Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40]CC2C=CC=CC=2)=[CH:36][CH:35]=1)[CH:11]([OH:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[C:1]([NH:9][CH:10]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)[CH:11]([OH:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(CC(O)C(Cc1ccc(O)cc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The ester product from part (c) is taken up into 125 ml. of methanol containing 400 mg. of palladium on carbon catalyst (10%) and stirred under positive hydrogen pressure for 20 hours. The reaction mixture is filtered and concentrated to dryness in vacuo. The crude product is purified chromatographically to yield (±)-1-[[[3-(benzoylamino)-4-(4-hydroxyphenyl)-2-hydroxybutyl]methylamino]carbonyl]-L-proline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20].[CH2:21]([CH2:23][NH2:24])[OH:22]>>[NH2:24][CH2:23][CH2:21][O:22][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([OH:20])=[C:2]([Cl:1])[CH:7]=1)=[N:10][CH:11]=[N:12]2
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Reactant: NCCO
Product: NCCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 84 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) and ethanolamine to give 4-{[5-(2-aminoethoxy)quinazolin-4-yl]amino}-2-chlorophenol in 84% yield. NMR spectrum (DMSO-d6) 3.12 (t, 2H), 4.27 (t, 2H), 6.96 (d, 1H), 7.11 (d, 1H), 7.31 (d, 1H), 7.53 (dd, 1H), 8.08 (d, 1H), 8.47 (s, 1H); Mass spectrum MH+ 331.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=1)[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:29]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A mixture of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (5.20 g), ammonium formate (1.50 g) and 10% Pd charcoal (0.52 g) in ethanol (50 ml) was refluxed for 7.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified on a silica gel column eluting with a mixture of dichloromethane and methanol (20:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (2.67 g, 61.5%) as a syrup.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(Cl)cc3Cl)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 30.3 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,4-dichlorobenzyl)-1-piperidinecarboxamide formate (0.30 g, 0.64 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.233 g, 0.577 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.145 g, 0.175 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([OH:23])(=[O:22])=[O:21])[CH:8]=2)[N:3]=1.[CH2:24]1[S:29](=[O:31])(=[O:30])[O:28][CH2:27][CH2:26][CH2:25]1.S1(CCCC1)(=O)=O>C(OCC)C>[CH3:1][CH:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([OH:23])(=[O:21])=[O:22])[CH:8]=2)[N:3]1[CH2:27][CH2:26][CH2:25][CH2:24][S:29]([OH:31])(=[O:30])=[O:28]
Reactant: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O
Reactant: O=S1(=O)CCCCO1
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: CC1N(CCCCS(=O)(=O)O)c2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O
Temperature: 140 °C
Yield: 86.8 %

Procedure:
To 2,3-dimethyl-3-(4-sulfobutyl)-5-sulfo-3H-indole (10 g) was added butane sultone (30 g) and the mixture heated to 140° C. overnight. On cooling to room temperature, sulfolan (20 ml) was added and the mixture poured into diethyl ether (500 ml). The resultant precipitate was removed by filtration and dried to give the desired product (12 g).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5](=[O:15])[CH2:4]1.[CH3:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]([OH:36])[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:22][C:20]=2[N:21]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:36][C@@H:28]([CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:19]2[S:18][C:17]([CH3:16])=[N:21][C:20]=2[CH:22]=1)[CH2:29][N:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH:3]2[CH2:7][N:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:5](=[O:15])[CH2:4]2)[CH2:34][CH2:35]1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: O=C1CC(CBr)CN1c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CC4CC(=O)N(c5ccc(F)cc5)C4)CC3)ccc2s1

Procedure:
A solution of 4-(bromomethyl)-1-(4-fluorophenyl)pyrrolidin-2-one (0.04 g, 0.15 mmol), (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol 2×HCl (0.09 g, 0.24 mmol), and potassium carbonate (0.150 g, 1.15 mmol) in N,N′dimethylformamide (2 ml) was heated to 70° C. for 16 hours. The solution was filtered and the filtrate concentrated. The residue was purified using preparative chromatography (15:1 DCM:MeOH) to yield 4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one (M+1=498.99).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[C:26]([F:39])[C:25]=1[O:40][CH3:41]>>[F:39][C:26]1[C:25]([O:40][CH3:41])=[C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)[CH:38]=[CH:37][C:27]=1[CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1F)OCC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1F)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 using 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A) and Diethyl (4-amino-2-fluoro-3-methoxybenzyl)phosphonate (Compound 147A). 1H NMR (CD3OD, 400 MHz): δ=1.26-1.36 (m, 6 H), 1.44 (t, J=6.95 Hz, 3 H), 3.32-3.39 (m, 2 H), 4.04-4.15 (m, 4 H), 4.22 (q, J=7.07 Hz, 2 H), 7.00 (dd, J=8.34, 1.77 Hz, 1 H), 7.21 (d, J=1.77 Hz, 1 H), 7.75 (d, J=8.34 Hz, 1 H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=3)=[C:12]([O:29][CH2:30][C:31]3(/[CH:34]=[CH:35]/[C:36]#[N:37])[CH2:33][CH2:32]3)[CH:11]=2)=[CH:4][N:3]=1.Cl>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:12]([O:29][CH2:30][C:31]3(/[CH:34]=[CH:35]/[C:36]#[N:37])[CH2:32][CH2:33]3)[CH:11]=2)=[CH:4][N:3]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2(/C=C/C#N)CC2)c1-c1ccc(OCOC)cc1
Agent: Cl
Solvent: CO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2(/C=C/C#N)CC2)c1-c1ccc(O)cc1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
(E)-3-[1-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6-ethoxy-4′-methoxymethoxy-biphenyl-2-yloxymethyl]-cyclopropyl]-acrylonitrile (350 mg; 0.698 mmol) is stirred in methanol (12 ml) and a 3 M hydrochloric acid solution in methanol (3.4 ml) for 30 minutes at a bath temperature of 60° C. The methanol is evaporated off, the residue is dissolved in water (33 ml) and the pH is adjusted to approx. 9 by addition of NH4OH conc., whereupon the substance precipitates out. After stirring for 2 hours the mixture is filtered with suction and the residue is washed with water and dried under a high vacuum. 295 mg (92%) (E)-3-[1-[4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-4′-hydroxy-biphenyl-2-yloxymethyl]-cyclopropyl]-acrylonitrile are obtained as a colourless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16](=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]3=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:23]=1.[C:24](O)(=[O:32])[C:25]1[CH:30]=[CH:29][N+:28]([O-])=[CH:27][CH:26]=1.[OH:34]N1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16](=[C:17]3[CH2:22][CH2:21][N+:20]([O-:34])([C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[O:32])[CH2:19][CH2:18]3)[C:10]3=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: Cc1cnc2c(c1)CCc1cc(Cl)ccc1C2=C1CCNCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cnc2c(c1)CCc1cc(Cl)ccc1C2=C1CC[N+]([O-])(C(=O)c2ccncc2)CC1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a mixture of 20 g of 8-chloro-11-(4-piperidylidene)-6,11-dihydro-3-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (product from Preparative Example 7, Step E), 1.39 g of isonicotinic acid N-oxide, and 1.35 g of 1-hydroxybenzotriazole in 60 mL CH2Cl2 at 0° C. was added 1.91 g of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC). The reaction mixture was slowly allowed to warm to room temperature overnight. The reaction mixture was quenched with water, basified with 10% NaOH, and extracted with CH2Cl2. The combined organic portions were washed with brine, dried over Na2SO4, and concentrated in vacuo. The product was flash chromatographed using 5% methanol in methylene chloride to give 2.52 g of a product which could be triturated with CH2Cl2 /diisopropylether (1:20 parts by volume) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH:11]([C:13]1[C:14](Cl)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1)[CH3:12].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[N-]=C=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N:10]([CH:11]([C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1)[CH3:12])[C:28]([NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:29]
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(Cl)c(NC(C)c2cnc(Cl)nc2Cl)c1
Agent: [N-]=C=O
Product: COc1ccc(Cl)c(N(C(=O)Nc2ccccc2)C(C)c2cnc(Cl)nc2)c1
Temperature: 150 °C

Procedure:
(±)-(2-Chloro-5-methoxy-phenyl)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-amine (70 mg; 0.21 mmol) (from Example 12a supra) was combined with phenyl isocyanate (60 μL; 0.55 mmol) (Aldrich) and heated (neat) at 150° C. for 65 minutes. Thin layer chromatography analysis showed some unreacted starting material remained. Additional isocyanate (20 μL; 0.18 mmol) was added and the mixture heated at 150° C. for an additional 30 minutes. Upon cooling, hexanes was added. After stirring, the supernatant was decanted off and the residue dried to give the intermediate (±)-1-(2-chloro-5-methoxy-phenyl)-1-[1-(2-chloropyrimidin-5-yl)-ethyl]-3-phenyl-urea which contained about 20% starting material by HPLC.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.O1CCOCC1.[S-:21][C:22]#[N:23]>C1COCC1.O>[NH2:23][C:22]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[S:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#C[S-]
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
1,1-Dimethylethyl 1-piperazinecarboxylate (24 g, 129 mmol) in THF (1 L) was treated with 4 N HCl in dioxane (32.2 mL, 129 mmol)), and thiocyanate (12.52 g, 129 mmol) dissolved in minimal amount of water was added. After stirring at rt overnight, the volatiles were removed under reduced pressure. The residue was taken up in MeOH and filtered to remove inorganic salts and the solvent removed in vacuo and the cycle was repeated 3 more times. Then twice taken up in DCM and filtered and concentrated to give the title compound of Step A (29 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (br. s., 2H), 3.50 (br. s., 4H), 3.07 (t, J=5.0 Hz, 4H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:19])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:20][C:21]1[C:22]([F:29])=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>N1C=CC=CC=1>[Cl:18][C:14]1[CH:13]=[C:12]2[NH:11][C:10](=[O:19])[C:9]3([CH:3]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:2][NH:1][CH:24]3[C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[C:22]=3[F:29])[C:17]2=[CH:16][CH:15]=1
Reactant: CC(C)(C)CC(CN)C1C(=O)Nc2cc(Cl)ccc21
Reactant: O=Cc1cccc(Cl)c1F
Solvent: c1ccncc1
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 100 °C

Procedure:
To a solution of racemic 3-(1-aminomethyl-3,3-dimethyl-butyl)-6-chloro-1,3-dihydro-indol-2-one prepared in Example 3 (1.2 g, 4.3 mmol) in pyridine (50 mL) was added 3-chloro-2-fluoro-benzaldehyde (Oakwood) (0.68 g, 4.3 mmol). The reaction mixture was heated at 100° C. for 2 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved into ethyl acetate, washed with aqueous saturated CuSO4 solution, and brine. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (Yield, 0.29 g, 16%).
Reaction SMILES: C(OC([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[C:13]([OH:22])[CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=O)C.[ClH:23]>>[ClH:23].[ClH:23].[OH:22][C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH3:21])=[C:18]3[CH2:19][CH2:20][NH:6][CH2:7][CH2:8][C:9]3=[N:10][C:11]=2[CH:12]=1
Reactant: CCOC(=O)N1CCc2nc3cc(O)ccc3c(C)c2CC1
Agent: Cl
Product: Cc1c2c(nc3cc(O)ccc13)CCNCC2
Yield: 34 %

Procedure:
8-Hydroxy-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline dihydrochloride was prepared by hydrolysis of 8-hydroxy-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester in concentrated hydrochloric acid. Yield: 34% of theory; m.p. 245° C (decomp.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[Cl:26])=[O:19])([CH3:4])([CH3:3])[CH3:2].[C:28]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]([CH3:52])=[C:37]([CH2:39][CH2:40]OS(C3C=CC(C)=CC=3)(=O)=O)[N:38]=2)=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:40][CH2:39][C:37]2[N:38]=[C:34]([C:31]3[CH:32]=[CH:33][C:28]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:29][CH:30]=3)[O:35][C:36]=2[CH3:52])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[Cl:26])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1cc(Cl)sc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)c2cc(Cl)sc2Cl)c1
Yield: 81.5 %

Procedure:
A mixture of 3-(2-{[(2,5-dichloro-thiophene-3-carbonyl)-amino]-methyl}-4-hydroxy-phenyl)-propionic acid tert-butyl ester (280 mg, 0.651 mmol) and toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (498 mg, 1.15 mmol), were reacted according to Standard procedure A to give, after radial chromatography (hexanes/EtOAc 98:2 to 90:10), the title compound as a white solid (367 mg, 82%). 1H NMR (400 MHz, CDCl3): 1.36 (s, 9H), 2.37 (s, 3H), 2.55 (t, 2H, J=7.3 Hz), 2.87 (t, 2H, J=7.3 Hz), 2.96 (t, 2H, J=6.6 Hz), 4.22 (t, 2H, J=6.8 Hz), 4.58 (d, 2H, J=5.4 Hz), 6.80 (dd, 1H, J=8.3 Hz, J=2.4 Hz), 6.88 (d, 1H, J=2.9 Hz), 6.97 (t, 1H, J=5.9 Hz), 7.10 (d, 1H, J=8.8 Hz), 7.13 (s, 1H), 7.36 (t, 1H, J=7.3 Hz), 7.45 (t, 2H, J=7.8 Hz), 7.63 (d, 2H, J=8.3 Hz), 7.65 (d, 2H, J=6.3 Hz), 8.02 (d, 2H, J=7.8 Hz). MS (ES) m/e 691.2 [M+1].
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[N:11]=1.C1COCC1.[OH-].[Na+]>CCO>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:19])=[O:2])[O:8][CH:9]=1
Reactant: COC(=O)CCCc1nc(-c2ccccc2N)co1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccccc1-c1coc(CCCC(=O)O)n1

Procedure:
Combine 4-[4-(2-amino-phenyl)-oxazol-2-yl]-butyric acid methyl ester (2.36 g, 9.1 mmol) with THF (3 mL), EtOH (3 mL) and 2N NaOH (20 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 3.5-4.0 with aq HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 4-[4-(2-amino-phenyl)-oxazol-2-yl]-butyric acid (1.63 g, 73%). MS (ES): (M+1)+ 247.1 m/z.
Reaction SMILES: C[Zn]C.Cl[C:5]1[N:14]=[C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].Cl[C:22]1C=CC(C(OC)=O)=C(OCC(F)(F)F)N=1>>[CH3:22][C:5]1[N:14]=[C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(Cl)nc1OCC(F)(F)F
Reactant: COC(=O)c1ccc(OCC(F)(F)F)nc1Cl
Agent: C[Zn]C
Product: COC(=O)c1ccc(OCC(F)(F)F)nc1C
Temperature: 75 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Dimethylzinc (40.0 mL, 40.0 mmol) is added dropwise a solution of methyl 2-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (2.70 g, 10.0 mmol, Step-2) including methyl 6-chloro-2-(2,2,2-trifluoroethoxy)nicotinate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.816 g, 1.00 mmol) and stirred at 75° C. for 1 hour. After cooling room temperature, the resulting mixture is quenched by carefully added water. The reaction mixture is extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-Hexane/ethyl acetate (20:1) to give 0.89 g (36% yield) of the title compound as a white solid.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=S.S(Cl)([Cl:14])(=O)=O>>[Cl:14][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2
Reactant: S=c1[nH]c2ncccc2s1
Reactant: O=S(=O)(Cl)Cl
Product: Clc1nc2ncccc2s1
Reaction time: 8 h
Yield: 39.8 %

Procedure:
The intermediate [1,3]thiazolo[4,5-b]pyridine-2(3H)-thione (644.0 mg, 3.83 mmol, dry powder) was treated with neat sulfuryl chloride (3.08 ml, 38.28 mmol) and allowed to stir at it overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with 1N NaOH, followed by brine, and dried over Na2SO4. Concentration in vacuo gave the title compound (260.0 mg, 40%). LC/MS m/z 171.2 (MH+); retention time 1.55 min. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (m, 1H), 8.62 (d, 1H), 8.78 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]Cl)[O:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[N-:21]=[N+:22]=[N-:23].[Na+]>ClCCl.CO>[N:21]([CH2:13][C@H:11]1[O:10][C:9](=[O:15])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)=[N+:22]=[N-:23]
Reactant: O=C1OC(CCl)CN1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: [N-]=[N+]=NC[C@@H]1CN(Cc2ccccc2)C(=O)O1
Temperature: 120 °C

Procedure:
A 40 ml vial was charged with 3-benzyl-5-(chloromethyl)-1,3-oxazolidin-2-one (112 mg, 0.5 mmol, INTERMEDIATE 13), dimethylformamide (5 ml), and sodium azide (130 mg, 2 mmol). The mixture was heated to 120° C. for 15 h. The crude was applied to a pad of silica and washed with methanol (2×10 ml). The organics were pooled and concentrated to provide a residue. The title compound was isolated on silica gel eluting with a gradient of dichloromethane/methanol from 0% to 100% to provide 100 mg (86%) as a tan oil. Mass spectrum (ESI) 233.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: Clc1ncccn1
Reactant: C1CNCCN1
Product: c1cnc(C2CNCCN2)nc1
Reaction time: 21 h

Procedure:
A mixture of 2-chloropyrimidine (10.0 g) and piperazine (16 g) in alcohol (120 ml) is stirred for 21 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated and the organic phase is dried with sodium sulfate and concentrated to give 2-pyrimidinyl piperazine. The 2-pyrimidinyl piperazine (4.64 g) is stirred at 70° in acetonitrile (200 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (11.52 g) and potassium carbonate (3.75 g) for 1.5 hr and at 20°-25° for 2 days. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated and the organic phase is dried with sodium sulfate and concentrated. The concentrate is chromatographed on silica gel eluting with 4 to 6% methanol/methylene chloride. The appropriate fractions are pooled and concentrated to give the title compound which is crystallized from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.O.[Cl-].[NH4+]>CO.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1cc(Br)cc(OC)c1N
Temperature: 80 °C

Procedure:
5-Bromo-1,3-dimethoxy-2-nitro-benzene (2.6 g, 10 mmol) was dissolved in 200 mL of methanol and 40 mL of water was added, followed by 2.5 g of Fe powder and 2.5 g of ammonium chloride. The mixture was heated to reflux at 80° C. for 2 hours and the cooled reaction mixture was filtered and washed with methanol. The filtrate was evaporated under reduce pressure to give the crude product, which was used for next step without further purification.