Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19](O)=[O:20].Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29][CH2:28]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[N:6]=[C:5]2[C:19]([N:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([O:24][CH3:23])[CH:26]=2)[CH2:31]1)=[O:20]
Reactant: COc1ccc2c(c1)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Agent: Cl
Product: COc1ccc2c(c1)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccc(F)cc13)C2
Yield: 50.6 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 99 (50.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.80 and 3.03 (2t, 2H), 3.54 and 4.02 (2t, 2H), 3.72 and 3.74 (2s, 3H), 4.47 and 4.92 (2s, 2H), 6.65-7.27 (m, 3H), 7.40-7.48 (m, 1H), 7.62-7.82 (m, 2H), 8.05-8.10 (m, 1H), 8.20-8.39 (m, 3H); MS (ESI) m/z 432 ([M+H]+).
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)#[N:13]>N1C=CC=CC=1.C(Cl)Cl>[S:2]1[C:6]([NH:7][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:19][CH:18]=2)(=[O:22])=[O:21])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2
Reactant: Nc1cc2ccccc2s1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)Nc2cc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.6 %

Procedure:
To a stirred solution of compound 1-C (0.927 g, 5.0 mmol) in pyridine (10 mL) and methylene chloride (5 mL), cooled on an ice bath, was added 4-cyanobenzene-1-sulfonyl chloride (1.01 g, 5.0 mmol) portion-wise over 3 min. The reaction was allowed to warm slowly to ambient temperature and allowed to stir for 72 h. The reaction mixture was concentrated under reduced pressure, the crude residue was partitioned between EtOAc (100 mL) and 1N HCl (25 mL), the layers separated, the organic phase washed with brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2) eluting with an EtOAc-heptane gradient to afford 1.22 g of compound 389-A as a tan-brown powder. 1H-NMR (DMSO-d6): δ 6.91 (s, 1H), 7.33-7.21 (m, 2H), 7.69-7.64 (m, 1H), 7.82-7.76 (m, 1H), 7.99-7.93 (m, 2H), 8.11-8.05 (m, 2H), 11.49 (br s, 1H); MS: m/z 313.1 (M-H)−.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:10][C@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:12]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].Br[C:33]1[N:34]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:35]2[C:40]([C:41]=1[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:39][CH:38]=[CH:37][CH:36]=2.C(=O)(O)[O-].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([O:26][C:25]([NH:24][C@H:11]([C:12]([N:14]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:15])=[O:13])[CH2:10][C:6]1[CH:5]=[C:4]([CH2:1][CH:2]=[CH:3][C:33]2[N:34]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[C:35]3[C:40]([C:41]=2[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:9]=[CH:8][CH:7]=1)=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccccc12
Reactant: C=CCc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccc(OC)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C=CCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)n(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 125 °C
Yield: 48.1 %

Procedure:
A suspension of (5)-tert-butyl 3-(3-allylphenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (220 mg, 0.52 mmol), tert-butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (297 mg, 0.78 mmol), sodium bicarbonate (435 mg, 5.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) in 4 ml of DMF was heated to 125° C. overnight. The reaction was cooled to room temperature and then filtered through celite. The filtrate was concentrated and the crude product was introduced to a silica gel loading column and purified by column chromatography (30-60% EtOAc/Hexans) to provide the desired product (178 mg, 0.25 mmol), 47%. MS (m/z) 726 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:7]2[NH:6][C:5]3[CH:21]=[CH:22][C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH:23]=[O:24])=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Reactant: O=Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 90 °C
Yield: 75.8 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.700 g, 1.89 mmol), 2-formylphenylboronic acid (0.424 g, 2.83 mmol), sodium carbonate (1.200 g, 11.3 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.123 g, 0.189 mmol) in DME (14 mL) and H2O (3.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the product as a yellow oil (0.568 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH:32][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c2ccc(Cl)cc2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Yield: 33.5 %

Procedure:
N-(2-(5-Chloro-2-methyl-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to method A with 4-(3-fluorobenzyl)benzoic acid (0.080 g, 0.347 mmol), 2-(5-chloro-2-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.094 g; 0.382 mmol), HATU (0.132 g; 0.347 mmol) and N,N-diisopropylethylamine (0.150 mL; 0.869 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.049 g (34%) of the title compound as a pale yellow solid.
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[N:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH:17]([NH:33]C(OC(C)(C)C)=O)[C:16]1=[O:41])=[O:13])([CH3:11])([CH3:10])[CH3:9]>C(O)C>[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[N:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH:17]([NH2:33])[C:16]1=[O:41])=[O:13])([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)CN2c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
4N HCl-dioxane (5 ml) was added to a solution of 1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (100 mg) in ethanol (5 ml ), the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 78 mg of the titled compound (Yield: 100%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]#[N:13]>CCOCC>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C#N)cc1Br
Reactant: Oc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C#N)cc1Oc1ccccc1

Procedure:
Phenol and 3-bromo-4-methoxybenzonitrile were subjected to Ullman ether coupling according to the procedure described in synthetic method 9 to afford product as a white solid: 1H NMR (CDCl3) δ 7.43 (dd, J=8.6, 2.0 Hz, 1H), 7.40-7.32 (m, 2H), 7.19-7.11 (m, 2H), 7.03 (d, J=8.6 Hz, 1H), 7.01-6.94 (m, 2H), 3.93 (s, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:25][C@H:26]1[O:28][CH2:27]1)(=O)=O>CN(C)C=O>[O:28]1[CH2:27][C@H:26]1[CH2:25][O:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7]
Reactant: O=C1OCCC1=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To α-(2′-hydroxybenzylidene)-γ-butyrolactone (60 g) were added dimethylformamide (600 ml) and potassium carbonate (87 g) and (S)-glycidyl nosylate (82 g) was added. The reaction mixture was stirred for 2 days at room temperature. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate to give the title compound (55 g), melting point 68–70° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].C([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](F)=[C:25]([Cl:30])[CH:24]=2)[CH2:17]1)C1C=CC=CC=1.O>CN(C)C=O>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C@H:18]2[O:19][CH2:20][CH2:21][NH:16][CH2:17]2)=[CH:24][C:25]=1[Cl:30]
Reactant: OCC(F)(F)F
Reactant: Fc1ccc(C[C@@H]2CN(Cc3ccccc3)CCO2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 10 °C
Reaction time: 18 h

Procedure:
To a suspension of sodium hydride (50 mg, 1.25 mmol) in N,N-dimethyl formamide (0.5 mL) at 0° C. was added 2,2,2-trifluroethanol (125 mg, 1.25 mmol), and the resultant mixture stirred for 5 mins. N-Benzyl-(R)-2-(4-fluoro-3-chlorobenzyl)morpholine, example 27, intermediate (a) (100 mg, 0.31 mmol) was added in one portion as a solution in N,N-dimethyl formamide (1.0 mL) via syringe and the reaction mixture warmed to 10° C. and shaken at that temperature for 18 hrs. The reaction was cooled to room temperature and poured into water (20 ml). The suspension was extracted with ethyl acetate (20 mL×2). Combined organic extracts were washed with water (20 mL×2) and brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 20% ethyl acetate/isohexane) to yield the desired product as a light yellow oil (38 mg) and used directly in the next reaction. The material was dissolved in 1,2-dichloroethane (2 mL), and 1-chloro-ethyl-chloroformate (33 mg, 0.23 mmol) added in one portion. The resulting mixture was heated at 90° C. for 24 hrs. The reaction was then concentrated in vacuo. The residue was dissolved in methanol (10 mL), and heated at 80° C. for 5 hrs. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane and poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The column was then washed with ammonia (2N solution in methanol, 2 mL×3) and the ammonia washes were concentrated in vacuo to yield example 40 as a yellow oil (20 mg).
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[Cl:16].[CH3:18][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[O:17])[CH3:18])=[C:10]([Cl:16])[CH:11]=1
Reactant: C[Mg]Br
Reactant: O=C(Sc1ccccn1)c1ccc(Br)cc1Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 80 %

Procedure:
4-Bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl ester (1.86 g, 5.66 mmol) from Step 1 above was dissolved in dry THF (30 mL) and cooled to −78° C. A solution of methyl magnesium bromide in 75:25 toluene/THF (1.4 M, 4.45 mL, 6.23 mmol) was added dropwise. After stirring 35 min, the cooling bath was removed. The reaction mixture was quenched with saturated 1N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (1.05 g, 80%) as a colorless oil.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][C:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[C:24]([C:28]([NH:31][S:32]([CH2:35][C:36]([F:39])([F:38])[F:37])(=[O:34])=[O:33])([CH3:30])[CH3:29])[CH:25]=[CH:26][CH:27]=2)[N:19]([CH3:40])[N:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:60][C:61]1[CH:66]=[CH:65][C:64](O)=[CH:63][CH:62]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:37][C:36]([F:39])([F:38])[CH2:35][S:32]([NH:31][C:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20]2[N:19]([CH3:40])[N:18]=[C:17]([CH2:16][O:15][C:64]3[CH:65]=[CH:66][C:61]([F:60])=[CH:62][CH:63]=3)[CH:21]=2)[CH:23]=1)([CH3:30])[CH3:29])(=[O:34])=[O:33]
Reactant: Oc1ccc(F)cc1
Reactant: Cn1nc(CO)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nc(COc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisopropyl azodicarboxylate (57 mg, 0.27 mmol) was added dropwise to a stirred solution of the alcohol from Step 5 (75 mg, 0.19 mmol), PPh3 (75 mg, 0.27 mmol) and 4-fluorophenol (26 mg, 0.23 mmol) in THF (10 mL) under N2 and the resulting mixture was stirred at RT for 2 hours. Further DIAD (19 mg, 0.09 mmol), PPh3 (25 mg, 0.09 mmol) and 4-fluorophenol (11 mg, 0.09 mmol) were added and stirring was continued for a further 30 min. The reaction mixture was then concentrated under reduced pressure while loading on to MgSO4 and then purified by column chromatography on silica eluting with 100% Et2O to yield the desired ether (19 mg, 20%). 1H NMR (CDCl3, 360 MHz) δ 7.58-7.53 (2H, s), 7.49 (1H, t, J=7.5 Hz), 7.37 (1H, d, J=7.5 Hz), 6.97 (4H, app. d, J=6.1 Hz), 6.41 (1H, s), 5.05 (2H, s), 4.99 (1H, s), 3.88 (3H, s), 3.48 (2H, q, J=8.9 Hz), 1.81 (6H, s). MS (ES+) C22H23F4N3O3S requires: 485, found: 486 (M+H+, 100%).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[CH:11][C:10]=2[N+:20]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[NH2:20][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:13]=[CH:14][C:9]=1[NH:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(NCC2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl {4-[(cyclohexylmethyl)amino]-3-nitrophenyl}carbamate (1.05 g, 3.42 mmol) was dissolved in 30 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken in a Parr hydrogenation apparatus under H2 atmosphere (40 psi) at RT overnight The solution was filtered through Celite and the solvent was evaporated. The product was directly used in the next step without further purification. Yield: 950 mg (99%). MS (ESI) (M+H)+: 277.9.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]([CH3:35])([CH3:34])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:14]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCCC2)C(C)(C)C
Yield: 99.8 %

Procedure:
A solution of Compound 312 (0.48 g) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for thirty minutes. The solvents were removed by evaporation under reduced pressure and the residue was extracted between saturated aqueous NaHCO3 and EtOAc. The aqueous phase was saturated with sodium chloride and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give Compound 314 (0.38 g).
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH:9][OH:10]>>[CH3:1][C:2]1([O:9][O:10][C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OO
Reactant: CC1(O)CCCCC1
Product: CC1(OOC2(C)CCCCC2)CCCCC1

Procedure:
1-methylcyclohexanol (30 g, 0.26 mol) was placed in a 100 mL three necked round bottomed flask and was stirred. The flask was cooled in a brine/ice bath, dropping funnel fitted and fitted with a static N2 supply. The dropping funnel was charged with 98% sulfuric acid (16.14 ml) and water (6.45 ml) giving a 70% sulfuric acid solution. This was added dropwise to the 1-methylcyclohexanol and stirring continued to give a viscous brown mixture. The bath was recharged with ice/brine, dropping funnel rinsed with water and recharged with 35% hydrogen peroxide (6.98 mL, 0.125 mol) and added dropwise. The solution separated into two phases. Cyclohexanol (150 mL) was added and the mixture was transferred to a separating funnel. The aqueous fraction was extracted with another portion of cyclohexane (150 ml) and the combined organic fractions washed with 1M NaOH (2×100 mL), water (2×150 mL), dried and evaporated to give a viscous colourless oil. (12.98 g). The oil was sorbed onto silica gel then placed on a silica gel column and eluted with cyclohexane. After evaporation at reduced pressure 0.7 g colourless oil of di(1-methyl-cyclohexyl)peroxide was obtained. 13C-NMR (CDCl3) δ 22.45, 25.01, 25.95, 35.39, 78.58
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 3.22 g) and 2-(3-bromopropoxy)-tetrahydropyran (4.14 g) were dissolved in DMF (30 ml), and sodium hydride (445 mg) was added. After stirring at RT for 3 h, the mixture was left to stand overnight. Then the DMF was drawn off and the residue was taken up in EA, washed with water, dried, filtered and concentrated. 5.37 g of product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](O)=[O:12])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[CH2:35]([N:38]1[CH2:43][CH2:42][N:41]([CH:44]2[CH2:48][CH2:47][NH:46][CH2:45]2)[CH2:40][CH2:39]1)[CH2:36][CH3:37].C(=O)([O-])[O-]>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11](=[O:12])[N:46]3[CH2:47][CH2:48][CH:44]([N:41]4[CH2:42][CH2:43][N:38]([CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40]4)[CH2:45]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C(c1ccccc1)n1c(=O)[nH]c2cc(Cl)ccc21
Reactant: CCCN1CCN(C2CCNC2)CC1
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN1CCN(C2CCN(C(=O)C(c3ccccc3)n3c(=O)[nH]c4cc(Cl)ccc43)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
110 mg (0.36 mmol) of (5-chloro-2-oxo-2,3-dihydrobenzimidazol-1-yl)phenyl-acetic acid (VIIIe), 69.1 mg (0.51 mmol) of HOBt and 335 mg (0.44 mmol, 1.3 mmol/g) of solid phase-bound PS-carbodiimide were dissolved in 6 ml of dry dichloromethane in a screw-cap tube and shaken mechanically at room temperature for 10 min. 78.9 mg (0.40 mmol) of 1-propyl-4-pyrrolidin-3-ylpiperazine were added, and the mixture was then shaken mechanically overnight. Three equivalents of solid phase-bound MP-carbonate were then added to the reaction mixture, and shaking was continued for 2 h. The solid phase-bound reagents were filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue was dried in vacuo. The reaction product was used without further purification for the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]1>[Ni].C1COCC1>[O:19]=[S:15]1(=[O:18])[CH2:16][CH2:17][N:12]([C:3]2[C:4]([F:11])=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 40 °C

Procedure:
To an autoclave is added the product of example 2 (7.0 kg, 24 moles, 1.0 eq). Raney Nickel (1.4 kg) is activated and suspended in 4 L of THF. The slurry is added to the autoclave followed by additional THF (66 L). The mixture is heated at 40° C. and under 40 psi H2 till completion. The mixture is filtered and the filtrate is directly used in the next step. A small portion of the filtrate is concentrated and recrystallized in isopropanol to give the title compound.
Reaction SMILES: NN.C1(=O)[N:7]([CH2:8][C:9]2[S:13][C:12]3=[CH:14][N:15]=[CH:16][N:11]3[CH:10]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:7][CH2:8][C:9]1[S:13][C:12]2=[CH:14][N:15]=[CH:16][N:11]2[CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cn2cncc2s1
Agent: NN
Solvent: CCO
Product: NCc1cn2cncc2s1
Yield: 102.6 %

Procedure:
A 0.046 ml potion of anhydrous hydrazine was added to 10 ml of a dry ethanol solution containing 278.6 mg of 2-phthalimidomethylimidazo[5,1-b]thiazole, and the solution was then heated under reflux for 2 hours. The reaction solution was cooled on ice, and the resulting crystal was removed therefrom by filtration, followed by washing with a small amount of dichloromethane. The filtrate was concentrated under reduced pressure, and to the resulting residue, 15 ml of dichloromethane was added, and the solution was then alkalified with 1N sodium hydroxide. The aqueous layer was extracted with dichloromethane (20 ml×10). The combined organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was then evaporated under reduced pressure to obtain 154.6 mg of 2-aminomethylimidazo[5,1-b]thiazole.