Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH:12][CH3:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N:12]([CH3:13])[C:29]([NH:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[F:20])=[O:30])=[C:5]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CNc1cnc2ccc(Cl)cc2c1-c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C(=O)Nc1ccc(F)cc1F)c1cnc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
A mixture of 6-chloro-3-methylamino-4-phenylquinoline (0.54 g), 2,4-difluorophenyl isocyanate (0.48 ml) and anhydrous toluene (10 ml) was refluxed for 22 hrs. and then concentrated. The residue was purified by a column chromatography on silica gel and recrystallized from a mixture of ethyl acetate and ethanol to give 6-chloro-3-[3-(2,4-difluorophenyl)-1-methylureido]-4-phenylquinoline as colorless crystals. Yield 0.56 g (66%). m.p. 200°-201° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]([CH3:27])([CH2:25][OH:26])[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:11]1([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]([CH3:27])([CH:25]=[O:26])[CH2:21][CH2:20]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC1(CO)CCN(CCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C=O)CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 10 mL of methylene chloride and 0.4 mL (4.4 mmol) of oxalyl chloride was cooled under nitrogen to -60°. A solution of 0.68 mL of dimethylsulfoxide in 2 mL of methylene chloride was added dropwise to the solution. After stirring for 2 minutes 0.95 g (4 mmol) of 1-(2-phenylethyl)-4-methyl-4-hydroxymethyl-piperidine was added in 2-3 mL of methylene chloride. Stirring was continued for an additional 15 minutes. Triethylamine (2.8 mL, 20 mmol) was added to the reaction mixture and stirring was continued for 5 min, then the mixture was allowed to warm to room temperature. Water (20 mL) was added and the aqueous mixture was extracted with methylene chloride. The-organic extracts were washed with brine, dried and evaporated to give 1-(2-phenylethyl)-4-methyl-4-formyl-piperidine as a clear oil in quantitative yield. NMR (CDCl3) δ9.46 (s, 1H); 7.16-7.27 (m, 5H); 2.84-3.00 (br, 1H); 2.75-2.82 (m, 2H); 2.65-2.75 (m, 2H); 2.55-2.63 (m, 2H); 2.27 (t, 2H); 1.98-2.09 (m, 2H); 1.51-1.63 (m, 2H); 1.05 (s, 3H).
Reaction SMILES: [Br:1]Br.[C:3]([Si:7]([CH3:24])([CH3:23])[N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=[C:11]2[CH:10]=[CH:9]1)([CH3:6])([CH3:5])[CH3:4].N1C=CC=CC=1.C(=O)(O)[O-].[Na+].[Na].S([O-])([O-])(=O)=S>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[N:8]([Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:24])[CH3:23])[CH:9]=1
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccnc3)cnc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)n1cc(Br)c2cc(-c3cccnc3)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of bromine (0.166 mL, 0.0032 mol) in 1 mL of CCl4 was added dropwise to a stirred solution of 20 (1.0 g, 0.0032 mol) and pyridine (0.314 mL, 0.0039 mol) in dry CHCl3 (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then neutralized with 10 mL of a mixture of sodium bicarbonate-sodium:thiosulfate (1:1). The organic layer was separated and further extracted with dichloromethane (3×10 mL) and the combined organics dried and concentrated in vacuo. The residue was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 0.97 g (78%) of the desired material 21. 1H NMR CDCl3 8.9 (s, 1H), 8.55 (d, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.4 (dd, 1H), 7.2 (s, 1H), 0.9 (s, 9H), 0.5 (s, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9]1>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1
Reactant: O=C(OCc1ccccc1)N1CCC(OC2CCCCO2)C1
Agent: [Pd]
Solvent: CO
Product: C1CCC(OC2CCNC2)OC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250 mL round bottom flask was placed a solution of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate (15 g, 44.26 mmol) and Pd/C (2.3 g) in CH3OH (absolute) (100 mL). Hydrogen gas was bubbled. The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at room temperature. A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 5.6 g (67%) of 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine as a yellow liquid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:21][S:22]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(C(C#N)=NO)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C#N)=NOS(C)(=O)=O)cc1C
Yield: 93 %

Procedure:
23.2 g (0.13 mol) of α-hydroxyimino-3,4-dimethylbenzylcyanide are reacted with 27.2 ml (0.20 mol) of triethylamine and 11.1 ml (0.14 mol) of methansulfonyl chloride in tetrahydrofuran, as described under 3.2. After the usual processing, 32.6 g of a crude product are obtained, which is then recrystallised from isopropanol, giving 30.5 g (93%) of α-(methyl-sulfonyloxyimino)-3,4-dimethylbenzylcyanide in the form of a brownish powder having an m.p. of 91-95° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>ClCCl.CO>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: CC(C)N=C=O
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CO
Product: CC(C)NC(=O)NCc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.060 g, 0.192 mmol) in dichloromethane (3 mL) is added isopropyl isocyanate (0.027 g, 0.240 mmol) and the reaction is stirred at room temperature for 45 min. The mixture is then washed with water and extracted with dichloromethane twice. The organic phase is concentrated in vacuo to give a residue which is redissolved in methanol. A precipitate crashes out upon standing. The solid is filtered to afford 1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-isopropyl-urea as a solid. 1H NMR (400 MHz, MeOD) δ ppm 1.17 (d, J=6.6 Hz, 6H), 3.76-3.91 (m, 4H), 4.52 (s, 2H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.08 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 382.1431 [(M+H)+ Calcd for C20H21N5OCl: 382.1435].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)morpholine-4-carboxylate (Example 11, step 1) (1 g, 2.308 mmol) and sodium hydride (60% in oil) (0.111 g, 2.77 mmol) in DMF (20 mL) was stirred at 0° C. for 15 minutes. Iodomethane (0.216 mL, 3.46 mmol) was added and the mixture was left to stir at room temperature for 16 hours. The reaction was quenched with water (10 ml) to form a suspension. The suspension was diluted with H2O (100 ml) and extracted with EtOAc (200 ml). The organic portion was separated and washed with H2O (100 ml), dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[NH:4]1)[CH3:2].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>>[CH2:1]([N:3]1[C:7]([O:8][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:6][C:5]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:4]1)[CH3:2]
Reactant: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Reactant: O=Cc1ccc(F)cc1
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(C=O)cc1

Procedure:
3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]benzonitrile was prepared from 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile and 4-fluorobenzaldehyde with a procedure similar to Example 1, Step 3. Calc'd (M+1) 318.1. Found: 318.0
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[O:17]=[C:18]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:63][C:64]1[CH:72]=[C:71]([CH3:73])[CH:70]=[CH:69][C:65]=1[C:66](O)=[O:67]>CN(C=O)C.O>[CH3:63][C:64]1[CH:72]=[C:71]([CH3:73])[CH:70]=[CH:69][C:65]=1[C:66]([N:38]1[CH2:39][CH2:40][N:35]([C:18](=[O:17])[CH2:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[O:22])[CH2:36][CH2:37]1)=[O:67]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(-c4ccccc4)cc3)CC2)c(C)c1
Reaction time: 8 h
Yield: 84.4 %

Procedure:
DIPEA (77.35 mg, 0.60 mmol) was added to a stirred solution of biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (70 mg, 0.16 mmol) in DMF (2 mL). HOBT (19.8 mg, 0.14 mmol) and EDCI.HCl (63.74 mg, 0.33 mmol) were then added. After 2 minutes 2,4-dimethylbenzoic acid (20 mg, 0.13 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the product was precipitated and filtered to afford 50 mg (82.4% yield) of biphenyl-4-carboxylicacid {2-[4-(2,4-dimethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 95.3%, 1H NMR: (CDCl3) δ 7.9 (d, 2H), 7.6 (dd, 4H), 7.5 (t, 2H), 7.35 (t, 1H), 7.3 (s, 1H), 7.0 (s, 3H), 4.4-4.2 (d, 2H), 3.9-
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]1(O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: Oc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 70 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.72 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (418 mg, 2.58 mmol) in N,N-dimethylformamide (7 mL) was stirred for 16.75 hours. In one portion, phenol (486 mg, 5.16 mmol) was added and the solution was stirred for 24 hours at 70° C. To the resulting solution was added water (30 mL), giving a precipitate which was separated by filtration. This crude product was purified by chromatography eluting with chloroform: 2-propanol (98:2-90:10) to give the title compound (330 mg, 53% yield, m.p. 265° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:32][C@@H:33]1[CH2:37][NH:36][C@H:35]([CH2:38][O:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)[CH2:34]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:36]3[CH2:37][C@@H:33]([O:32][C:23]4[CH:24]=[CH:25][C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:22]=4)[CH2:34][C@H:35]3[CH2:38][O:39][C:40]3[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In DMF (10 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (141 mg, 0.50 mmol), methyl 4-((2S,4S)-4-(2-naphthyloxy)-2-pyrrolidinylmethoxy)benzoate (189 mg, 0.50 mmol), EDC•HCl (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol) and triethylamine was stirred at room temperature for 16 hours. The reaction mixture was poured in ice water (30 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was separated and purified by chromatography on a thin-layer silica gel column with (chloroform/acetone (5/1)), whereby the title compound (312 mg, 97%) was obtained as a colorless amorphous substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:14]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH2:12]([N:9]1[CH2:10][CH2:11][C:5]2[N:4]=[CH:3][C:2]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:14][C:6]=2[CH2:7][CH2:8]1)[CH3:13]
Reactant: C1CNCCN1
Reactant: CCN1CCc2ncc(Cl)nc2CC1
Product: CCN1CCc2ncc(N3CCNCC3)nc2CC1
Yield: 52.6 %

Procedure:
3 g 2-chloro-7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine are combined with 23.3 g piperazine and heated for 5 hours to 145° C. Excess piperazine is distilled off and the residue is treated with dichloromethane and methanol. Any precipitated product is suction filtered and purified by chromatography (Alox, dioxane/toluene/methanol/NH4OH 50/20/20/2). 1.95 g of product are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23](=[O:57])[N:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[N:34]=[CH:35][N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:37]=3)=[CH:28][N:27]=2)[CH:25]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH2:17][N:34]2[C:33]([CH2:32][C:29]3[CH:30]=[CH:31][C:26]([N:24]4[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]4=[O:57])=[N:27][CH:28]=3)=[CH:37][N:36]=[CH:35]2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)cc1OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 2-benzyloxy-4-hydroxymethyl-benzonitrile from step 2 (100 mg, 0.42 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (221 mg, 0.42 mmol) in CH2Cl2 (2.1 ml) was added DIEA (325 μl, 0.92 mmol) followed immediately by the addition of Tf2O (160 μl, 0.63 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH and heated to 60° C. for several hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[OH:11]
Reactant: CC1(C)Cc2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2ccccc2C1O

Procedure:
To a solution of 2,2-dimethyl-indan-1-one, which can be prepared as described in Ranu, B. C.; Jana, U. Journal of Organic Chemistry, 1999, 64, 6380-6386, (13.0 g, 81.3 mmol) in methanol (200 mL) at −20° C. is added NaBH4 (3.07 g, 81.3 mmol). Upon complete consumption of the starting ketone, as determined by TLC analysis, the reaction is quenched with saturated aqueous NH4Cl. The reaction mixture is then concentrated to near dryness, diluted with ethyl acetate and washed with water. The organic layer is then dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:8) to provide 2,2-dimethyl-indan-1-ol. 1H NMR (400 MHz, CDCl3) δ ppm 1δ ppm 1.05 (s, 3 H), 1.20 (s, 3 H), 2.56-2.89 (m, 2 H), 4.70 (s, 1 H), 7.16-7.26 (m, 3 H), 7.35-7.42 (m, 1 H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:30]=3[N:29]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:39](O)[CH2:40][CH3:41].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]([C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][C:36]([O:38][CH2:39][CH2:40][CH3:41])=[CH:37][C:30]=3[N:29]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCO
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N(c1nc2cc(O)ccc2n1C)[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(c1nc2cc(OCCC)ccc2n1C)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of butyl 1-[(trans-4-tert-butylcyclohexyl)(5-hydroxy-1-methyl-1H-benzimidazol-2-yl)amino]indane-5-carboxylate (49.0 mg, 0.095 mmol) in dry dichloromethane was added 1-propanol (18.0 □L, 0.24 mmol), diisopropyl azodicarboxylate (37.0 μL, 0.19 mmol) and Ph3P (50.0 mg, 0.19 mmol). After stirring at room temperature for 2 h, solvent was removed. Chromatography (15% EtOAc in Hexane) afforded butyl 1-[(trans-4-tert-butylcyclohexyl)(1-methyl-5-propoxy-1H-benzimidazol-2-yl)amino]indane-5-carboxylate. HPLC/MS: m/z=560.5 (M+1), Rt=2.43 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:41][CH:42]([C:48]#[N:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C1COCC1>[C:48]([CH:42]([NH:41][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])#[N:49]
Reactant: O=C(O)c1ccccn1
Reactant: CCOC(=O)C(N)C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)NC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
To a solution of picolinic acid (1.23 g, 10 mmol), EDC.HCl (1.91 g, 10 mmol) and HOBT (1.35 g, 10 mmol) in THF (80 mL) was added DIPEA (3.6 g, 30 mmol) at ambient temperature. The reaction mixture was maintained at the same temperature for 1 hr at which time a solution of ethyl 2-amino-2-cyanoacetate (1.28 g, 10 mmol) in THF (5 mL) was added. The reaction mixture was stirred at ambient temperature for additional 6 hr. It was then concentrated, and the residue was purified by silica gel column chromatography (5:1 PE/EtOAc) to give ethyl 2-cyano-2-(picolinamido)acetate (0.7 g, 30%) as yellow solid.
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[CH3:5][C:6](O)([CH2:8][CH:9](O)[CH3:10])[CH3:7].O>C1C=CC=CC=1>[CH3:5][C:6]1([CH3:7])[CH2:8][CH:9]([CH3:10])[O:3][B:1]([OH:4])[O:2]1
Reactant: OB(O)O
Reactant: CC(O)CC(C)(C)O
Solvent: c1ccccc1
Solvent: O
Product: CC1CC(C)(C)OB(O)O1

Procedure:
Boric acid (1 mole) and 2-methyl-2,4-pentanediol (1 mole) were placed in a reaction vessel with 1000 ml of benzene and the mixture refluxed until 2 moles of water were removed. Evaporation of the benzene at reduced pressure gave a liquid which slowly crystallized to give a white solid mp 73°-75° C [literature mp 69°-70° C, H. Steinberg and D. L. Hunter, Ind. & Eng. Chem 49°, 174°-181 (1957)].
Reaction SMILES: [C:1]([C:8]1[NH:9]C=CN=1)([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)=S.NC1N(C)N=CC=1.[NH:20]([C:22](=[O:43])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][C:39]([O:41]C)=[O:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)=[O:24])[NH2:21].CCN=C=NCCCN(C)C.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(N(C)C)=O.C1COCC1.O.CO>[CH3:5][N:4]1[C:3]([NH:7][C:6]2[O:43][C:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C@H:32]4[CH2:37][CH2:36][C@H:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[O:24])=[N:20][N:21]=2)=[CH:1][CH:8]=[N:9]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1nccc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1Nc1nnc(C(=O)Nc2ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc2)o1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Thiocarbonyl diimidazole (179 mg, 1.00 mmol) was added in one portion to a solution of 5-amino-1-methylpyrazole (98 mg, 1.00 mmol) in DMA (5 mL) and the solution was stirred at room temperature for 6 h. Methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)-cyclohexyl]acetate (Intermediate 43, 267 mg, 0.80 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 20 h and then heated at 80° C. for 10 minutes in the microwave. The solution was cooled to room temperature and EDCI (192 mg, 1.00 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 15 minutes in the microwave. The reaction mixture was cooled to room temperature and poured into water (200 mL). The mixture was concentrated in vacuo to leave a gum, which was recrystallised (CH3CN) to leave a gummy solid. Filtration followed by concentration in vacuo of the filtrate gave the crude oxadiazole methyl ester intermediate that was used with no further purification; MS m/e MH+ 439. Lithium hydroxide (420 mg, 10.0 mmol) was added in one portion to a solution of the crude oxadiazole methyl ester intermediate in a mixture of THF (4 mL), MeOH (8 mL) and water (4 mL) and the reaction mixture was stirred at 35° C. for 4 h. Citric acid (30 mL) was added and the mixture was filtered to leave a solid that was recrystallised (MeOH) to give the title compound (87 mg, 26%) as a solid; 1H NMR δ 1.07-1.17 (2H, m), 1.41-1.51 (2H, m), 1.70-1.84 (5H, m), 2.14-2.16 (2H, d), 3.75 (3H, s), 6.70 (1H, s), 7.21-7.24 (2H, m), 7.40 (1H, s), 7.67-7.74 (2H, m); MS m/e MH+ 425.