Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21]CC2C=CC(OC)=CC=2)[CH:12]=[C:11]([CH:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:32]2)[C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:12]=[C:11]([CH:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:32]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(COc2ccccc2-c2cc(C3CCCN(C(=O)OCc4ccccc4)C3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(-c2ccccc2O)cc(C2CCCN(C(=O)OCc3ccccc3)C2)c1C(=O)O
Reaction time: 8 h
Yield: 147.2 %

Procedure:
To a solution of tert-butyl 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-{2-[(4-methoxybenzyl)oxy]phenyl}nicotinate (0.95 g, 1.67 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (10 mL), and the stirring was continued at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was diluted with toluene, then concentrated under reduced pressure to remove excess of trifluoroacetic acid by azeotropic distillation to give 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-(2-hydroxyphenyl)nicotinic acid (1.1 g, yield; quant.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>ClCCl>[CH3:13][O:12][C:3]1[C:2]([NH:1][C:15](=[O:16])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
3-Amino-2-methoxyquinoline(4 g, 23 mmol) and phenyl chloroformate(4.04 g, 25 mmol) were dissolved in dichloromethane and stirred at room temperature for 2 hours. The above mixture was concentrated under the reduced pressure to remove dichloromethane and purified by column chromatography(hexane:ether=8:1) to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20]C)=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([F:19])[CH:12]=1)[CH:8]=[CH:7]2.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:19])[CH:12]=3)[CH:8]=[CH:7][C:6]=2[C:5]([OH:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2ccc3c(OC)ccc(Cl)c32)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-n2ccc3c(O)ccc(Cl)c32)cc1F
Temperature: 25 °C
Yield: 8 %

Procedure:
To a solution of 7-chloro-1-[3-fluoro-4-(methyloxy)phenyl]-4-(methyloxy)-1H-indole (D12) (533 mg, 1.75 mmol) in dichloromethane (50 mL) at −78° C. was added boron tribromide (1M solution in dichloromethane, 7 mL, 7.0 mmol). The reaction mixture was allowed to warm to room temperature and then quenched by the addition of methanol and then water and dichloromethane. After separation of the layers, the aqueous phase was re-extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate, filtered and concentrated at reduced pressure. The product was partially purified by silica gel chromatography eluting with 5-70% ethyl acetate in hexane. The product was further purified by MDAP to yield the title compound (E7), (39 mg).
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[N:10]=1)(=O)=O.[NH3:19]>>[F:18][C:13]1[CH:12]=[C:11]([C:9]2[N:10]=[C:5]([NH2:19])[N:6]=[N:7][CH:8]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: N
Reactant: CS(=O)(=O)c1nncc(-c2cc(F)cc(F)c2)n1
Product: Nc1nncc(-c2cc(F)cc(F)c2)n1
Yield: 74 %

Procedure:
5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine (18 g, 74%) was prepared from 3-(methylsulfonyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (31.0 g, 115.0 mmol) and ammonia gas according to the general procedure of Preparation 2.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1CCCO1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)[C@@H]4CCCO4)c23)C1
Temperature: 160 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A mixture of (S)-N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (195 mg, 0.594 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (357 mg, 1.78 mmol), and N-ethyl-N-isopropylpropan-2-amine (207 μL, 1.19 mmol) in n-BuOH (5 mL) were purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide tert-butyl (R)-1-(5-bromo-3-((S)-tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.295 mmol, 49.6% yield) as a solid. LCMS (APCI+) m/z 508.1, 510.1 (M+H)+; Retention time=3.85 minutes (Method 2).
Reaction SMILES: [CH2:1]([C:3]([OH:18])([CH2:6][CH2:7]/[CH:8]=[C:9](/[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)\[CH3:10])[CH2:4][CH3:5])[CH3:2].Br[CH2:20][C:21]1[CH:22]=[C:23]([C:31](OC)=[O:32])[C:24](=[CH:29][CH:30]=1)[C:25](OC)=[O:26]>>[OH:32][CH2:31][C:23]1[CH:22]=[C:21]([CH:30]=[CH:29][C:24]=1[CH2:25][OH:26])[CH2:20][O:17][C:13]1[CH:12]=[C:11](/[C:9](/[CH3:10])=[CH:8]/[CH2:7][CH2:6][C:3]([CH2:4][CH3:5])([OH:18])[CH2:1][CH3:2])[CH:16]=[CH:15][CH:14]=1
Reactant: CCC(O)(CC)CC/C=C(\C)c1cccc(O)c1
Reactant: COC(=O)c1ccc(CBr)cc1C(=O)OC
Product: CCC(O)(CC)CC/C=C(\C)c1cccc(OCc2ccc(CO)c(CO)c2)c1
Yield: 84.3 %

Procedure:
In a manner similar to Example 64(d), by reacting 112 mg (0.39 mmol) of (E)-3-ethyl-7-(3-hydroxyphenyl)oct-6-en-3-ol with 145 mg (0.51 mmol) of dimethyl 4-bromomethylphthalate, 131 mg (74%) of expected product are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[F:15]C12CC3CC(CC(N)(C3)C1)C2>>[F:1][C:2]12[CH2:11][CH:6]3[CH2:7][C:8]([F:15])([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: O=C(O)C12CC3CC(CC(F)(C3)C1)C2
Reactant: NC12CC3CC(C1)CC(F)(C3)C2
Product: O=C(O)C12CC3CC(F)(CC(F)(C3)C1)C2

Procedure:
The procedure of Example 2 for the conversion of 3-fluoroadamantane-1-carboxylic acid to 3-fluoroadamantan-1ylamine was utilized. 4.32 g (20 mmol) of 3,5-difluoroadamantane-1-carboxylic acid provided after 96 hours crude product which was chromatographed on silica gel using 4:1 hexane:EtOAc to afford 4.7 g (73%) of benzyl carbamate: mp 71.9-72.9° C.; 1H NMR (CDCl3) 1.80-1.90 (7H, m), 2.02-2.25 (6H, m) 2.40-2.50 (1H, m), 4.84 (1H, bs),5.04 (2H, bs), 7.30-7.40 (5H, m); 13C NMR (CDCl3) 29.07, 38.98, 40.15, 45.54, 47.16, 54.25, 66.37, 92.24 (188.67), 128.09, 128.17, 128.52, 128.56, 136.26, 154.18. Anal. Calc'd for C18H2NO2F2 : C, 67.27; H, 6.59; N, 4.36; F, 11.82; Found: C, 66.96; H, 6.54; N, 4.33; F, 11.71. Hydrogenation (HOAc/Pd/C/50 PSI) of 7.84 g (24.4 mmol) of this intermediate for a period of 5 hours provided 7.8 g (>100%) of 3, 5-difluoro-adamantan-1ylamine as its acetate salt.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:30]=2[N:31]=[CH:32][N:33]=1)[C@@H:15]1[O:29][C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35]([CH3:37])=O.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:30]=2[N:31]=[CH:32][N:33]=1)[C@@H:15]1[O:29][C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23])[C@@H:17]([O:18][CH2:34][S:35][CH3:37])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
3.0 g N6-Benzoyl-5′-O-tert-butyldimethylsilyl-2′-deoxyadenosine (5a) (6.38 mmol) was dissolved in a mixture consisting of 11.96 mL DMSO, 5.46 mL acetic acid, and 17.55 mL acetic anhydride and stirred at room temperature for 48 h. The reaction mixture was then neutralized treating with a sufficient amount of saturated NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extract was then washed with a saturated NaHCO3 solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The resultant yellowish oil was then purified on silica gel column (Hex: EtOAc/1:1 to 1:4) to obtain the product N6-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxyadenosine (6a) as white powder in 71% yield (2.4 g, Rf0.6, EtOAc: hex/7:3). HR-MS: obs. m/z 530.2273, calcd. for C25H36O4N5SiS 530.2257 [M+H]+. 1H-NMR (CDCl3): δH 9.00 (s, 1H), 8.83 (s, 1H), 8.35 (s, 1H), 8.05 (d, J=7.6 Hz, 2H), 7.62 (m, 1H), 7.55 (m, 2H), 6.55 (t, J=7.19 Hz, 1H), 4.73 (m, 2H), 4.68 (m, 1H), 4.24 (m, 1H), 3.88 (dd, J=11.19, 3.19 Hz, 1H), 2.74-2.66 (m, 2H), 2.35 (s, 3H), 0.94 (s, 9H) and 0.13 (s, δH) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[N:10][C:9]([C:13]([OH:15])=O)=[CH:8]2.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[NH:31][C:30]([NH2:33])=[N:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:18]1[CH:19]=[CH:20][N:16]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[N:31]=[C:30]([NH:33][C:13]([C:9]3[N:10]=[CH:11][C:12]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])=[O:15])[NH:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23]
Reactant: COc1cccc2cc(C(=O)O)ncc12
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ncc12
Yield: 37.8 %

Procedure:
32.3 mg (38%) of the 8-methoxy-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was synthesized according to General Procedure A from 41 mg (0.2 mmol) of 8-methoxy-isoquinoline-3-carboxylic acid, 48 mg (0.2 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 100 mg (0.264 mmol) of HBTU, 0.167 mL (0.97 mmol) of DIEA and 1 mL of DMF stirring at 80° C. for 2 h. LCMS: 428 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:4][N:5]([CH3:7])[CH:6]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Br:1][C:2]1[C:3]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cn1cc(Br)c(C2(O)CCC(=O)CC2)n1
Product: Cn1cc(Br)c(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(4-bromo-1-methyl-1H-pyrazol-3-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: BrCCC1OCCO1
Product: CCOC(=O)N1CCC(c2cn(CCC3OCCO3)c3ccccc23)CC1
Reaction time: 15 h
Yield: 94.9 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 4 g (0.015 mol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 2.07 mL (0.018 mol) of 2-(2-bromo-ethyl)-[1,3]dioxolane. After standard work-up, 5.3 g of 4-[1-(2-[1,3]dioxolan-2-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[C:9]([F:15])[C:8]=1[F:16])([CH3:4])([CH3:3])[CH3:2].C[N+]([O-:22])(C)C>CS(C)=O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:22])=[C:9]([F:15])[C:8]=1[F:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c(F)c1F
Reactant: C[N+](C)(C)[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(C=O)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
To a solution of 4-bromomethyl-2,3-difluoro-benzoic acid tert-butyl ester (12.9 g, 42.1 mmol) in DMSO (80 mL) and DCM (40 mL) at 0° C. was added trimethylamine N-oxide (3.4 g, 45.3 mmol). The reaction mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The resultant residue was partitioned between iced water and ethyl acetate. The organic layer was separated and washed with brine twice, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue which was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, TBME in cyclohexane) to afford the title compound as a white solid (4.34 g, 43%). 1H NMR (CDCl3, 400 MHz) 10.38 (1 H, d, J=0.8 Hz), 7.71 (1 H, dddd, J=7.4, 5.6, 1.7, 0.8 Hz), 7.63 (1 H, ddd, J=7.4, 5.6, 1.5 Hz), 1.61 (9 H, s).
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:43][N:44]([CH3:50])[S:45]([CH:48]=[CH2:49])(=[O:47])=[O:46]>>[CH3:43][N:44]([CH3:50])[S:45]([CH2:48][CH2:49][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:25]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)(=[O:47])=[O:46]
Reactant: C=CS(=O)(=O)N(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CCS(=O)(=O)N(C)C)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 375 (188 mg, 0.37 mmol) and triethylamine (0.18 mL, 1.3 mmol) in IMS (3 mL) was added ethenesulfonic acid dimethylamide and the reaction mixture stirred at RT for 18 h before being concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM) to give 499 as a beige solid (145 mg, 74%). LCMS: RT=3.47 min, [M+H]+=531. 1H NMR δ (ppm) (DMSO-d): 8.23 (1 H, d, J=8.19 Hz), 8.05 (1 H, s), 7.04 (1 H, dd, J=8.26, 1.80 Hz), 6.88 (1 H, d, J=1.76 Hz), 5.82-5.72 (1 H, m), 4.30 (2 H, t, J=5.02 Hz), 3.37 (2 H, t, J=5.04 Hz), 3.19 (2 H, t, J=7.23 Hz), 2.95 (2 H, d, J=10.97 Hz), 2.75 (6 H, s), 2.65 (2 H, t, J=7.25 Hz), 2.04 (2 H, t, J=11.43 Hz), 1.75 (2H, d, J=12.62 Hz), 1.67-1.53 (2 H, m), 1.50 (6 H, d, J=6.58 Hz). 1 H obscured by solvent
Reaction SMILES: [CH2:1]([C:7]12[S:14][CH2:13][C:10]([CH2:15][CH2:16][CH3:17])([CH2:11][S:12]1)[CH2:9][S:8]2)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].ClC1C=CC=C(C(OO)=[O:26])C=1.C([O-])(=O)C.[Na+]>C(#N)C>[CH2:1]([C:7]12[S:12][CH2:11][C:10]([CH2:15][CH2:16][CH3:17])([CH2:9][S:8]1)[CH2:13][S:14]2=[O:26])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCCC12SCC(CCC)(CS1)CS2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: C#CCCCCC12SCC(CCC)(CS1)CS2=O
Reaction time: 24 h
Yield: 41.6 %

Procedure:
A mixture of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo [2.2.2]octane (1.07 g. 1.0 equivalent), 3-chloroperbenzoic acid (0.80 g., 1.05 equivalent, 85% Lancaster Synthesis), and anhydrous sodium acetate (1.0 g.) in anhydrous acetonitrile was stirred at 20° from 24 hours. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was separated, washed with sodium hydrogen carbonate solution and brine before drying over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica. Elution with hexane: ethyl acetate mixtures (20% 75%) ethyl acetate gave 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[ 2.2.2]octane 2-oxide as a colourless solid (0.47 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][N:18]=1)[C:5]([NH:7][CH3:8])=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:39][C:40]([F:44])([F:43])[CH2:41]O.O>C1COCC1>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([O:26][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:25])=[CH:19][N:18]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: OCC(F)(F)F
Reactant: CNC(=O)C(=NOC)c1ccccc1COc1ncc(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncc(C(=O)OCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 38 (0.3 g, 0.79 mmol) was dissolved in THF (10 mL) to which carbonyldiimidazole (0.129 g, 0.79 mmol) was added. The solution was stirred at room temperature for one hour, at which time 2,2,2-trifluoroethanol (10 mL) was added and the solution stirred overnight at room temperature. The solution was poured into 4-5 volumes of water and extracted with Et2O (2×100 mL). The organics were dried over MgSO4 and concentrated to a yellow-brown oil (0.19 g). Crude product was chromatographed using silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 petroleum ether/ethyl acetate as the mobile phase. Elution and concentration gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(2,2,2-trifluoroethoxycarbonyl)-2-pyridinyl]oxy]methyl]-benzeneacetamide (0.09 g) as a green oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:14].Br[CH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]>CC(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=O)c1sccc1CBr
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(=O)c1sccc1CSc1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 68281936 %

Procedure:
2.62 g (19 mmol) of potassium carbonate and 2.74 g (19 mmol) of 2-chlorothiophenol are added to a solution of 5 g (19 nmol) of methyl 3-bromomethylthien-2-ylglyoxylate in 50 ml of acetone, the mixture is stirred for 72 hours at room temperature and filtered and the filtrate is evaporated down. The residue is taken up in methylene chloride, and the solution is washed with Na2CO3 solution, dried and evaporated down. The crude product is recrystallized from methanol. 4.24 g (68%) of the abovementioned compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Br:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:34][CH:35]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(CBr)cc3)cc2)n(C)c1=O
Yield: 40.1 %

Procedure:
A solution of 1,3-dimethylxanthine (990 mg), potassium carbonate (1348 mg) and 4-(4-bromomethylbenzoyl)benzyl bromide (2007 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:5) and recrystallized from ethyl acetate-isopropyl ether to provide the title compound as colorless solid (1021 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:11][C:8]1[S:7][C:6]([C:4](=[O:5])[CH2:3][NH:2][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:15][CH:16]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(C(=O)CN)s1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred suspension of 2-amino-1-(5-methylthienyl)ethanone hydrochloride (3.0 g of a mixture containing approximately 60% 2-amino-1-(5-methylthienyl)ethanone hydrochloride) in methylene chloride (100 ml) was cooled in an ice bath. To this cold mixture was added 4-(trifluoromethyl)benzoyl chloride (2.8 g, 0.013 mole), followed by the slow addition of a 2N solution of sodium hydroxide (9.4 ml). After complete addition, the mixture was stirred at room temperature for three days. The mixture was washed first with an aqueous 5% hydrochloric acid solution, followed by water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, yielding 3.9 g of N-[2-(5-methylthienyl)-2-oxoethyl]-4-trifluoromethylbenzamide as a solid. A small portion was recrystallized from ethanol for analysis, m.p. 182°-183° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:33](=[O:43])[N:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:35])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:36]([N:34]([CH3:35])[C:33]([C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][NH:8]1)=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccc1)C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Yield: 94.3 %

Procedure:
19176 B73: A solution of 9.68 g (16.33 mmol) (2S,4R)-2-(Benzyl-methyl-carbamoyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 33 ml CH2Cl2 was treated at −20° C. with 36 ml TFA, warmed up to RT during 5.5h and kept over night at 0° C.. The reaction was evaporated and treated with aqueous saturated NaHCO3 solution/EtOAc (3×), the organic phase was dried (Na2SO4) and evaporated to give 7.59 g (95%) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-2-carboxylic acid benzyl-methyl-amide, MS: 493 (MH+).