Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[C:39]2[C:40]3[CH:53]=[CH:52][S:51][C:41]=3[C:42](=[O:50])[NH:43][C:44]=2[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]>>[CH3:49][O:48][C:47]1[CH:46]=[CH:45][C:44]2[NH:43][C:42](=[O:50])[C:41]3[S:51][CH:52]=[CH:53][C:40]=3[C:39]=2[C:38]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Br)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Yield: 52.6 %

Procedure:
Following General Procedure E, tert-butyl 2-(4-bromophenyl)propan-2-ylcarbamate (160 mg, 0.50 mmol) was reacted with bis(pinacolato)diboron (140 mg, 0.55 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (140 mg, 0.45 mmol) to afford the desired product (110 mg, 47%) as a brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10](Cl)[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCCCCC.CCOC(C)=O>[CH:1]1([NH:7][C:10]2[CH:9]=[CH:8][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(NC2CCCCC2)nc1
Temperature: 120 °C
Yield: 96.6 %

Procedure:
Add cyclohexylamine (7.1 g, 72 mmol) to a mixture of 6-chloronicotinitrile (1 g, 7.2 mmol), potassium carbonate (3 g, 21.7 mmol), and anhydrous DMF (10 mL). Heat the mixture in a sealed flask at 120° C. for 1.5 h. Cool the reaction to ambient temperature, dilute with hexane/EtOAc (1:1, 100 mL) and wash the mixture with aqueous 5% sodium chloride (3×30 mL). Collect the organic layer and concentrate in vacuo to obtain the desired intermediate (1.4 g, 97%). GC-MS m/z: 201 (M+).
Reaction SMILES: [NH2:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>>[CH3:19][C:8]1([CH3:20])[C:7]2[CH:6]=[C:5]3[NH:21][C:2]([NH:1][C:22](=[O:25])[CH2:23][CH3:24])=[N:3][C:4]3=[CH:12][C:11]=2[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]1=[O:18]
Reactant: CCC(=O)Cl
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)CC)nc3cc21
Yield: 30.9 %

Procedure:
N-(7,7-Dimethyl-6-oxo-5-pentyl-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-propionamide (37 mg) is prepared from D5 (100 mg) and propionyl chloride (71 mg; 0.77 mmol) as described in Example 173.
Reaction SMILES: [N:1]1([CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:20]1[C:21]2[CH:29]=[N:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=2[N:23]=[CH:24][N:25]=1>>[N:1]1([CH2:5][C@@H:6]([NH:7][C:20]2[C:21]3[CH:29]=[N:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=3[N:23]=[CH:24][N:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1cncc2c(O)ncnc12
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)c(C(F)(F)F)c1
Product: NC(=O)c1cncc2c(N[C@H](CN3CCC3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 20 was prepared following general synthetic scheme 7 wherein (S)-2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethanamine was reacted with 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxamide to give the title compound. LC-MS [451 (M+1)], 1H NMR (400 MHz, Chloroform-d) δ 10.43 (s, 1H), 9.75 (s, 1H), 9.59 (s, 1H), 8.62 (s, 1H), 7.98 (s, 1H), 7.69 (s, 1H), 7.48 (d, 2H), 6.12 (s, 1H), 5.18 (d, 1H), 3.25 (dq, 4H), 3.05-2.89 (m, 2H), 2.14 (p, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=1.[CH2:16]([NH:20][C:21]([N:23]1[C:31]2[C:26](=[C:27]([CH:32]=[O:33])[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].[OH-].[K+].O>CO>[CH2:16]([NH:20][C:21]([N:23]1[C:31]2[C:26](=[C:27]([CH:32]([OH:33])[C:15]3[C:9]4[C:10](=[N:11][CH:12]=[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:8]=4)[NH:13][CH:14]=3)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNC(=O)n1ccc2c(C=O)cccc21
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCNC(=O)n1ccc2c(C(O)c3c[nH]c4ncc(-c5cccnc5)cc34)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 51 mg, 0.26 mmol, prepared as in Example 17) in methanol (2 mL), was added 4-Formyl-indole-1-carboxylic acid butylamide (519, 84 mg, 0.34 mmol) and potassium hydroxide (44 mg, 0.78 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography to give an off-white solid (520, 7 mg, 6%). MS (ESI) [M+H+]+=440.3.
Reaction SMILES: [Br:1][CH:2]([CH2:8][Br:9])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:11]1([NH:10][C:6]([NH:5][C:3](=[O:4])[CH:2]([Br:1])[CH2:8][Br:9])=[O:7])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C=NC(=O)C(Br)CBr
Reactant: Nc1cccc2ccccc12
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)C(Br)CBr)Nc1cccc2ccccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
26.0 g of 2,3-dibromopropionyl isocyanate in 100 ml of toluene are added dropwise at 5 to 10° C to a solution of 14.5 g of 1-aminonaphthalene in 200 ml of dry benzene. After stirring for 2 hours at 20° C., the reaction product is diluted with petroleum ether, filtered and dried. Yield: 35.0 g, m.p: 194° - 195° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:19](=[O:20])[N:18]([CH3:22])[CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Product: CN(C)C(=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-(3,5-dichloro pyridin-2-yloxy)-phenol and dimethyl-carbamoyl chloride. The crude product was purified by preparative HPLC (38%). HPLC-MS m/z=327.0 (M+1), Rt: 4.7 min.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([C:14]2N3CCCC3=NC=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=[O:25])(O)O.C1(NC(N)=N)C=CC=CC=1.C[C:37](N(C)C)=[O:38]>>[NH:1]([C:8]1[N:13]=[C:12]([CH:14]([O:25][CH3:22])[O:38][CH3:37])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)O
Reactant: CC(=O)N(C)C
Reactant: c1ccc(Nc2nccc(-c3cnc4n3CCC4)n2)cc1
Agent: N=C(N)Nc1ccccc1
Product: COC(OC)c1ccnc(Nc2ccccc2)n1
Temperature: 130 °C
Yield: 88 %

Procedure:
A mixture of 1,1-dimethoxy-4-dimethylaminobut-3-en-2-one (Method 1; 20.0 g, 0.116 mol) and phenyl guanidine bicarbonate (25 g, 0.126 mol) in anhydrous dimethylacetamide (350 ml) was stirred and heated at 130° C. under nitrogen for 18 hours. The reaction mixture was allowed to cool and the solvent removed by evaporation. The residue was dissolved in EtOAc and the solution washed with water (×5), saturated sodium chloride (×2), dried and evaporated to give the title compound (24.7 g, 88%) as a dark brown oil. NMR: (CDCl3): 3.42 (s, 6H), 5.20 (s, 1H), 6.94 (d, 1H), 7.04 (t, 1H), 7.31 (m, 3H), 7.64 (d, 2H), 8.47 (d, 1H), m/z: 246.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(OCC)C>[O:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:11][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: C=C1CC(=O)O1
Solvent: CCOCC
Product: CC(=O)CC(=O)NCCN1CCOCC1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of diketene (23.0 ml) in diethyl ether (115 ml) was added dropwise a solution of N-(2-aminoethyl)morpholine (34.7 g) in diethyl ether (300 ml) at -40° C. After stirring for 2 hours at the same condition, the resulting precipitates were collected by filtration and dried in vacuo to give N-(2-morpholinoethyl)acetoacetamide (41.1 g, yield 72.0 %).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: Nc1ccccc1
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
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: O
Solvent: ClCCl
Product: CN(C)CCNc1nc(-c2cccc(C(=O)Nc3ccccc3)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 55.2 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (23 mg, 0.05 mmol) in CH2Cl2 (3 mL) were added aniline (0.005 mL, 0.055 mmol), HATU (20 mg, 0.052 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (15 mg, 56%). LC-MS m/z 544 (M+H)+; 1H-NMR (MeOD) δ 2.43 (s, 6H), 2.70 (m, 2H), 3.48 (m, 2H), 4.52 (s, 2H), 7.17 (m, 3H), 7.39 (m, 2H), 7.52 (m, 1H), 7.69 (m, 3H), 7.79 (d, 1H), 8.08 (d, 1H), 8.15 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH2:35]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:35][C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:25]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccc2ccccc2c1
Product: Clc1ccc(-c2nn(Cc3ccc4ccccc4c3)c3c2CCNCC3)cc1
Yield: 55.4 %

Procedure:
The title compound (0.043 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using naphthalen-2-ylmethyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C24H22ClN3, 387.15; found, m/z 388.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.74-7.69 (m, 3H), 7.45-7.38 (m, 5H), 7.34-7.32 (m, 1H), 7.18-7.16 (m, 2H), 5.43 (s, 2H), 3.04 (m, 2H), 2.99-2.97 (m, 2H), 2.87-2.85 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81 %

Procedure:
After the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (90 mg, 0.21 mmol) obtained in Example 338, N-methylpiperazine (0.036 ml, 0.33 mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) was added to the resulting solution at room temperature. The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture, N-methylpiperazine (0.036 ml, 0.33 mmol), triethylamine (0.045 ml, 0.32 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) were added further. The resulting mixture was stirred at room temperature for 14 hours, followed by concentration under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography and a fraction obtained from the elution portion with dichloromethane:methanol=25:1 was concentrated under reduced pressure, whereby the title compound (86 mg, 0.17 mmol, 80%) was obtained as a white powder.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1.[Cu]Br>[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([O:18][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: Ic1ccccc1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 96 mg, 2.4 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (435 mg, 2.0 mmol) and copper (I) bromide (402 mg, 2.8 mmol) in pyridine (10 ml) at 0° C. After stirring for 0.5 hour at room temperature, iodobenzene (0.45 ml, 4.0 mmol) was added and the reaction mixture was heated to reflux for 24 hours. The reaction was allowed to cool, filtered and the filtrate then concentrated in vacuo. The crude residue was dissolved with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.25:2.25:97.5 to 1:9:90) to afford the title compound (E128); MS (ES+) m/e 294 [M+H]+.
Reaction SMILES: C([N:8]([CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.CCOCC.N#N.C(O)=O>[Pd].O>[NH2:8][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1
Reactant: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Agent: N#N
Solvent: O=CO
Solvent: O
Solvent: CCOCC
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
Compound 4 (0.95 g, 2 mmol) and 10% Pd—C (0.02 mmol) were added to 20 mL of ether and the air was replaced with N2. Formic acid (94 mg, 2 mmol) was added and the mixture was stirred at 80° C. for 2 hours, Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to provide 0.46 g of white solid in 78% yield. HPLC: 99.2%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].C(O)(=O)C.[NH3:15].CCO[C:19](OCC)(OCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOC(C)=O>[CH3:9][C:5]1[C:6]2[C:7]([NH2:15])=[N:8][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:1][C:2]=2[S:3][C:4]=1[CH3:10]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1sc2nc(-c3ccccc3)nc(N)c2c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
A mixture of 2-amino-4,5-dimethylthiophene-3-carbonitrile (152 mg, 1.0 mmol), ammonia acetate (308.3 mg, 4.0 mmol) and triethyl orthobenzoate (2.0 mL) in a sealed tube was put in a microwave at 200° C. for 20 min. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc, washed with saturated NaHCO3 and H2O. The solvent was removed by vacuum and the residue was purified by preparative HPLC eluting with acetonitrile and water to give the title compound (80 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 2.45 (s, 3H), 2.48 (s, 3H), 5.34 (bs, 2H), 7.46-7.43 (m, 3H), 8.4-8.38 (m, 2H). MS 256 (MH+).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1.C(OCC)(=O)C>C1COCC1.O>[Si:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCO
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A solution of 1,4-butanediol (10.54 g, 0.117 mol) in dry THF (100 mL) was treated with t-butyl dimethylsilylchloride (17.30 g, 0.114 mol) and imidazole (7.80 g, 0.114 mol). After 2 h at room temperature, work-up with ethyl acetate and water, followed by drying the organic phase and concentration, gave a crude product that was purified by silica gel flash chromatography (being eluted with 20% ethyl acetate in hexane) to yield 15.5 g (Y: 65%) of 4-(t-butyldimethylsilyloxy)-1-butanol (XXVIIa) as a colorless oil; 1H-NMR (CDCl3, 300 MHz) δ ppm: 3.58 (m, 4H) 1.58 (m, 4H) 0.84 (s, 9H) 0.01 (s, 6H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[S:40]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41]1>C1COCC1.O.[Na+].[Cl-]>[CH3:3][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:47][CH2:46][CH2:45][C:42]2[CH:43]=[CH:44][S:40][CH:41]=2)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:7])([CH3:1])[CH3:4]
Reactant: NCCc1ccsc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCCc2ccsc2)c1F
Reaction time: 8 h
Yield: 109.8 %

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (1.84 g, 3.71 mmol) was dissolved in THF (5 mL). To this solution was added triethylamine (0.62 mL, 4.4482 mmol), followed by [2-(3-thienyl)ethyl]amine (0.470 g, 3.70 mmol) which was semi-suspended in THF (15 mL). The reaction was left to stir overnight, then diluted with water and saturated NaCl. The aqueous layer was extracted with ethyl acetate. The organics were dried (MgSO4) and concentrated to produce tris(1,1-dimethylethyl)2-(2-chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate as an orange oil (2.389 g). LCMS: (M+H)+=588.3.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[C:8]1([CH:18]=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:18][N:1]2[CH2:7][CH2:6][CH2:5][C@H:2]2[CH2:3][OH:4])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: OC[C@@H]1CCCN1
Product: OC[C@@H]1CCCN1Cc1cccc2ccccc12

Procedure:
Using (S)-prolinol ((S)-VIII-1) and α-naphthoaldehyde as the starting materials, a similar operation was carried out to obtain (S)-N-(α-naphthyl)methyl-2-pyrrolidine methanol ((S)-II-2). ##STR317##
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7](=[O:8])[O:6][C:5]2[CH:9]=[C:10]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:11]=[CH:12][C:4]=2[O:3]1.[OH-:23].[Na+:24]>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH2:13][C:10]2[CH:11]=[CH:12][C:4]([O:3][C:2]([CH3:22])([CH3:1])[C:7]([O-:6])=[O:8])=[C:5]([OH:23])[CH:9]=2)=[CH:16][CH:17]=1.[Na+:24]
Reactant: [OH-]
Reactant: CC1(C)Oc2ccc(CNc3ccc(Cl)cc3)cc2OC1=O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(Oc1ccc(CNc2ccc(Cl)cc2)cc1O)C(=O)[O-]

Procedure:
To a solution of 158.7 mg of 3,3-dimethyl-7-(4-chloroanilinomethyl)-1,4-benzodioxan-2-one in 10 ml of ethanol is added 5 ml of a 1/10 N sodium hydroxide aqueous solution and the mixture is warmed to give clear solution. The solution is concentrated and the precipitated crystals are collected by filtration, washed with water and ether, and dried to give 140 mg of sodium 2-[4-(4-chloroanilinomethyl)-2-hydroxyphenoxy]-2-methylpropionate, mp 121° to 125° C.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH2:5]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[O:25][CH2:26][C:27]([OH:29])=[O:28])=[O:20])=[CH:14][CH:13]=[CH:12]2)[CH2:6][CH2:7][CH3:8].C([O-])(O)=O.[Na+].CN(C=O)C>CCOC(C)=O.O>[CH2:5]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[O:25][CH2:26][C:27]([O:29][CH2:2][CH2:3][OH:4])=[O:28])=[O:20])=[CH:14][CH:13]=[CH:12]2)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1ccc2c(C(=O)Nc3cccc(OCC(=O)O)c3)cccc2c1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1ccc2c(C(=O)Nc3cccc(OCC(=O)OCCO)c3)cccc2c1
Temperature: 70 °C
Yield: 69 %

Procedure:
2-Bromoethanol was added to a 1 dram vial containing a mixture of 2-(3-(6-butyl-1-naphthamido)phenoxy)acetic acid (27 mg, 0.07 mmol), NaHCO3 (6 mg, 0.07 mmol) and DMF (03 mL). A single drop of water from a 22 gauge needle was added and the vial was sealed under nitrogen and heated at 70° C. After several days, the mixture was cooled to room temperature and diluted with EtOAc (20 The organic mixture was and washed with water (2×5 mL) and brine (5 mL) then dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified on 4 g silica gel (100% hexanes→100% EtOAc, gradient) to afford 24 mg (69%) of the title compound.