromoisonicotinate and 597 mg (3.47 mmol) of 2-chlorophenylboronic acid were reacted with one another analogously to the process of Example 58A. This gave 323 mg (56% of theory) of the target compound.
Reaction SMILES: C(OC1C=C(C(C)(C)O)C=C(C(C)(C)O)C=1)C1C=CC=CC=1.C([O:30][C:31]1[CH:32]=[C:33]([C:51]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)O)[CH:34]=[C:35]([C:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)O)[CH:36]=1)C1C=CC=CC=1>>[CH:51]([C:33]1[CH:32]=[C:31]([OH:30])[CH:36]=[C:35]([CH:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:34]=1)([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1cc(OCc2ccccc2)cc(C(O)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(O)c1cc(OCc2ccccc2)cc(C(C)(C)O)c1
Product: Oc1cc(C(c2ccccc2)c2ccccc2)cc(C(c2ccccc2)c2ccccc2)c1

Procedure:
The procedure (including reaction and treatment) of Example 2 was repeated, except that 5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol was replaced by 5benzyloxy-α,α, α′,α′-tetraphenyl-1,3-benzenedimethanol, to thereby yield the above-described target as a colorless oil. IR(film)cm−1: 3536, 3410, 3061, 3026, 1597, 1494. 1H-NMR(CDCl3)δ: 4.52(1H,br.s), 5.40(2H,s), 6.37(2H,s), 6.57(1H,s), 7.05(8H,dd,J=8.3,1.5 Hz), 7.15-7.26(12H,m).
Reaction SMILES: [CH3:1][CH:2]1[S:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH3:16][N:17]([CH:19]=[C:3]1[CH:2]([CH3:1])[S:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:18]
Reactant: CC1CC(=O)c2ccccc2S1
Reactant: CCOC(OCC)N(C)C
Product: CC1Sc2ccccc2C(=O)C1=CN(C)C

Procedure:
3,4-Dihydro-2-dimethylaminomethylene-3-methyl-4-thia-1(2H)-naphthalenone was prepared from 3,4-dihydro-3-methyl-4-thia-1(2H)naphthalenone (1.55 mg, 0.87 mmol),[Clayton, S E et al. Tetrahedron (1993) 49, 939], and N,N-dimethyl formamide diethylacetal (2 ml) to give the compound as yellow crystals (161 mg). δH (CDCl3) 8.12 (1H, dd, J 1.5, 7.8 Hz), 7.50 (1H, s), 7.34-7.16 (3H, m), 4.36 (1H, q, J 7.1 Hz), 3.16 (6H, s) and 1.57 (1H, d, J 7.0 Hz). MS (ES+) 234 (MH+, 100%).
Reaction SMILES: [ClH:1].CCOC(C)=O.[OH:8][C:9]1([C:21]2[C:22]([NH:27]C(=O)OC(C)(C)C)=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>>[ClH:1].[NH2:27][C:22]1[C:21]([C:9]2([OH:8])[CH2:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4N HCl-EtOAc (5 mL) was added to tert-butyl [3-(1-hydroxy-4-phenylcyclohexyl)pyridin-2-yl]carbamate (450 mg) and the mixture was stirred at room temperature overnight. The resulted precipitates were collected and dried in vacuo to give 1-(2-aminopyridin-3-yl)-4-phenylcyclohexanol hydrochloride.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12](Cl)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=[NH:33])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:33][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH3:17])[N:13]=1)[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19]
Reactant: COc1cc(C(=O)NCc2ccccc2)cc(Cl)n1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)NCc2ccccc2)cc(N)n1
Temperature: 90 °C
Reaction time: 20 h
Yield: 62.2 %

Procedure:
To a degassed mixture of N-benzyl-2-chloro-6-methoxyisonicotinamide (1.38 g, 5.00 mmol), benzophenone imine (1.0 mL, 5.78 mmol), sodium t-butoxide (1.20 g, 12.0 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.02 g, 0.03 mmol) in toluene (40 mL) was added tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol). The resulting solution was heated at 90° C. for 18 hours and concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran (20 mL) and 10% hydrochloric acid solution (20 mL) and stirred for 20 hours at ambient temperature. The resulting solution was neutralized with saturated sodium bicarbonate solution until pH 8-9 and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 2-amino-N-benzyl-6-methoxyisonicotinamide (0.80 g, 62%): MS (ES+) m/z 258.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH:16]=[C:15]([CH3:22])[C:14]=2[C:13]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:10])=[O:9]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH:15]([CH3:22])[C:14]=2[C:13]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:10])=[O:9]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(C)=CCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(C)CCC2
Yield: 94.4 %

Procedure:
A solution of Example 275E (1.58 g) in 100 mL of ethyl acetate was hydrogenated under 60 psi pressure for 16 hours in the presence of 475 mg of 10% palladium on charcoal. The mixture was filtered, concentrated, treated with diethyl ether, and filtered. The filter cake was washed with diethyl ether to provide 1.5 g of the desired product as a mixture of R and S isomers. MS (ESI(+)) m/e 395 (M+NH4)+; MS (ESI(−)) m/e 376 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.61-7.71 (m, 2H), 7.40-7.46 (m, 1H), 7.31 (dt, 1H), 7.08 (d, 1H), 6.87 (d, 1H), 3.65 (s, 3H), 3.05-3.08 (m, 1H), 2.64-2.78 (m, 2H), 1.58-1.79 (m, 4H), 1.02 (d, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[N:22]=[C:21]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][N:18]=1>O>[CH3:24][N:23]([CH3:25])[C:21]1[CH:20]=[CH:19][N:18]=[C:17]([NH:15][CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)[N:22]=1
Reactant: CN(C)c1ccnc(Cl)n1
Reactant: NC1CCN(CCc2ccccc2)CC1
Solvent: O
Product: CN(C)c1ccnc(NC2CCN(CCc3ccccc3)CC2)n1
Temperature: 120 °C
Reaction time: 20 h
Yield: 28.4 %

Procedure:
A mixture of 1-(2-phenylethyl)-4-piperidinamine (8.17 g) and 2-chloro-N,N-dimethyl-4-pyrimidinamine (6.3 g) was stirred for 20 hours at 120° C. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH(NH3) 96/4). The pure fractions were collected and the solvent evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 3.69 g (28.4%) of N4,N4 -dimethyl-N2 -[1-(2-phenylethyl)-4-piperidinyl]-2,4-pyrimidinediamine (comp. 11).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18](O)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 68.6 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (116 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B2) (150 mg, 1 equiv), HATU (151 mg, 1.2 equiv), DMF (2.72 ml) and DIPEA (0.17 ml, 3 equiv) was shaken at room temperature for 3.25 h. The reaction mixture was partitioned between ethyl acetate/methanol and aqueous sodium bicarbonate, the organic layer was brine-washed, dried and treated with activated charcoal (250 mg). Flash chromatography (silica, 3-4% methanol in DCM) gave ethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]-acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (178 mg).
Reaction SMILES: O=S(Cl)Cl.[CH2:5]([O:7][C:8](=[O:23])[CH:9]([NH:19][C:20](=[O:22])[CH3:21])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=O)[CH3:6].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[CH2:5]([O:7][C:8]([C:9]1[N:19]=[C:20]([CH3:21])[O:22][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[O:23])[CH3:6]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(C)oc1-c1cccc(F)c1

Procedure:
At 0° C. SOCl2 (0.88 mmol) is added to a stirred solution of 2-acetylamino-3-(3-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (0.63 mmol) in CHCl3 (0.38 mL). After 30 min the mixture is heated to reflux for 60 min. An additional portion of SOCl2 (0.16 mmol) is added and the mixture is heated to reflux for further 60 min. An aq. K2CO3 solution (1.0 M) is added, the layers are separated and the aq. layer is extracted twice with ether. The combined organic layers are washed with water, dried over MgSO4, filtered and concentrated in vacuo to give the desired ester which is used without further purification. LC-MS: tR=0.93 min; [M+H]+=250.3.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][CH:19]=[C:20]([C:22]([O:24]C)=O)[CH3:21])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:22](=[O:24])[C:20]([CH3:21])=[CH:19][NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COC(=O)C(C)=CNC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cc1c[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(methoxycarbonyl)propenyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 170°-173° C.,
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:15])[CH3:14])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([O:15][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][O:17]2)[CH3:14])[C:9]1=[O:16])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(O)C1CCN(C(=O)OC(C)(C)C)C1=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(OC1CCCCO1)C1CCN(C(=O)OC(C)(C)C)C1=O
Reaction time: 1 h

Procedure:
To a solution of 1-t-butyloxycarbonyl-3-(1-hydroxyethyl)-2-oxopyrrolidine (15 g) in dichlormethane (200 ml) were added 3,4-dihydro-2H-pyran (11.9 ml) and p-toluenesulfonic acid (1.2 g) at 0° C. After stirring for 1 hour at the same temperature, the solution was washed in turn with saturated aqueous bicarbonate and brine. The dried solution was evaporated, and the obtained residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1-3:1, V/V) to give 1-t-butyloxycarbonyl-3-{1-(tetrahydropyran-2-yloxy)ethyl}-2-oxopyrrolidine (18.4 g).
Reaction SMILES: [CH:1]1([C@H:7]([NH:41][C:42]([C:44]2[CH:49]=[N:48][CH:47]=[CH:46][N:45]=2)=[O:43])[C:8]([NH:10][C@@H:11]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:12]([N:14]2[CH2:18][C@@H:17]3[CH2:19][CH2:20][CH2:21][C@@H:16]3[C@H:15]2[C:22]([NH:24][C@@H:25]([CH2:34][CH2:35][CH3:36])[C@@H:26]([OH:33])[C:27]([NH:29][CH:30]2[CH2:32][CH2:31]2)=[O:28])=[O:23])=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[Na+].C(=O)(O)[O-].[Na+].CC1(C)N([O])C(C)(C)CCC1.Cl[O-].[Na+]>ClCCl.O>[CH:1]1([C@H:7]([NH:41][C:42]([C:44]2[CH:49]=[N:48][CH:47]=[CH:46][N:45]=2)=[O:43])[C:8]([NH:10][C@@H:11]([C:37]([CH3:38])([CH3:39])[CH3:40])[C:12]([N:14]2[CH2:18][C@@H:17]3[CH2:19][CH2:20][CH2:21][C@@H:16]3[C@H:15]2[C:22]([NH:24][C@@H:25]([CH2:34][CH2:35][CH3:36])[C:26](=[O:33])[C:27]([NH:29][CH:30]2[CH2:31][CH2:32]2)=[O:28])=[O:23])=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC[C@H](NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)[C@@H](O)C(=O)NC1CC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)C(=O)C(=O)NC1CC1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Compound 45 (2.0 g, 2.9 mmol) was dissolved in dichloromethane (14 mL), and to this solution was added a solution of sodium bromide (144 mg) in water (1.0 mL) followed by a solution of sodium bicarbonate (300 mg) in water (4.0 mL). The mixture was cooled to 0° C., whereupon TEMPO (53 mg, 0.34 mmol) was added. Commercial bleach solution containing sodium hypochlorite (3.3 mL) further diluted with water (9.6 mL) was added drop-wise over the course of 10 minutes. The mixture was stirred 1.5 hours at 5° C. after which the organic layer was separated and washed with 10% aqueous sodium sulfite (8 mL) then brine. The resulting solution was dried over magnesium sulfate, filtered, and then concentrated to dryness. After crystallization from dichloromethane/ethyl acetate, compound 4 showed spectroscopic properties identical to those reported in Example 14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[C@@H:14]([CH3:28])[CH2:13]3)[C:11](=[NH:29])[NH:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1.[CH:31]1(N)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[CH:31]1([NH:29][C:11]2[C@:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[C@@H:14]([CH3:28])[CH2:13]3)[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:9](=[O:30])[N:10]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C[C@H]1C[C@]2(CCN1C(=O)OCc1ccccc1)C(=N)NC(=O)N2c1cccc(F)c1
Reactant: NC1CCCCC1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@H]1C[C@]2(CCN1C(=O)OCc1ccccc1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Temperature: 110 °C

Procedure:
Benzyl (5R,7S)-1-(3-fluorophenyl)-4-imino-7-methyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (27.2 g, 0.066 moles) was dissolved in 100 mL toluene, cyclohexylamine (60 mL, 0.523 moles) was added and the mixture was heated to 110° C. over the weekend in a 1 L roundbottom flask fitted with a condenser. The reaction was diluted with CHCl3 and MeOH until soluble and washed with 1 Normal HCl three times to remove excess cyclohexylamine. The organic was dried with MgSO4, filtered and concentrated to give the product which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:19][CH:18]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Product: COc1ccc(CCNc2c([N+](=O)[O-])cnc3ccccc23)cc1

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-(4-methoxyphenyl)ethylamine to provide 4-[2-(4-methoxyphenyl)ethylamino]-3-nitroquinoline.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14][C:15]=2[CH3:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[NH3:23]>>[CH:17]1([C:13]2[N:4]3[C:5]4[C:10]([N:11]=[C:2]([NH2:23])[C:3]3=[C:15]([CH3:16])[N:14]=2)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=4)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N
Reactant: Cc1nc(C2CCCCC2)n2c1c(Cl)nc1ccc(F)cc12
Product: Cc1nc(C2CCCCC2)n2c1c(N)nc1ccc(F)cc12

Procedure:
640 mg 4-Chloro-1-cyclohexyl-8-fluoro-3-methyl-imidazo(1,5-a)quinoxaline (2 mmol) and 30 ml 32% aqueous ammonia were heated 7 hours at 130-135° C. After cooling the product was filtered off, washed with water, dried and chromatographed on silica gel with 2% MeOH/CH2Cl2.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:20])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1ncc2c(Cl)c3ccccc3nc21
Temperature: 0 °C
Yield: 68.3 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)anthranilic acid (278 g, 1.2 mol) and POCl3 (550 g, 3.6 mol) was refluxed for 3 hours. The reaction mixture was cooled and then was poured into ice/water (3-4 L). A solid formed which was collected by filtration and washed with water. The filtrate was extracted with CH2Cl2 (1 L) and the CH2Cl2 layer was evaporated to about 50 ml and both this solution and the previously isolated solid were purified by column chromatography on silica gel eluting with CH2Cl2 to afford 190 g (68%) of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[F:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(F)cc4F)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, B and C subsequently) (56 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([C:3]1([CH3:20])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14](OCC)=[O:15])[C:4]1=[O:19])#[N:2].Cl.[C:22]([O:26][C:27](=[O:30])[CH2:28][NH2:29])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[C:1]([C:3]1([CH3:20])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([NH:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[O:15])[C:4]1=[O:19])#[N:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(C#N)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccccc2C(C)(C#N)C1=O

Procedure:
Ethyl 1-cyano-4-hydroxy-1-methyl-2-oxo-naphthalene-3-carboxylate (0.225 g, 0.829 mmol), glycine tert-butyl ester hydrochloride (0.167 g, 0.995 mmol), and glycine tert-butyl ester hydrochloride (0.167 g, 0.995 mmol) were refluxed in dioxane (50 mL) for 14 hours. The solvent was then removed in vacuo. The resulting residue was concentrated in vacuo and purified using silica flash chromatography (10-40% EtOAc/hexanes). MS (m/z)=301 (M+H)+(hydrolyzed product) 379.1 (product+Na).