Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH2:31][NH:33][C:34]5[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=5)=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ccc(CNc6cccnc6)o5)cc34)cc2)cc1

Procedure:
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde and 3-aminopyridine were reacted in an analogous manner to Example 10 to give the title compound; δH [2H6]-DMSO 9.82 (1H, b), 8.70 (1H, s), 8.42 (1H, s), 8.11-8.01 (2H, m), 7.80-7.70 (2H, m), 7.62 (2H, d), 7.49-7.25 (5H, m), 7.10-6.95 (5H, m), 6.48 (1H, d), 6.40 (1H, t), 5.10 (2H, s), 4.38 (2H, d); m/z 500 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:3]=1.Cl.[NH2:21][C:22]1[C:27]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:26][CH:25]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[N:23]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[ClH:1].[NH2:21][C:22]1[N:23]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:2]3[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:3]=3)[CH2:36]2)[CH:25]=[CH:26][C:27]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 140 °C

Procedure:
255 mg (0.533 mmol) of methyl 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carboxylate (Example 16A), 259 mg (0.799 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.56 ml (3.2 mmol) of N,N-diisopropylethylamine were initially charged in 4.5 ml of DMSO. The mixture was heated at 140° C. in a microwave for 45 min. The crude product was purified by means of preparative HPLC (method 10). 28 mg (8% of theory) of the product were obtained in solid form.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H][H]>[Pd].CO>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Yield: 96.2 %

Procedure:
20 mg of 10% w/w palladium on charcoal was added to a solution of 100 mg of benzyl 9-benzoyl-1,2,3,4-tetrahydrocarbazole-3-carboxylate, as obtained in Example 51, in 5 ml each of methanol and of tetrahydrofuran. The reaction mixture was stirred for 3 hours under a stream of hydrogen gas at room temperature, filtered to remove the catalyst, and concentrated by evaporation under reduced pressure. The resulting residue was recrystallized from ethyl acetate and hexane, to yield 75 mg of the title compound, melting at 189°-190° C.
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1.[H][H]>CO.[Rh]>[CH:17]1([C:6]2([OH:5])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:7]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C1
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(O)(C2CCCCC2)C1
Temperature: 85 °C
Yield: 100 %

Procedure:
0.5 ml of acetic acid and 40 mg of rhodium on alumina 5% are added to a solution containing 117 mg (0.470 mmol) of 3-hydroxy-3-phenyl-1-(tert-butoxy-carbonyl)azetidine (cf. procedure 1-2-1) dissolved in 4 ml of methanol. The reaction medium is placed at 4 bar of hydrogen and heated at 85° C. for 4 hours. The catalyst is filtered off and washed with methanol and the solvents are evaporated off. 120 mg in the form of a beige powder are obtained with a yield of 100%.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][N:29]=2)=[CH:24][CH:23]=1>>[CH:1]1([N:4]([CH:5]2[CH2:6][CH2:7][N:8]([C:11]3[O:15][N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=3)[CH2:9][CH2:10]2)[C:34]([C:31]2[CH:32]=[N:33][C:28]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[N:29][CH:30]=2)=[O:35])[CH2:3][CH2:2]1
Reactant: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Reactant: O=C(O)c1cnc(-c2ccncc2)nc1
Product: O=C(c1cnc(-c2ccncc2)nc1)N(C1CC1)C1CCN(c2nc(-c3ccccc3)no2)CC1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 2-pyridin-4-yl-pyrimidine-5-carboxylic acid following a procedure analogous to that described in Example 1. LC (method 2): tR=1.76 min; Mass spectrum (ESI+): m/z=468 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([N:11]=[C:12]=[O:13])=[CH:3][C:2]=1[C:14]([F:17])([F:16])[F:15].[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1.Cl>O1CCCC1.C(N(CC)CC)C>[F:17][C:14]([F:15])([F:16])[C:2]1[CH:3]=[C:4]([NH:11][C:12]([C:23]2[C:22]3[C:26](=[CH:27][C:19]([Cl:18])=[CH:20][CH:21]=3)[NH:25][C:24]=2[OH:28])=[O:13])[CH:5]=[C:6]([C:7]([F:10])([F:8])[F:9])[CH:1]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1c(O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.7 %

Procedure:
Under argon atmosphere, 3,5-bis(trifluoromethyl)isocyanate (255 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL). A solution of 6-chloro-oxindole (184 mg, 1.1 mmol) in tetrahydrofuran (5 ml) and triethylamine (0.3 mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (172.2 mg, 40.7%) as a pink solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:10].[NH2:21][OH:22].[OH-].[K+].CO>C1COCC1>[OH:22][NH:21][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: COC(=O)CCCCCS(=O)c1ccc(N(C)C)cc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(S(=O)CCCCCC(=O)NO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of the 6-(4-dimethylamino-benzenesulfinyl)-hexanoic acid methyl ester (1.2 g, 4.0 mmol) in distilled THF (30 mL) containing 50% aqueous hydroxylamine (2.65 mL, 40 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (6.8 mL, 1M, 6.8 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (30 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with brine (100 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The solid residue was recrystallised from acetone to give the title compound (728 mg, 61%) as a white powder, mp 95-97° C.
Reaction SMILES: [C:1]([C:3]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].Cl[C:24]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:9][CH2:10][C:11]1=[O:13])([O:8][CH3:24])=[O:7]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: COc1ccc(CC(C#N)(CCC(=O)O)CCC(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(Cc2ccc(OC)cc2)CCC1=O
Yield: 95 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 53.94 gm. (0.169 mole) of the dimethyl ester of 4-cyano-4-(p-anisyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 1100 ml. of the tetrahydrofuran, 38.0 ml. (0.34 mole) of the potassium tert-butoxide, and 270 ml. of the 2.5 N hydrochloric acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 46.2 gm. (95% yield) of 2-carbomethoxy-4-cyano-4-(p-anisyl)cyclohexanone as a gum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[NH:35][NH2:36]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:36][NH:35][C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:12])[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1H-indole-7-carboxylic acid (510.9 mg, 2.85 mmol, commercially available from e.g. Maybridge, Apollo or Fluorochem) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (443 mg, 2.85 mmol) in Dichloromethane (15 ml) stirred under argon at room temp was added solid 1-H-1,2,3-benzotriazol-1-ol (43.7 mg, 0.285 mmol) in dichloromethane (15 ml). The reaction mixture was stirred at RT for 1 hr. Solid t-butyl carbazate (571 mg, 4.28 mmol) was added and the reaction mixture stirred at room temp for 18 hr. The reaction mixture was partitioned between dichloromethane (˜50 ml) and saturated sodium bicarbonate solution (˜25 ml). The aqueous phase was extracted with dichloromethane (2×25 ml) and the combined organic extracts washed with saturated sodium bicarbonate solution (˜25 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product as a yellow gum. The residue was purified via Biotage (1:1 Hex/EtOAc; 25+M Biotage column) to afforded the required product as a white foam in 360.0 mg.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](B(O)O)[CH:38]=2)[CH:33]=[CH:32]1>>[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)[NH:20][C:19]4=[O:29])[CH:38]=2)[CH:33]=[CH:32]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccc5cc[nH]c5c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and indole-6-boronic acid in step C. MS (ESI): mass calcd. for C20H13N5O3, 371.1; m/z found, 372.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (s, 1H), 12.86 (s, 1H), 11.23 (s, 1H), 8.99 (s, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.77 (s, 2H), 7.67 (d, J=8.2 Hz, 1H), 7.43 (s, 2H), 6.48 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: C1CCNC1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCCC1

Procedure:
Using 3.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) and 18 ml of pyrrolidine, a reaction similar to that conducted in Example 142 was carried out. As a result, 2.68 g of N-(trans-4-methylcyclohexyl)-4-[2-(1-pyrrolidinyl)ethoxy]-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH2:33][CH2:34][CH:35]([OH:40])[CH2:36][C:37]([OH:39])=[O:38]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([NH:33][CH2:34][CH:35]([OH:40])[CH2:36][C:37]([OH:39])=[O:38])=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: NCC(O)CC(=O)O
Product: O=C(O)CC(O)CNC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyric acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-amino-3-hydroxy-butyric acid following General Procedure B.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[CH:13]([CH3:15])[CH3:14])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[N:24][C:25]([O:27][Si](C)(C)C)=[CH2:26])[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C:6]3([CH:12]([CH:13]([CH3:14])[CH3:15])[CH2:27][C:25](=[O:26])[NH:24][CH:23]3[C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: CC(C)/C=C1\C(=O)Nc2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: CC(C)C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 56.4 %

Procedure:
In a manner similar to the method described in example 1c, E/Z-6-chloro-3-isobutylidene-1,3-dihydro-indol-2-one (0.25 g, 1.1 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (1.2 g, 4.7 mmol) prepared in example 1b, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 56%).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Cl)[CH3:23]>CN(C)C=O>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][O:18][C:17](=[O:19])[C:7]1[C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]([I:11])=[C:9]([NH:12][C:13](=[O:14])[CH3:15])[C:8]=1[I:16])[CH3:23]
Reactant: CCOC(=O)CCl
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To 175 mL of dry N,N-dimethylformamide (DMF) was added 63.6 g (0.100 mol) sodium diatrizoate and 14.7 g (0.120 mol) of ethylchloroacetate and the mixture was heated on a steam bath for 6 hr. The reaction was filtered while hot and the filtrate cooled to room temperature and diluted to 500 ml with water. The mixture was cooled and filtered and the collected solid washed with water. The solid was then dissolved in 350 ml hot DMF, filtered and added to an equal volume of water. The mixture was cooled, filtered, washed with water, and the solid dried at 100° C. overnight to afford 53.0 g (76% yield) of a white powder, mp 269.5°-270.5° C.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:18])C=C[CH:4]=[CH:3][CH:2]=1.[Cl:19]CCCCCCCl>>[Cl:19][CH2:4][CH2:3][CH2:2][CH2:1][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18]
Reactant: O=c1[nH]c2ccccc2n1C=Cc1ccccc1
Reactant: ClCCCCCCCl
Product: O=c1[nH]c2ccccc2n1CCCCCCCl

Procedure:
The above mentioned compound was prepared analogously to the procedure described in J. Het. Chem. 18, 85 (1981) from 1-( -phenylvinyl)-2,3-dihydro-1H-benzimidazol-2-one and 1,6-dichloro hexane. The protecting group was then removed by acid hydrolysis with hydrochloric acid following the above procedure. M.p. 80°-84° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:26])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:9])(C)(C)C.Cl>C(Cl)(Cl)Cl>[CH3:9][CH:8]1[C:10](=[O:26])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7]1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a stirred solution of the benzophenone 109 (10.65 g, 29.38 mmol) in CHCl3 (400 mL) at rt, hydrogen chloride gas was added in slowly. After 20 min, the addition was stopped and the solution was stirred overnight at rt. The reaction mixture was washed with a saturated solution of sodium bicarbonate (2×50 mL) and water (2×50 mL). The organic layer was concentrated under reduced pressure. The residual oil was dissolved in methanol-water (2:1, 500 mL) and the pH was adjusted to 8.5 by the addition of aqueous sodium hydroxide (1 N). The reaction mixture was stirred for 10 h at rt. The solution was concentrated under reduced pressure and water (100 mL) was added. The solution was extracted with CH2Cl2 (3×100 mL) and concentrated under reduced pressure. The crude solid 110 was purified by recrystallization from methanol/water to provide 110 (6.10 g, 83%). mp 160-162° C.; IR (KBr, cm−1) 3215, 3059, 2974, 2932, 1681, 1574, 1478, 1445, 1372, 1321, 1242, 1160, 1131; 1H NMR (CDCl3) δ 9.65 (s, 1H), 7.54-7.13 (m, 9H), 3.78 (q, J=6.5 Hz, 1H), 1.78 (d, J=7.1 Hz, 3H); MS (EI) m/e (relative intensity) 250 (M+, 40), 249 (83), 234 (15), 209 (75), 208 (76), 207 (100), 180 (17), 152 (19) 103 (23), 77 (40); [α]26D=290.2 (c 0.78, EtOAc).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3Br)=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([O:38]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:37].Cl>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:35])[N:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:36](=[O:38])[CH3:37])=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2c(Sc3ccccc3Br)cn(Cc3cc(F)cc(F)c3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1Sc1cn(Cc2cc(F)cc(F)c2)c2cc(N(C)C(=O)OC(C)(C)C)ccc12
Reaction time: 1 h
Yield: 26.2 %

Procedure:
i)—A solution of [3-(2-bromo-phenylsulfanyl)-1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (Example 6, method 2, step i; 1.00 g, 1.79 mmol) in toluene (oxygen-free, 25 ml), containing dichlorobis(triphenylphosphine)palladium(II) (0.076 g, 0.0672 mmol) and (1-ethoxyvinyl)tributyltin (0.824 ml, 2.44 mmol) was heated under reflux overnight. After cooling, hydrochloric acid (2M, 15 ml) was added and the mixture was stirred for 1 h. The mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 9:1→85:15) afforded [3-(2-acetyl-phenylsulfanyl)-1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (0.245 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][O:35][C:34]4=[O:39])=[CH:28][CH:27]=3)[S:25][C:18]=12.O>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][O:35][C:34]5=[O:39])=[CH:28][CH:27]=4)[S:25][C:18]=23)=[C:4]([F:9])[CH:3]=1
Reactant: O=C1OCCCN1Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCOC5=O)cn4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 117.4 %

Procedure:
To a solution of 4-amino-2-fluorophenol (70.7 mg, 0.556 mmol) in DMSO (5 mL) was added sodium tert-butoxide (53.4 mg, 0.556 mmol) and the reaction mixture was stirred for 30 min. Chloride 199 (100 mg, 0.278 mmol) was added and the reaction mixture was heated at 100° C. overnight. The mixture was then cooled to RT and poured into water (20 mL) and the precipitated product was collected by filtration and purified by Biotage (MeOH/EtOAc 0-50%, SNAP 25 g cartridge) to give title compound 200 (147 mg, 33% yield) as a beige solid. MS: 451 (MH+).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH3:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>O>[CH:9]([C:14]1[S:13][C:12]([CH3:11])=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1)=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1sccc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1sc(C=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.166 mol (15 mL) of POCl3 was added at 0° C. to a 0.5 mol (39 mL) of DMF. At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then it was cooled again to 0° C. and treated with 2-methyl-3-phenylthiophene (29 g, 0.166 mol). The resulting reaction mixture was allowed to reach room temperature and after 12 h stirring at the same temperature was heated at 80° C. for 2 days. Then it was poured into a mixture of ice and water and added of sodium acetate. The precipitate so obtained was filtered, washed with water and subsequently with hexane. The yellow powder was dried in vacuo.
Reaction SMILES: O[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)on1
Product: COc1cc(CCl)on1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
A mixture of 1.0 g 5-hydroxymethyl-3-methoxy-isoxazole and 10 g thionyl chloride was stirred at room temperature for 20 h. The excess thionylchloride was removed in vacuo, dissolved in toluene and the solvent evaporated. 1.0 g of an oil was obtained.