Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[C:12]=[O:13])[C:10]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=[C:4]1[C:5]([OH:7])=O.[NH2:25][C:26]1[C:34]2[N:33]=[C:32]([CH3:35])[N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1.OS1C2C=CC=CC=2N=C1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH:3]1[C:11](=[C:12]=[O:13])[C:10]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=[C:4]1[C:5]([NH:25][C:26]1[C:34]2[N:33]=[C:32]([CH3:35])[N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:7]
Reactant: Cc1nc2c(N)cccc2n1C(=O)OC(C)(C)C
Reactant: COC1C(=C=O)C(N2CCCCc3ccccc32)=CC=C1C(=O)O
Agent: O[SH]1C=Nc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1C(=C=O)C(N2CCCCc3ccccc32)=CC=C1C(=O)Nc1cccc2c1nc(C)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
A mixture of 2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-carbonylbenzoic acid (200 mg), 4-amino-1-tert-butoxycarbonyl-2-methyl-1H-benzimidazole (152 mg), WSCD·HCl [water soluble carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 141 mg] and 1-hydroxybenzotiazole (100 mg) in N,N-dimethylformamide (5 ml) was stirred at room temperature overnight, and the mixture was diluted with ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogencarbonate solution, water, and brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography using chloroform as an eluent to give 2-methoxy-N-[2-methyl-1-(tert-butoxycarbonyl)-1H-benzimidazol-4-yl]-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-carbonylbenzamide (185 mg).
Reaction SMILES: [C:1]([O:6]CC)(=O)[C:2]([NH2:4])=[O:3].[NH2:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1>>[CH3:18][C:12]1([CH3:19])[CH2:11][CH:10]([NH:9][C:1]([C:2]([NH2:4])=[O:3])=[O:6])[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CCOC(=O)C(N)=O
Product: CC1(C)CC(NC(=O)C(N)=O)CC(C)(C)N1
Reaction time: 3 h

Procedure:
The filtrate was transferred back to the 250 ml 3-neck flask and another 30.5g of ethyl oxamate was added. An additional 39g of 4-amino-2,2,6,6-tetramethylpiperidine were added over 7 minutes as the temperature slowly rose to 28° C. The reaction was stirred 3 hours and filtered. After air drying overnight, the filter cake weighed 50.0g and had a melting point of 198°-200° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[Cl:16].[H-].[Na+].CC1C=CC(S(O[CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][O:33][CH2:32]2)(=O)=O)=CC=1>CN(C=O)C.[NH4+].[Cl-]>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][O:33][CH2:32]2)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:5]=[CH:4][C:3]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(Br)n1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCOC2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC1CCCOC1)c1ccc(Cl)c(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a cooled (0° C.), stirred solution of tert-butyl 6-bromo-5-chloropyridin-2-ylcarbamate (1.00 g, 3.25 mmol) in DMF (13.0 mL) was added 60% dispersion NaH (0.156 g, 3.90 mmol) under Argon. Stirred at 0° C. for 30 mins then added racemic (tetrahydro-2H-pyran-3-yl)methyl 4-methylbenzenesulfonate (1.143 g, 4.23 mmol). The mixture was then allowed to warm to 25° C. and stirring continued for 19 h. The reaction mixture then was diluted with saturated NH4Cl and then extracted with EtOAc (×3). Organics washed with water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; 5% to 15% EtOAc/heptanes) to give racemic tert-butyl 6-bromo-5-chloropyridin-2-yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate (938 mg).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[C:16]([Cl:19])[C:15]([C:20](=[O:30])[N:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:14]2)=[C:9]([C:31]([N:33]2[C@H:42]([CH2:43][OH:44])[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[CH:8]=1)C.Cl>[OH-].[Na+].CO>[Cl:19][C:16]1[C:15]([C:20](=[O:30])[N:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:45])=[O:3])=[CH:8][C:9]=2[C:31]([N:33]2[C@H:42]([CH2:43][OH:44])[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[C:17]=1[CH3:18]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OCC(=O)OCC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OCC(=O)O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Yield: 19.4 %

Procedure:
A solution of [4-(4-chloro-3-dibutylcarbamoyl-5-methyl-pyrazol-1-yl)-3-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenoxy]-acetic acid ethyl ester (10 mg, 0.016 mmol) in sodium hydroxide (2N, 0.039 mL) and methanol (0.1 mL) was stirred at ambient temperature for 12 hours. Added aqueous HCl solution until pH is about 5. The crude material was purified by HPLC to afford the title compound (1.9 mg, 20% yield). MS (ESI) [m/e, (M+H)+]=611.5. 1H NMR (400 MHz, chloroform-d) δ ppm 6.78-7.37 (m, 7H), 4.08-5.51 (m, 5H), 2.33-3.75 (m, 8H), 2.13-2.33 (m, 3H), 0.60-1.72 (m, 14H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[C:24]([C:31](O)=[O:32])=[N:25][CH:26]=[C:27]([C:29]#[N:30])[CH:28]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:24]3[C:23]([Cl:22])=[CH:28][C:27]([C:29]#[N:30])=[CH:26][N:25]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.5 %

Procedure:
To solution of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (2b, 0.093 g, 0.301 mmol) and 3-chloro-5-cyano-2-pyridinecarboxylic acid (Bionet Research, 0.056 g, 0.307 mmol) in THF (1 mL) and MeOH (0.25 mL) at 0° C. was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (Aldrich, 0.084 g, 0.304 mmol). The reaction mixture was warmed to room temperature, stirred for 17 h and concentrated. Purification by flash column chromatography on silica gel (24 g, 10% to 60% EtOAc (10% 2M NH3 in MeOH) in hexanes) afforded the title compound (0.069 g, 0.146 mmol, 48.4% yield) as a pale yellow solid. MS m/z=474.0 (M+H); Calculated mass for C19H13ClF5N5O2: 473.1
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH:14]([CH:15]([CH:17]=C)[CH3:16])[O:13][C:12](=[O:19])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.I([O-])(=O)(=O)=[O:22].[Na+].[BH4-].[Na+]>[Os](=O)(=O)(=O)=O.CO.O>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH:14]([CH:15]([CH3:16])[CH2:17][OH:22])[O:13][C:12](=[O:19])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC(C)C1OC(=O)N[C@@H]1COCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(CO)C1OC(=O)N[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (4R)-4-(benzyloxymethyl)-5-(but-3-en-2-yl)oxazolidin-2-one (1.0 equiv.) in 2:1 MeOH/H2O (0.04 M) was added osmium tetroxide 4% in H2O (0.07 equiv) and sodium periodate (3.0 equiv.). After stirring for 3 hours, the white precipitate was filtered and rinsed with EtOAc. The combined filtrate was concentrated in vacuo and the residue was dissolved in EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered and concentrated. The crude aldehyde was dissolved in EtOH (0.08 M) and upon cooling to 0° C., sodium borohydride (2.0 equiv.) was added. After stirring for 15 hours and coming to room temperature the reaction was quenched by addition of H2O. After stirring for 20 minutes, the EtOH was removed in vacuo, EtOAc was added and the solution was washed with 1N HCl, NaHCO3(sat.) and NaCl(sat.), dried over MgSO4, filtered and concentrated yielding after purification by silica gel chromatography (4R)-4-(benzyloxymethyl)-5-(1-hydroxypropan-2-yl)oxazolidin-2-one as a 3:1 mixture of isomers (60%). LCMS (m/z): 266.1 (MH+); LC Rt=2.28 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15].[Si](OC)(OC)(OC)OC.[F-].[K+].[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)([O-:29])=[O:28]>CN(C)C=O.CCOCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:13])([CH3:14])[C:7](=[CH:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1)[C:6]2=[O:15]
Reactant: COc1ccc2c(c1)C(=O)CC(C)(C)O2
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CO[Si](OC)(OC)OC
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)(C)O2
Temperature: 80 °C
Yield: 59.8 %

Procedure:
A mixture of 7.0 g (0.034 mole) of the product of Example 109, 2.5 mL (2.6 g, 0.017 mole) tetramethyl orthosilicate, 1.9 g (0.034 mole) potassium fluoride and 5.1 g (0.034 mole) 3-nitrobenzaldehyde in 10 mL dimethylformamide was heated to 80° C. for 4 hours. The mixture was diluted with ether and washed successively with 1N HCl, 5% NaHCO3, water and brine and then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes yielded an oil. Recrystallization from ether/hexanes afforded 6.9 g (60%) of the title product as a solid. Mp 103°-105° C. Analysis calculated for C15H17NO5 : C, 67.25; H, 5.05; N, 4.13. Found: C, 67.22; H, 4.87; N, 4.11.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: C1COCCN1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCOCC5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and morpholine. LCMS (M+H)+=517.0/519.0.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH:34]1[S:38][CH:37]=[CH:36][C:35]=1[C:39]([CH:41]([CH3:43])[CH3:42])=[O:40]>O1CCCC1>[Br:1][C:41]([C:39](=[O:40])[C:35]1[CH:36]=[CH:37][S:38][CH:34]=1)([CH3:43])[CH3:42]
Reactant: CC(C)C(=O)c1ccsc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)c1ccsc1

Procedure:
2.88 g of phenyltrimethylammonium tribromide was added to a mixed solution comprising 1.54 g of 2-(3-thenoyl)propane and 30 ml of tetrahydrofuran, followed by a reaction at room temperature for 15 hours. After completion of the reaction, the precipitate was separated by filtration and concentrated, and then purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/8-4/6) to obtain 0.87 of 2-bromo-2-(3-thenoyl)propane. The NMR spectrum data of this product were as follows.
Reaction SMILES: NCC1C=CC2N(CCC(C)C)C(CN3C4C=CC=CC=4N(C(C)C)C3=O)=NC=2C=1.[CH:31]([N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]([CH2:43][C:44]2[N:48]([CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[C:47]3[CH:54]=[CH:55][C:56]([CH2:58][C:59]#[N:60])=[CH:57][C:46]=3[N:45]=2)[C:35]1=[O:61])([CH3:33])[CH3:32]>>[NH2:60][CH2:59][CH2:58][C:56]1[CH:55]=[CH:54][C:47]2[N:48]([CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[C:44]([CH2:43][N:36]3[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[N:34]([CH:31]([CH3:33])[CH3:32])[C:35]3=[O:61])=[N:45][C:46]=2[CH:57]=1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CC#N)ccc21
Agent: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CN)ccc21
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CCN)ccc21

Procedure:
1-[5-(2-Amino-ethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one was prepared by the same procedure as 1-[5-aminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one, except using [2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-yl]-acetonitrile.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:17][CH:16]3[N:18](C(OC(C)(C)C)=O)[CH:13]([CH2:14][CH2:15]3)[CH:12]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]>O1CCOCC1.C(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:12][CH:13]3[NH:18][CH:16]([CH2:15][CH2:14]3)[CH:17]=2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1C2C=C(c3ccc([N+](=O)[O-])cc3)CC1CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C2=CC3CCC(C2)N3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Hydrogen chloride (22 mL of a solution 4N in dioxane) was added to a solution of tert-butyl 3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (1.97 g; 5.96 mmol; 1.0 eq.) in DCM (20 mL) and the reaction mixture was stirred at RT. After 1 h, the reaction mixture was diluted with DCM and organic phase was washed with NaOH 1N and brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow solid (1.05 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J=9.0 Hz, 2H), 7.65 (d, J=9.0 Hz, 2H), 6.82 (dt, J=6.0 Hz, 1.5 Hz, 1H), 3.74-3.69 (m, 2H), 2.76 (dd, J=17.5 Hz, 4.5 Hz, 1H), 2.17 (dd, J=17.5 Hz, 1.5 Hz, 1H), 1.92-1.68 (m, 3H), 1.56-1.46 (m, 1H). HPLC (max plot) 91.7%; Rt %1.84 min. UPLC/MS: (MS+) 231.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]2[N:5]([CH2:9][CH2:10][N:11]=2)[C:6](=[O:8])[CH:7]=1.O.[N:17]([O-])=[O:18].[Na+]>CC(O)=O>[NH2:1][C:2]1[N:3]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]2[N:5]([CH2:9][CH2:10][N:11]=2)[C:6](=[O:8])[C:7]=1[N:17]=[O:18]
Reactant: O=N[O-]
Reactant: CC(C)CN1C(N)=CC(=O)N2CCN=C21
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CN1C2=NCCN2C(=O)C(N=O)=C1N
Reaction time: 0.5 h

Procedure:
To a solution of 5.00 g. (0.024 mole) of the product of Procedure 30 in 15 ml. H2O and 4 ml. HOAc (0°) was added (portionwise) 1.72 g. (0.024 mole) NaNO2. The mixture was stirred at 24° for 30 min., cooled to 0° and filtered to yield 4.44 g. (72%) of a purple solid, mp 203°-205° d.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])=[O:6])([CH3:3])[CH3:2].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([C:28]([F:31])([F:30])[F:29])[N:21]=1>ClCCCl>[CH3:27][O:26][C:24]1[N:23]=[C:22]([C:28]([F:31])([F:29])[F:30])[N:21]=[C:20]([NH:19][C:17](=[O:18])[NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])(=[O:15])=[O:14])[N:25]=1
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(C(F)(F)F)n1
Solvent: ClCCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC(C)C)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of 5.4 g of 2-(i-propoxycarbonyl) benzenesulfonyl isocyanate (20 mmol) in 5.4 g of 1,2-dichloroethane is added dropwise over the course of 5 min to a solution of 3.9 g of 2-amino-4-methoxy-6-trifluoromethyl-1,3, 5-triazine (20 mmol) in 150 ml of 1,2-dichloroethane at 25° C. The mixture is stirred at 25° C. for 16 h and then at 50° C. for 2 h. After removal of the volatiles under waterpump vacuum at 60° C., the residue is stirred with a mixture of ethanol and pentane, when crystallization occurs. The product is filtered off with suction and dried at 50° C. under waterpump vacuum. 6.1 g of the title compound (13 mmol; 66% of theory) are isolated with melting point 182°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>CO>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][C@@H:26]([OH:27])[CH2:28][NH:36][CH3:35])=[CH:22][CH:23]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: CO
Product: CCOCc1nc(-c2ccc(OC[C@@H](O)CNC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate B3) in 4 mL of methylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0 M) in EtOAc as an eluent to afford (S)-1-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C@@H:5]([CH3:7])[C@H:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[S:3]1.[CH:15]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC=CC=1.C(N(CC)CC)C>[CH:15]1([NH:21][C:22]([N:1]=[C:2]2[N:6]([C:22](=[O:23])[NH:21][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C@@H:5]([CH3:7])[C@H:4]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[S:3]2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1ccc([C@@H]2SC(=N)N[C@H]2C)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc([C@@H]2SC(=NC(=O)NC3CCCCC3)N(C(=O)NC3CCCCC3)[C@H]2C)cc1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
1.0 g of trans-2-imino-4-methyl-5-(4-methylphenyl)thiazolidine was dissolved in 20 ml of benzene. To the solution were added 1.3 g of cyclohexylisocyanate and one drop of triethylamine, respectively. The mixture was stirred for an hour at room temperature and refluxed for further an hour. The reaction solution was condensed under reduced pressure. The oily product obtained was purified by column chromatography to give 1.1 g of the title compound.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH3:24][C@@H:25]([OH:29])[CH2:26][CH2:27][CH3:28]>>[CH3:24][C@@H:25]([O:29][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCC[C@@H](C)O
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCC[C@@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C

Procedure:
Sodium t-butoxide (27.3 g, 284 mmol) was added portionwise to (R)-2-pentanol (140 ml) at room temperature, the mixture was stirred until homogeneous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (18.0 g, 71.0 mmol) was added and the reaction mixture heated at 50° C. for 160 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was washed with saturated sodium chloride solution (100 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with ether and the solid material filtered. The precipitate was re-washed with ether and the filtrates combined and evaporated. The crude material (ca. 10 g) was dissolved in DMSO:methanol (1:1) and purified on a reverse phase (C18) column (330 g) using a gradient of 25-65% acetonitrile (+0.1% TFA)-water (+0.1% TFA) over 8 column volumes, the fractions were immediately neutralised with saturated aqueous sodium carbonate solution. Appropriate fractions were combined and partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic phase was dried (MgSO4), filtered and evaporated to give the title compound as a pale cream foam (5.05 g).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH:6]1(B(O)O)[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][N:29]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:28](=[O:36])[C:27]=1I)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][N:29]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:28](=[O:36])[C:27]=1[CH:6]1[CH2:8][CH2:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)C1CC1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1CC1CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1c(C2CC2)c(OCc2ccccc2)ccn1CC1CC1
Temperature: 175 °C

Procedure:
NaHCO3 (1.0 g, excess), cyclopropylboronic acid (0.74 g, 8.93 mmol), potassium carbonate (1.23 g, 8.93 mmol) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II)-DCM complex (0.36 g, 0.45 mmol) were added to a solution of intermediate D10 (1.0 g, 2.98 mmol) in 1,4-dioxane (10 ml). The resulting mixture was heated at 175° C. for 20 minutes under microwave irradiation, after which it was filtered through diatomaceous earth and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; 0-3% methanol/DCM as eluent). The desired fractions were collected and evaporated in vacuo yielding D34 (0.6 g, 69%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)ccc21
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.506 g, 1.76 mmol) in dichloromethane (20 mL) was treated with BBr3 (4.1 mL of a 1.0M solution in CH2Cl2, 4.1 mmol) and stirred overnight while warming to 20 C. The excess BBr3 was quenched with water, and the resulting mixture was diluted with ether (200 mL), washed with Na2CO3 (100 mL) and brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.460 g of a white solid foam. MS calculated for C13H14F3NO2+H: 274, observed: 274.