Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=C)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[O:35]1CCCC1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=[O:35])=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: C=Cc1ccc2nc(C)c(-c3nc(-c4ccccc4)c(-c4ncn(C5CCCCO5)n4)s3)n2c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.1 %

Procedure:
To the solution of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}-6-vinylimidazo[1,2-a]pyridine (0.747 g, 1.59 mmol) in Tetrahydrofuran (55 mL, 680 mmol) and Water (16 mL, 890 mmol) was added Sodium metaperiodate (0.852 g, 3.98 mmol), followed by 0.157 M of Osmium tetraoxide in Water (0.53 mL, 0.083 mmol). The solution was stirred at r.t. for 3 days. The mixture was diluted with ˜100 mL of water, filtered to collect the solid product as the first crop of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.255 g, 24% yield). LCMS: (FA) ES+ 471. 1H NMR (400 MHz, d1-chloroform) δ 10.56 (s, 1H), 10.00 (s, 1H), 8.30 (s, 1H), 7.94-7.97 (m, 2H), 7.82-7.85 (m, 1H), 7.69-7.71 (m, 1H), 7.46 (m, 3H), 5.48-5.51 (dd, J=8.78, 2.76 Hz, 1H), 4.06-4.09 (m, 1H), 3.73-3.77 (m, 1H), 2.85 (s, 3H), 2.02-2.15 (m, 3H), 1.59-1.69 (m, 3H). The filtrate was rotavaped to remove THF, extracted with 5% MeOH/DCM (4×60 mL). The combined DCM solution was dried over Na2SO4, filtered, rotavaped to give a crude material. Chromatograph in a 40 g ISCO column using MeOH/DCM (0/100 to 5/95) gave the second crop of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (fast fraction, 0.104 g, 14% yield), and 1-(2-methyl-3-[4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl]imidazo[1,2-a]pyridin-6-yl)ethane-1,2-diol (slow fraction, 0.243 g, 30.3% yield). LCMS: (FA) ES+ 503. 1H NMR (400 MHz, d1-chloroform & d4-methanol) δ 9.90 (s, 1H), 8.28 (s, 1H), 7.86-7.88 (m, 2H), 7.54-7.57 (d, J=9.29 Hz, 1H), 7.37-7.41 (m, 4H), 5.44-5.47 (m, 1H), 4.80-4.82 (m, 1H), 4.02-4.05 (m, 1H), 3.68-3.80 (m, 3H), 2.73 (s, 3H), 2.00-2.11 (m, 3H), 1.65-1.68 (m, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](O)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(OCC)C>[CH2:7]([OH:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCCCc1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
Into a solution of 12 g (0.31 mole) of lithium aluminum hydride in 100 ml of anhydrous diethyl ether was added dropwise a solution prepared by dissolving 37 g (0.25 mole) of cinnamic acid in 100 ml of anhydrous diethyl ether at a temperature of 0° to 20° C. After completion of the dropwise addition of the solution, the mixture was further agitated for additional 30 minutes at 20° C. and then admixed with 100 ml of a 10% hydrochloric acid followed by phase separation. The organic solution taken by phase separation was subjected to evaporation of the ether and then distilled under reduced pressure to give 11 g of dihydrocinnamyl alcohol, which yield was 31% of the theoretical value, but neither cinnamyl alcohol nor cinnamic aldehyde could be obtained.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[O:10]C(C)C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:19]>C(O)C.[Hg]>[CH:1]1([C:7]2[CH:18]=[CH:17][C:16]([CH:8]([CH3:7])[C:9]([OH:10])=[O:19])=[C:9]([OH:10])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(Oc1cccc(C2CCCCC2)c1)C(=O)O
Reactant: O
Agent: [Hg]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C2CCCCC2)cc1O

Procedure:
2 g of 2-(3-cyclohexyl-phenoxy)propionic acid in 180 cc of 95% ethanol are irradiated with a 150 Watt mercury high pressure burner for 2 hours in an atmosphere of argon and while cooling with water. The solution is concentrated by evaporation and the residue is chromatographed on 150 g of silica gel. By-products are first eluted with ethyl acetate/hexane (1:1). Elution with ethyl acetate finally yields pure 2-(4-cyclohexyl-2-hydroxyphenyl)propionic acid.
Reaction SMILES: FC1C(CO)=NC=CC=1F.[F:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:20])[C:17]=1[CH:18]=[O:19]>CO>[F:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:20])[C:17]=1[CH2:18][OH:19]
Reactant: O=Cc1c(F)cncc1F
Agent: OCc1nccc(F)c1F
Solvent: CO
Product: OCc1c(F)cncc1F
Yield: 73 %

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 7, replacing 3,4-difluoro-2-pyridinecarbaldehyde with 3,5-difluoro-4-pyridinecarbaldehyde (FRONTIER) and using MeOH as solvent. (200 mg, 1.398 mmol, 73% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.51 (s, 2H), 5.55 (t, 1H), 4.55-4.57 (m, 2H). [ES+MS] m/z 146 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH2:7]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[S:11])[CH3:8]>C(Cl)Cl>[CH2:7]([N:9]1[C:2](=[O:3])[C:1](=[O:5])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10]1=[S:11])[CH3:8]
Reactant: CCNC(=S)Nc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCN1C(=O)C(=O)N(c2ccc(F)cc2)C1=S
Yield: 94.6 %

Procedure:
Oxalyl chloride (12.7 g; 0.1 mol) was added dropwise to the stirring solution of N-ethyl-N′-(4-fluorophenyl) thiourea (16 g; 0.08 mol) in methylene chloride (200 mL). The mixture was heated at reflux for 1 hour then evaporated to dryness. Ethanol (200 mL) was added and the mixture was heated at reflux for 1 hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with 2N hydrochloric acid (2×400 mL) then with water (400 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethyl acetate/hexane to give 19.1 g of 1-ethyl-3-(4-fluorophenyl)-2-thioxo-4,5-imidazolidinedione, m.p. 172–174° C. Mass spectrum; FAB (M+H)+ m/z 253. 1H-NMR (DMSO-d6; 300 MHz): δ 7.42–7.34 (m, 4H), 3.92 (q, 2H), and 1.22 ppm (t, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>>[CH3:11][C:10]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][CH2:8][N:9]=1
Reactant: CC(=O)NCCc1ccccc1
Agent: N
Product: CC1=NCCc2ccccc21
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
The compound (25.3 g, 154.8 mmol) prepared in Step 1 above was added to polyphosphoric acid (250 g) and then stirred for 1.5 hours at 160° C. The reaction mixture was poured into ice water, neutralized with ammonia solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (eluent: methanol/dichloromethane ={fraction (1/20)}) to give 21.8 g of the titled compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](Cl)(=[O:15])=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][NH2:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](=[O:15])(=[O:14])[NH:28][CH2:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([CH3:17])[CH:19]=[CH:20]2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: Cn1ccc2cc(CN)ccc21
Product: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from ethyl 3-chloro-4-(chlorosulfonyl)benzoate and (1-methyl-1H-indol-5-yl)methanamine.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[F:39])[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>C1COCC1.CO>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[F:39])[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1ncc(F)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(F)c1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c1
Reaction time: 12 h

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (135 mg, 0.242 mmol) in THF-MeOH (1:1, 2 mL) was added hydrazine (75 uL, 2.42 mmol). After 12 h, the solution was filtered and the filtrate was concentrated, dry loaded onto silica and purified via column chromatography (3% MeOH in DCM (1% NH4OH)). The title compound was further purified via Gilson reverse phase chromatography using 5-95% mobile phase gradient affording the TFA-salt of the title compound which was neutralized through a silica plug ((5% MeOH in DCM (1% NH4OH)) then transferred to the HCl salt using excess 4M HCl in dioxane (40 mg, 26%): LCMS (ES) m/z 427 (M+H)+, 1H NMR (400 MHz, DMSO-d6) d ppm 8.88 (d, J=8.84 Hz, 1H) 8.13 (s, 1H) 8.06 (bs, 3H) 7.70 (d, J=7.83 Hz, 1H) 7.55-7.62 (m, 3H) 7.54 (br. s., 1H) 7.41 (d, J=2.53 Hz, 1H) 4.49 (d, J=5.05 Hz, 1H) 3.92 (s, 3H) 2.99-3.11 (m, 4H).
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:23][CH2:24][C:25](=O)[CH2:26][F:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CN(C)C=O>ClCCl>[F:23][CH2:24][CH:25]([N:5]1[CH2:6][CH2:7][C:2]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])([F:1])[CH2:3][CH2:4]1)[CH2:26][F:27]
Reactant: O=C(CF)CF
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C(CF)CF)CC2)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
To a suspension of EXAMPLE 341C (0.100 g) and 1,3-difluoropropan-2-one (0.025 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (0.071 g). After 15 minutes, N,N-dimethylformamide was added dropwise until an orange solution resulted (˜15 drops). After stirring overnight additional 1,3-difluoropropan-2-one and sodium triacetoxyborohydride were added. After 3 hours, the reaction was loaded onto silica gel (Reveleris 40 g) and eluted with a gradient of 0.5-5% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes) to provide the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][S:5][C:6]=1[NH:7][C:8]([C@@H:10]1[CH2:12][C@H:11]1[CH3:13])=[O:9].[CH2:20]([Li])CCC.CI>C1COCC1>[CH3:13][C@@H:11]1[CH2:12][C@H:10]1[C:8]([NH:7][C:6]1[S:5][N:4]=[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]=1[CH3:20])=[O:9]
Reactant: [Li]CCCC
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccccc2)c1Br
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(-c2ccccc2)nsc1NC(=O)[C@@H]1C[C@H]1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To (R,R)—N-[4-bromo-3-phenylisothiazol-5-yl]-2-methylcyclopropane-carboxamide (0.50 g, 1.48 mmol) in THF (3 mL), cooled to −78° C., is added 1.1 equivalent n-butyllithium (n-BuLi) (1.6M in hexane, 0.204 mL, 3.26 mmol). Internal temperature is maintained below −68° C. Following addition, the reaction mixture is allowed to stir for 1 h. 1.1 additional equivalents of n-BuLi (1.6M in hexane, 0.204 mL, 3.26 mmol) is then added while keeping the internal temperature below −66° C. After stirring for 2 h, the reaction mixture is warmed to −40° C. for 15 min; and then cooled back down to −78° C. Methyl iodide (0.10 mL, 1.63 mmol) is then added. The reaction mixture is allowed to warm to room temperature and stir over a weekend before the reaction is quenched with satd NH4Cl and diluted with EtOAc. The organic phase is washed with brine, dried (K2CO3) and evaporated. Chromatography over silica gel, eluting with 5-35% EtOAc in hexane, affords (R,R)-2-methyl-N-(4-methyl-3-phenylisothiazol-5-yl)-cyclopropanecarboxamide. Yield: 16.4%. ES-MS: 273.2 (m+1).
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([OH:14])=[O:13])[S:5]([CH3:8])(=[O:7])=[O:6].O[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:1][C:2](=[O:20])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([O:14][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:13])[S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1N(CC(N)=O)S(C)(=O)=O
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1N(CC(N)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoic acid (150 mg, 0.496 mmol), benzyl 2-hydroxyacetate (165 mg, 0.992 mmol), DMAP (121 mg, 0.992 mmol), and EDC (285 mg, 1.489 mmol) were dissolved in DMF (2 ml). The reaction was stirred at RT for 3 h to achieve completion. The reaction mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with HCl 1N, Na2CO3 sat. sol. and brine, dried over Na2SO4 and concentrated under vacuum to give 2-(benzyloxy)-2-oxoethyl 3-(N-(2-amino-2-oxoethyl)-methylsulfonamido)-4-methoxybenzoate (180 mg, 81% yield).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:11]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15]>>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:9][NH:10][C:22]([C@H:19]2[CH2:20][CH2:21][C@H:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]2)=[O:23])=[O:8])=[CH:3][CH:4]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CCCCCC1CCC(C(=O)O)CC1
Product: CCCCC[C@H]1CC[C@H](C(=O)NNC(=O)c2ccncc2)CC1

Procedure:
Isonicotinic acid hydrazide was reacted with 4-pentylcyclohexane carboxylic acid in a similar fashion to that described in Preparation 16 to afford the title compound: RT=4.79 min; m/z (ES+)=318.0 [M+H]+.
Reaction SMILES: Cl.C([N:9]1[C:13]([CH:14]([OH:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[OH:25][CH:14]([C:13]1[N:9]=[CH:10][NH:11][CH:12]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: OC(CCCCc1ccccc1)c1cncn1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OC(CCCCc1ccccc1)c1c[nH]cn1

Procedure:
1-benzyl-5-(1-hydroxy-5-phenylpentyl)-1H-imidazole hydrochloride (8,5 g), prepared in the Step a, is hydrogenated in the mixture of 100 ml of 2N hydrochloric acid and 10 ml of ethanol at 60° C. Pd/C (10%) as catalyst. When the uptake of the hydrogen ceases, the reaction mixture is cooled, filtered and evaporated to dryness. Water is added and the mixture is made alkaline with sodium hydroxide. The product is then extracted to methylene chloride which is washed with water, dried with sodium sulphate and evaporated to dryness. The residue is the product as base, and it is used as such in Step c.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:14](=[O:15])[CH2:13][C:12]2[CH:16]=[C:17]3[C:22](=[CH:23][C:11]=2[S:10]1(=O)=O)[CH2:21][CH2:20][CH2:19][CH2:18]3.FC1C=CC(N=C=O)=CC=1>CS(C)=O>[CH3:8][N:9]1[C:14](=[O:15])[CH2:13][C:12]2[CH:16]=[C:17]3[C:22](=[CH:23][C:11]=2[S:10]1)[CH2:21][CH2:20][CH2:19][CH2:18]3
Reactant: CN1C(=O)Cc2cc3c(cc2S1(=O)=O)CCCC3
Agent: O=C=Nc1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1Sc2cc3c(cc2CC1=O)CCCC3
Reaction time: 1 h
Yield: 97.1 %

Procedure:
0.76 g (7.5 mmol) triethylamine were added to a solution of 2 g (7.5 mmol) 3,4,6,7,8,9-hexahydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine 1,1-dioxide and 1.03 g (7.5 mmol) p-fluor-phenylisocyanate dissolved in 50 mL DMSO (dimethyl sulfoxide) at room temperature. After stirring for 1 hr the resulting mixture was quenched with dilute HCl in an ice bath and then extracted with ether (2 times). The combined ether extracts were washed, dried and concentrated to give 2.3 g crude product. This material was recrystallized from ethanol to give 1.7 g 3,4,6,7,8,9-hexahydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine-4-(4-fluor)carboxanilide 1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([F:24])([F:23])[F:12])=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1cc(-c2ccccc2C(F)(F)F)ccc1O
Temperature: 50 °C
Yield: 95 %

Procedure:
A mixture of 5-bromo-2-hydroxy acetophenone (3.00 g, 13.9 mmol), 2-(trifluoromethyl)benzeneboronic acid (3.97 g, 20.9 mmol), potassium carbonate (3.86 g, 27.9 mmol) and tetrakistriphenylphosphinepalladium (0) (1.61 g, 1.39 mmol) in 1,4-dioxane (90 mL) and water (18.0 mL) was heated to 50° C. over 2 days under an atmosphere of nitrogen. The reaction was allowed to cool to room temperature and poured into a 1M aqueous solution of hydrogen chloride (50 mL). The aqueous layer was then extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown oil. The oil was purified by silica gel column chromatography (10% ethyl acetate in heptane) to afford the title compound as a colourless oil (3.70 g, 95%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=O.C(N(CC)CC)C.[C:28]1([NH:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C(O)C>[O:10]=[C:8]1[C:7]2[C:2]([C:3]3[C:4](=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:14][CH:15]=3)[NH:5][CH:6]=2)=[N:35][N:34]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2c(C(=O)OCC)[nH]cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]cc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c12
Temperature: 75 °C

Procedure:
One equivalent of crude diethyl 4-chloro-6H-pyrrolo[3,4-b]pyridine-3,7-dicarboxylate was dissolved in ethanol (0.2 M) under an atmosphere of nitrogen. Following the addition of 2 equivalents of triethylamine and 1.2 equivalents of phenyl hydrazine, the reaction was heated at 75° C. for 21 hours. After cooling to room temperature a large excess of 1 N NaOH was added and after 5 hours the reaction was concentrated to dryness. 10% HCl (aq.) was added and the brown precipitate was collected by filtration and washed with methylene chloride to afford the product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (br. s., 3H) 4.23-4.52 (m, 2H) 6.96-7.22 (m, 1H) 7.26-7.54 (m, 2H) 7.64-7.89 (m, 1H) 7.99-8.27 (m, 3H) 11.60-11.89 (m, 1H) 13.04-13.29 (m, 1H).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(Nc1ccccn1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1b using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) and 2-pyridinamine (CAN 504-29-0) as starting materials; MS (ESI) 366.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].CN(C)C=O.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)C(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 5-chloroisatin, compound VIII, (10.0 g, 55.07 mmol) in anhydrous N,N-dimethylformamide (100 ml) potassium carbonate (9.87 g, 71.59 mmol) was added portionwise at 0-5° C. After stirring at 0-5° C. for further 10 minutes and at ambient temperature for one additional hour methyl bromoacetate (8.25 ml, 60.58 mmol) was added dropwise at such a rate that the internal temperature did not exceed 35° C. The resulting orange suspension was allowed to stir at ambient temperature overnight. Water was added (350 ml) and the product was extracted with ethyl acetate (5×100 ml). The combined organic extracts were washed with brine (100 ml), dried (MgSO4) and evaporated under reduced pressure to give the title compound (10.83 g, 76%) as orange solid (HPLC purity 98%). MS (ESI+): 254.1; MS (ESI−): 252.1
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][CH2:28][O:29]C6CCCCO6)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]>CO>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:27][CH2:28][OH:29])[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCOC4CCCCO4)C3)ccc1-2
Solvent: CO
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCO)C3)ccc1-2
Temperature: 30 °C

Procedure:
Following the procedure for 376, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with MeOH as the solvent and the reaction mixture was warmed to 30° C. The crude product was triturated with diethyl ether to give 322 as a yellow solid (92 mg, quant.) LCMS: RT=3.03 min, [M+H]+=412. 1H NMR δ (ppm) (DMSO-d6): 10.65 (1 H, s), 8.34-8.25 (1 H, m), 8.06 (1 H, s), 7.27-7.20 (1H, m), 7.15 (1 H, dd, J=14.90, 1.71 Hz), 5.80-5.71 (1 H, m), 4.41-4.21 (5 H, m), 4.20-4.08 (1 H, m), 3.67-3.56 (2 H, m), 3.45-3.30 (2 H, m), 3.26 (1 H, dd, J=10.12, 5.06 Hz), 1.51-1.46 (6 H, m). 2 Protons obscured by water peak and 1 exchangeable not observed
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[NH2:2].[C:14]1([C@@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C@@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:1]([CH2:4][C@H:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[NH2:2]
Reactant: CC(C)CC(CC(N)=O)CC(=O)O
Agent: C[C@H](N)c1ccccc1
Product: CC(C)C[C@@H](CC(N)=O)CC(=O)O

Procedure:
Combining (±)-3-(carbamoylmethyl)-5-methylhexanoic acid with (S)-(-)-α-phenylethylamine in a solution to obtain the (S)-(-)-α-phenylethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid, which crystallizes out of the solution;