Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:10][N+:11]([O-])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[H][H]>CO.O=[Pt]=O>[NH2:11][CH2:10][C@@H:9]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)[S@](=O)N[C@H](C[N+](=O)[O-])c1cc(F)cc(Br)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)[S@](=O)N[C@H](CN)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)—N—((S)-1-(3-bromo-5-fluorophenyl)-2-nitroethyl)-2-methylpropane-2-sulfinamide (2.2 g, 5.99 mmol) was dissolved in MeOH (19.97 mL), flushed with N2 for 10 min, and then PtO2 (0.408 g, 1.797 mmol) was added. The reaction mixture was charged with hydrogen balloon and stirred at room temperature overnight. The reaction mixture was filtered through celite and washed by methanol and EtOAc. The filtrate was dried over Na2SO4, filtered and concentrated. The crude material was used in next step reaction without further purification. LCMS (m/z): 337.1/339.1 (MH+), 0.64 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([NH2:10])=[S:9])[CH:2]=1.Br[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[C:13](=O)[CH3:14]>C(O)C>[Cl:26][C:18]1[CH:17]=[C:16]([C:12]2[S:9][C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:10][C:13]=2[CH3:14])[CH:21]=[CH:20][C:19]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: NC(=S)Nc1cccnc1
Reactant: CC(=O)C(Br)c1ccc(S(N)(=O)=O)c(Cl)c1
Solvent: CCO
Product: Cc1nc(Nc2cccnc2)sc1-c1ccc(S(N)(=O)=O)c(Cl)c1
Temperature: 60 °C
Yield: 16.9 %

Procedure:
3-Pyridylthiourea (0.047 g, 0.31 mmol) is added to a stirred solution of 4-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (Example 23d) (0.10 g, 0.31 mmol) in ethanol (5 ml). The solution is heated at 60° C. for 3 hours. The solvent is removed and the residue is purified by chromatography on silica eluting with ethyl acetate-hexane to give the title compound (0.020 g).
Reaction SMILES: COC[CH2:4][CH2:5][N:6]=[C:7]=O.[CH2:9]([C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:31])[N:19]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)[C:18]=2[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:43](=O)([O-])[O-].[Na+].[Na+].C(N)C>ClCCCl>[CH2:9]([C:16]1[N:24]([CH2:4][CH2:5][NH:6][CH2:7][CH3:43])[C:23]2[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:31])[N:19]([CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=3)[C:18]=2[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCCCN=C=O
Reactant: COCCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: O=C([O-])[O-]
Agent: CCN
Agent: [Na+]
Solvent: ClCCCl
Product: CCNCCn1c(Cc2ccccc2)nc2c1c(=O)n(CCCOC)c(=O)n2CCc1ccc([N+](=O)[O-])cc1

Procedure:
By methods well known in the art 3-methoxypropyl isocyanate is converted into 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine. By the method of Example 3, this substance is alkylated with a mixture of 1,2-dichloroethane, sodium carbonate and ethylamine to yield 8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine. By the method of Example 4 this substance is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-(3-methoxypropyl)xanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:24])[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1)=[O:4].O[Li].O>C1COCC1.O.CO>[CH2:17]([N:7]1[CH2:8][CH:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:5]([CH3:24])([C:3]([OH:4])=[O:2])[CH2:6]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C(=O)O)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Yield: 97.5 %

Procedure:
A mixture of 7.7 g (22.4 mmol) rac-(3R,4R)-1-Benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidine-3-carboxylic acid methyl ester and 1.41 g (22.4 mmol) LiOH.H2O in 80 mL THF, 80 mL water and 8 mL methanol was heated to reflux over night. The organic solvents were removed under vacuum and the pH was adjusted to 4-5 by addition of HCl aq. (1N). The mixture was extracted with ethyl acetate/THF (2:1) and the combined organic layers were washed with brine, dried with Na2SO4, filtered off and evaporated to dryness. The residue was dried to yield 7.2 g (97%) of the title compound as light brown foam. MS m/e: 328.3 [M+H]+.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH:17]2[CH2:22][C:21](=[O:23])[C:20]([C:24](=[O:27])[CH2:25][CH3:26])=[C:19]([OH:28])[CH2:18]2)=[C:12]([CH3:29])[CH:11]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH3:16][C:14]1[CH:15]=[C:10]([OH:9])[CH:11]=[C:12]([CH3:29])[C:13]=1[CH:17]1[CH2:18][C:19](=[O:28])[C:20]([C:24](=[O:27])[CH2:25][CH3:26])=[C:21]([OH:23])[CH2:22]1
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(OCc3ccccc3)cc2C)CC1=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(O)cc2C)CC1=O
Reaction time: 3 h
Yield: 100 %

Procedure:
Palladium on activated carbon (0.30 g), followed by concentrated hydrochloric acid (20 ml), were added to a solution of 5-(4-benzyloxy-2,6-dimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (see Example 36) (3.22 g; 8.5 mmole) in ethyl acetate (200 ml). The mixture was hydrogenated at atmospheric pressure for 3 hours, then filtered, washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 5-(2,6-dimethyl-4-hydroxyphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (2.45 g; 100%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)[CH:25]=[CH:26][CH:27]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2cccc(Cl)c2)n1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2cccc(Cl)c2)[C@H]1O
Yield: 46 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (150 mg, 0.53 mmol) obtained in step 1 of example 2 and N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:1), to give desired compound (124 mg, yield: 46%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][NH:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][N:29]([S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)(=[O:17])=[O:16])[O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccc(OCc2ccccc2)c1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1cccc(OCc2ccccc2)c1)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A mixture of 3-benzyloxybenzenesulfonyl chloride (65 mg; 0.230 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol) and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately one hour. An additional quantity of 3-benzyloxybenzenesulfonyl chloride (13 mg, 0.046 mmol) was added and the reaction was heated at reflux for approximately 1 hour. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The phases were separated and the organic layer was then washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[3-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (140 mg, 89%). H1-NMR (chloroform-D3): 1.22 (m, 6H), 1.62 (m, 5H), 2.05 (m, 2H), 2.90 (m, 4H), 3.11 (b, 1H), 3.66 (m, 2H), 3.87 (m, 4H), 4.18 (m, 1H), 4.77 (m, 1H), 4.95 (m, 1H), 5.10 (m, 2H), 5.60 (d, 1H), 7.29 (m, 14H). MS(ESI): 703(M+Na).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12]C)=[CH:7][CH:6]=2.B(Br)(Br)Br.O>C(Cl)Cl>[OH:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=1)=[C:3]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a cold (5° C.) solution of (2E)-3-(4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (10) (1.10 g, 2.68 mmol) in CH2Cl2 (60 mL) was added BBr3 (0.8 mL, 8 mmol) slowly. The reaction mixture was stirred between 5° C. and 20° C. for 1 h and poured into water (150 mL) slowly. The layers were separated and the aqueous layer was further extracted with EtOAc (3×150 mL). The combined organic layer was washed with brine (1×100 mL) dried (Na2SO4) and concentrated to afford the crude product. Purification by flash column chromatography on silica gel using CHCl3:MeOH as an eluent, gave 0.88 g (83%) of the title compound as an off-white solid. IR (film): 30.58, 1682, 1632, 1599, 1504, 1227, 1165 cm−1. 1H NMR (400 MHz, MeOH-d4): δ 7.60 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.27-7.20 (m, 3H), 7.14-11 (m, 3H), 6.96 and 6.94 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.57 (d, J=8.4 Hz, 2H), 6.75 (d, J=16.0 Hz, 1H), 2.19 (s, 3H). 13C NMR (100 MHz, MeOH-d4): δ 169.5, 161.3, 156.1, 147.1, 144.78, 136.82, 136.3, 135.9, 130.3, 129.8, 129.5, 127.8, 126.83, 124.0, 123.9, 120.9, 118.1, 115.8, 115.7, 108.6, 20.32. HRMS Calcd for C26H20O4: 397.1440. Found: 397.1439.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:25]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]=2[O:42][CH3:43])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([NH:32][C:30]([C:25]4[C:24]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])=[C:34]([O:42][CH3:43])[CH:35]=3)=[O:38])[CH2:6][C:5]=12
Reactant: COc1cc(C(=O)Cl)ccc1NC(=O)c1ccccc1-c1ccccc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1NC(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To a solution of 0.70 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.56 g of N,N-diisopropylethylamine in 50 ml of methylene chloride is added 1.35 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-3-methoxybenzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate two additional times to give upon concentration in vacuo to give 1.5 g of amorphous solid. M+=512.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:29]=2[F:38])=[CH:26][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[S:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[C:29]=4[F:38])=[CH:26][N:27]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Fc1c(-c2cnc(CBr)s2)cccc1C(F)(F)F
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2ncc(-c3cccc(C(F)(F)F)c3F)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
55 mg (0.18 mmol) of the compound from Example 5A were reacted with 61 mg (0.18 mmol) of the compound from Example 91A analogously to the preparation of the compound in Example 77. This gave 55 mg (52% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[C:34](C1NC=CN=1)(C1NC=CN=1)=[O:35].C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][C:25]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[NH:1][C:34]2=[O:35])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2c(=O)[nH]c3cc(Oc4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide [Example C1] (62 mg, 0.14 mmol) was dissolved in dichloromethane (5 ml) and treated with carbonyl diimidazole (50 mg, 0.31 mmol) and DBU (0.1 ml). The mixture was stirred for 4 h at RT then the solvent removed and the residue purified by flash chromatography on silica gel (eluting with ammonia-methanol-dichloromethane) to obtain the title compound;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11]Cl)[N:10]=[C:4]2[CH:3]=1.[NH3:13]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][NH2:13])[N:10]=[C:4]2[CH:3]=1
Reactant: N
Reactant: ClCc1cn2ccc(Br)cc2n1
Solvent: CO
Product: NCc1cn2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 7-Bromo-2-chloromethyl-imidazo[1,2-a]pyridine (0.325 g, 1.326 mmol) in methanol (5 mL), NH3 gas is purged at 0° C. for 30 minutes. The reaction is allowed to stir at room temperature for 16 hours. The solvent is concentrated to afford the title compound (0.315 g). 1H-NMR (400 MHz, DMSO-d6) δ: 4.15 (s, 2H), 7.12-7.15 (dd J1=1.96 Hz, J2=7.24 Hz, 1H), 7.90 (s, 1H), 8.03 (s, 1H), 8.32 (bs, 2H), 8.61 (d, J=7.2 Hz, 1H). LC-MS (m/z): [M+H]=225.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[CH:4][N:3]=1.C(C1C=CN=CC=1)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]=1
Reactant: C=C(C)c1ccc(F)nc1
Agent: CC(C)c1ccncc1
Product: CC(C)c1ccc(F)nc1

Procedure:
2-fluoro-5-isopropylpyridine was synthesized from 2-fluoro-5-(prop-1-en-2-yl)pyridine following the general procedure as described for 4-isopropylpyridine.
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[NH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16].C(N(CC)CC)C>C(O)CCC>[OH:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][NH:12][S:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)(=[O:10])=[O:2]
Reactant: CC(C)(CN)CO
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(N)cc1

Procedure:
A mixture of sulphanilyl fluoride (1 g, 5.7 mmol), 3-amino-2,2-dimethylpropan-1-ol (884 mg, 8.6 mmol) and triethylamine (0.876 ml, 6.3 mmol) in butan-1-ol (20 ml) was heated at reflux for 24 hours. The volatiles were removed by evaporation and residue was purified by chromatography on silica gel to give the title compound. NMR: 0.72 (s, 6H), 2.52 (d, 2H), 3.08 (d, 2H), 4.40 (t, 1H), 7.19 (t, 1H), 7.60 (s, 1H), 7.64 (d, 2H), 7.96 (d, 2H), 8.40 (s, 1H), m/z 259 (MN)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5](/[CH:18]=[CH:19]\[CH3:20])[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15].ClC1C(C#N)=CC=C2C=1C=C(/C=C/C)N2CC(F)(F)F>CCOC(C)=O.O=[Pt]=O>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][CH2:19][CH3:20])[N:6]2[CH2:13][C:14]([F:15])([F:16])[F:17]
Reactant: C/C=C\c1cc2c(Cl)c(C#N)ccc2n1CC(F)(F)F
Agent: O=[Pt]=O
Agent: C/C=C/c1cc2c(Cl)c(C#N)ccc2n1CC(F)(F)F
Solvent: CCOC(C)=O
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1CC(F)(F)F
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 4-chloro-2-[(1Z)-1-propen-1-yl]-1-(2,2,2-trifluoroethyl)-1H-indole-5-carbonitrile (Example 13) and 4-chloro-2-[(1E)-1-propen-1-yl]-1-(2,2,2-trifluoroethyl)-1H-indole-5-carbonitrile (Example 14) (˜2:1 mixture, 0.014 g, 0.046 mmol) in EtOAc (2 mL) under N2, was added PtO2 (4 mg) and the mixture was hydrogenated under balloon pressure for 15 min. The catalyst was filtered off and washed with EtOAc and MeOH. The filtrate was concentrated and the residue was purified by radial chromatography (2-30% EtOAc-hexanes gradient) to afford the title compound (0.013 g, 92% yield): MS (ES) m/z 301 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C([O-])([O-])=O.[Cs+].[Cs+].[C:22]([O:26][C:27](=[O:46])[NH:28][CH2:29][C:30]1[CH:45]=[CH:44][C:33]2[N:34]([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[C:35]([CH2:37]Cl)=[N:36][C:32]=2[CH:31]=1)([CH3:25])([CH3:24])[CH3:23].Cl>CN(C=O)C>[C:22]([O:26][C:27](=[O:46])[NH:28][CH2:29][C:30]1[CH:45]=[CH:44][C:33]2[N:34]([CH2:39][CH2:40][CH:41]([CH3:42])[CH3:43])[C:35]([CH2:37][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6](=[N:5][O:4][CH2:3][CH2:2][F:1])[C:7]3=[O:15])=[N:36][C:32]=2[CH:31]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)CCn1c(CCl)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Reactant: O=C1Nc2ncccc2C1=NOCCF
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(CN2C(=O)C(=NOCCF)c3cccnc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Reaction time: 0.33 h
Yield: 72 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine-2,3-dione 3-[O-(2-fluoro-ethyl)-oxime] (23 mg, 0.11 mmol) in DMF (1.6 mL) was added Cs2CO3 (108 mg, 0.33 mmol). After stirring for 20 minutes, [2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester; HCl salt (44 mg, 0.11 mmol) was added and the resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic fractions washed with water, brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (eluant 1%, 5% MeOH in CH2Cl2) to give [2-[3-(2-fluoro-ethoxyimino)-2-oxo-2,3-dihydro-pyrrolo[2,3-b]pyridin-1-ylmethyl]-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (53 mg, 72%) as an off-white solid:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].C(C1C=CC([CH:20]([O:24]C(C2C=CC(C#N)=CC=2)C2OC2)[CH:21]2[O:23][CH2:22]2)=CC=1)#N.[OH-].[CH2:38]([N+:45](C)(C)C)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(OCCO)C>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:22][CH:21]([OH:23])[CH2:20][O:24][C:42]2[CH:43]=[CH:44][C:39]([C:38]#[N:45])=[CH:40][CH:41]=2)=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:1]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: N#Cc1ccc(C(OC(c2ccc(C#N)cc2)C2CO2)C2CO2)cc1
Agent: [OH-]
Solvent: CCOCCO
Product: CC(=O)c1ccc(OCC(O)COc2ccc(C#N)cc2)cc1O

Procedure:
A solution of 2,4-dihydroxyacetophenone (15.2 g), p-cyano-phenylglycidyl ether (17.5 g) and benzyltrimethyl-ammonium hydroxide (10 drops of a 40% solution) in 2-ethoxyethanol (75 ml) was heated under relux for 48 hours. The solvent was then removed under reduced pressure to give a beige solid. This was triturated with a little ether and filtered to give a pale beige powder, (28.6 g). Recrystallization from ethanol yielded 1-(4-acetyl-3-hydroxy-phenoxy)- 2-hydroxy-3-(p-cyanophenoxy) propane as white needles, m.p. 161.5°-163° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a stirring solution of 1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinol (4.00 g, 15.0 mmol) in DCM (150 mL) was sequentially added solid NaHCO3 (6.31 g, 75.1 mmol), Dess-Martin Periodane (7.65 g, 18.0 mmol) and H2O (0.27 mL, 15.0 mmol). The reaction was then vigorously stirred at rt for 1 h. The reaction was quenched with equal volumes of saturated sodium thiosulfate (aq) and saturated NaHCO3 (aq) and allowed to stir for an additional 0.5 h. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were then dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford 1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinone (2.15 g, 54%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (d, J=9.3 Hz, 1H), 6.61 (dd, J=9.4, 2.6 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 4.21 (q, J=7.0 Hz, 2H), 3.81 (t, J=6.1 Hz, 4H), 2.46-2.53 (m, 4H), 1.36 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][CH:25]([F:37])[O:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([NH:21][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH:25]([F:24])[F:37])[CH:28]=3)(=[O:35])=[O:34])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: COc1ccc(N)cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCN(C(=O)OC(C)(C)C)CC1

Procedure:
0.5 g of 4-(5-amino-2-methoxy-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.556 mmol) was reacted as described for Preparation example 1 with 3-(difluoromethoxy)-benzene-sulfonylchloride to yield 0.64 g of the title compound.