Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8](=[O:20])[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1)([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[N+]([O-])=O>>[C:1]([O:5][C:6]([C:7]1[C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][C:30]=2[O:20][C:8]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1)([CH3:11])[CH3:10])=[O:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(C(C)(C)C(=O)CC(=O)OC(C)(C)C)n1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: COc1cccc(C(C)(C)c2oc3cc(C#N)ccc3c2C(=O)OC(C)(C)C)n1

Procedure:
According to the method that is used for the preparation of Compound FR1, the title compound was synthesized from 4-(6-methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butyl ester and 4-chloro-3-nitrobenzonitrile.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH:15]1([C:21]2[N:25]3[CH:26]=[C:27](F)[CH:28]=[CH:29][C:24]3=[N:23][N:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C=O)C>[CH:15]1([C:21]2[N:25]3[CH:26]=[C:27]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:28]=[CH:29][C:24]3=[N:23][N:22]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Fc1ccc2nnc(C3CCCCC3)n2c1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(C4CCCCC4)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
An opaque brown solution of Intermediate 1d (171 mg, 1.05 mmol) and sodium hydride (60% dispersion in oil, 120 mg, 3.00 mmol) in dry DMF (2 mL) was stirred at RT under Argon for 30 min. Intermediate 34b (219 mg, 1.00 mmol) was added, and the resulting dark solution stirred at 60° C. for 2 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge, and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo left a brown oil. Flash chromatography (silica 25 g, 2-10% [2M NH3 in MeOH] in DCM) gave a yellow oil. Freeze-drying from MeCN-water (1:2, 3 mL) left the title compound as a pale yellow solid (203 mg, 56%). LCMS (Method 3): Rt 2.29 min, m/z 363 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][C:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][C:11]3([CH:17]4[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Yield: 97.9 %

Procedure:
A mixture of 5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (1.4 g 5.36 mmol), and 10% palladium on carbon (48% water wet, 270 mg) in methanol (90 mL) was hydrogenated for 1 hour at 50 psi of hydrogen. The catalyst was filtered off through a pad of celite and the solvent was evaporated under reduced to obtain the amine (1.2 g, 5.25 mmol, 98%) as a tan solid: electrospray MS (m/z, relative intensity) 232 ([MH]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)([C:14]#[N:15])[CH3:13])[N:10]=[C:4]2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>C(#N)C>[Br:30][C:8]1[N:9]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)([C:14]#[N:15])[CH3:13])[N:10]=[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C#N)(Cn1cc2ncc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)cnc2c1Br)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
A mixture of N-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (134 mg described in Example 155) and N-bromosuccinimide (68 mg) in acetonitrile (3.5 mL) was heated to 60° C. overnight. The mixture was concentrated under reduced pressure to yield a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (125 mg, 80%). MS (ES): M/Z [M+H]=502. 1H NMR: (400 MHz, DMSO-d6): 1.78 (s, 3H), 5.10-5.22 (m, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H), 8.43 (d, J=2.0 Hz, 1H), 8.58 (d, J=1.9 Hz, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([OH:30])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:39][C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 8.0 g 4-{(S)-3-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]propionyl}-piperazine-1-carboxylic acid ethyl ester in 50 ml DMF were added 2.5 ml benzyl bromoacetate and 10.1 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 400 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:71])[NH:10][CH:11]([C:37](=[O:70])[N:38]([CH:40]([C:56](=[O:69])[NH:57][CH2:58][C:59]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:62][CH2:61][CH2:60]1)[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:44][CH:43]=1)[CH3:39])[CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:71])[NH:10][CH:11]([C:37](=[O:70])[N:38]([CH:40]([C:56](=[O:69])[NH:57][CH2:58][C:59]1([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH2:62][CH2:61][CH2:60]1)[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[CH:44][CH:43]=1)[CH3:39])[CH2:12][C:13]1[NH:14][CH:15]=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)C(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)C(Cc1cnc[nH]1)NC(=O)OCc1ccccc1)C(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To a solution of [S-[R*,R*)]-[1-({2-(4-Benzyloxy-phenyl)-1-[(1-phenyl-cyclobutymethyl)-carbamoyl}-ethyl}-methyl-carbamoyl)-2-(1-trityl-1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester (from Step 3, 1.28 g, 1.36 mmol) in methylene chloride (10 mL) was added TFA (10 mL). The solution was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and the solution was washed with saturated NaHCO3, dried over MgSO4, filtered, and concentrated. The residue was purified twice by chromatography (first: CH2Cl2:CH3OH 10:1; second: CH2Cl2:CH3OH 15:1) (0.23 g, 0.33 mmol; 24% yield); MS-APCI 700 (m+1).
Reaction SMILES: Cl.[CH3:2][CH:3]([C:37]([O:39]C)=[O:38])[CH2:4][CH2:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][C:12]2[C:13]3[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CC(C)=O>CO>[CH3:2][CH:3]([C:37]([OH:39])=[O:38])[CH2:4][CH2:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][C:12]2[C:13]3[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=3[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:21][CH:22]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)CCOc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: CC(CCOc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1)C(=O)O

Procedure:
The hydrolysis of the product from Example 31 was carried out at room temperature by NaOH solution using acetone and methanol as the solvent.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>COCCO.[Pd]>[CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([CH2:11][NH:12][CH2:13][CH2:14]2)[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccncc2C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: COCCO
Product: O=C1C2CCNCC2C(=O)N1Cc1ccccc1
Temperature: 35 °C
Reaction time: 6 h
Yield: 61.3 %

Procedure:
To a solution of 2-benzyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (3.50 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The suspension was heated to 35° C. and stirred for 6 h under H2, then cooled to rt, poured into 100 mL of water and extracted with CH2Cl2 (70 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (2.20 g, 60%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 245.2 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10]([OH:12])=O)=O)(C)(C)C.[ClH:20].[CH3:21][NH:22][CH3:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[ClH:20].[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10]([N:22]([CH3:23])[CH3:21])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@@H](N)Cc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-pyridin-3-ylpropionic acid (500 mg, 1.88 mmol) in DMF (10 mL) was added dimethylamine hydrochloride (153 mg, 1.88 mmol), DIPEA (1.2 mL, 6.57 mmol) and TBTU (602 mg, 1.88 mol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue dissolved in methanol (20 mL). To this was added 4M hydrochloric acid in dioxane (20 mL) and the reaction was stirred for 16 h at rt. The solvent was removed in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (2×100 mL). The aqueous layer was evaporated to dryness and the residue recrystallised from ethanol/ethoxyethanol (9:1), to give the title compound as a white solid. δH (CD3OD): 2.99 (3H, s), 3.06 (3H, s), 3.35-3.42 (1H, m), 3.45-3.53 (1H, m), 4.87-4.94 (1H, m), 8.04-8.10 (1H, m), 8.48-8.53 (1H, m), 8.84-8.90 (2H, m).
Reaction SMILES: [CH:1]([N:4](C(C)C)[C:5](=O)[C:6]1C=CN=CC=1)(C)[CH3:2].[C:16]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:28]=[C:27]([CH3:29])[O:26][C:25](=[O:30])[C:24]=2[CH:31]=1)(=[O:18])[CH3:17]>>[C:16]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:28][C:27](=[O:26])[C:29]3[CH:2]=[CH:1][N:4]=[CH:5][C:6]=3[C:25](=[O:30])[C:24]=2[CH:31]=1)(=[O:18])[CH3:17]
Reactant: CC(C)N(C(=O)c1ccncc1)C(C)C
Reactant: CC(=O)Oc1ccc2nc(C)oc(=O)c2c1
Product: CC(=O)Oc1ccc2[nH]c(=O)c3ccncc3c(=O)c2c1

Procedure:
The entitled compound (II-3) was synthesized from the compound (1a) and 6-acetoxy-2-methyl-4H-3,1-benzoxazin-4-one (2c) in the same manner as in Example 1.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Brc1ccc2sc3ccccc3c2c1
Reaction time: 23 h

Procedure:
Dibenzothiophene (27.6 g, 0.15 mole) was dissolved in 125 ml chloroform. Bromine (24.0 g, 0.15 mole) in 25 ml chloroform was added dropwise and the mixture was kept at room temperature for 23 hours.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH2:12])[C:7]([O:10][CH3:11])=[N:8][CH:9]=1.[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[C:16](Cl)[N:15]=1>O1CCCC1>[Cl:13][C:14]1[N:15]=[C:16]([NH:12][C:6]2[C:7]([O:10][CH3:11])=[N:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][C:19]=1[CH3:20]
Reactant: COc1ncc(Cl)cc1N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Cl)cc1Nc1nc(Cl)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.80 mmol) was added to a stirred solution of 5-chloro-2-methoxypyridin-3-amine (Preparation 23b, 1.15 g, 7.25 mmol) in tetrahydrofuran (11 mL) and the resulting mixture was stirred at ambient temperature for 30 minutes. A solution of 2,6-dichloro-3-methyl-5-nitropyridine (prepared according to the method described in WO2010/094645(A1), 1.0 g, 4.83 mmol) in tetrahydrofuran (10 mL) was then added and the reaction mixture was heated at reflux overnight and then stirred at ambient temperature for 3 days. Solvent was evaporated under reduced pressure and the resulting residue was treated with methanol, filtered, washed with additional methanol and dried to yield the title compound (1.18 g, 74%) as an orange solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:18])([CH3:17])[CH2:5][CH2:6][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])O.[Na+]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]([CH3:18])([CH3:17])[CH2:5][CH2:6][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)CCSc1cccc2nccn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 304 mg (1.15 mmol) of 5-(5-hydroxy-3,3-dimethylpentylthio)imidazo[1,2-a]pyridine and 0.16 ml (1.15 mmol) of triethylamine in 5 ml of dichloromethane, 89 μl (1.15 mmol) of methanesulfonyl chloride was added at 0° C., followed by stirring at room temperature for 1 hour, after which saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and dried, after which the solvent was distilled off to yield 5-(5-methanesulfonyloxy-3,3-dimethylpentylthio)imidazo[1,2-a]pyridine.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24](=[S:26])[NH2:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:6])[CH3:5].[CH2:27](N)[CH2:28][CH3:29]>C(O)C>[ClH:1].[CH3:2][N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24](=[S:26])[NH:25][CH2:27][CH2:28][CH3:29])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)N(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CCCN
Agent: Cl
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN(C)C(C)C)c1ccccc1S2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 10-{(2RS)-1-[N-methyl-N-(1-methylethyl)amino]-2-propyl}-2-phenothiazinecarbothioamide hydrochloride (1.6 g) and propylamine (4.8 cc) in absolute ethanol (32 cc) is heated for 16 hours at a temperature in the region of 100° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is dissolved in ethyl ether (100 cc) and the solution obtained is washed with N aqueous sodium hydroxide solution (4 cc) and then with saturated aqueous sodium chloride solution (2×10 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual red-brown gum is purified by chromatography on a column (height: 25 cm; diameter: 3 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (97:3 by volume) (1 liter) of methylene chloride and methanol and collecting 60-cc fractions. Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.85 g) is dissolved in ethyl ether (50 cc) in the presence of charcoal 3S. The mixture is filtered and a 3N solution (1 cc of hydrochloric acid in ethyl ether is added to the yellow filtrate, and the mixture is stirred for 1 hour at a temperature in the region of 20° C. The solid formed is drained washed with ethyl ether (5 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-{(2RS)-1-[N-Methyl-N-(1-methylethyl)amino]-2-propyl}-N-propyl-2-phenothiazinecarbothioamide hydrochloride (0.58 g) is thereby obtained in the form of a yellow solid, m.p. about 140° C. (melts forming a a paste).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[C:28]([N+:38]([O-:40])=[O:39])[CH:27]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[C:28]([N+:38]([O-:40])=[O:39])[CH:27]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=[N+]([O-])c1cc(Br)ccc1OC1CCCC1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC3CCCC3)c([N+](=O)[O-])c2)cc1

Procedure:
The title compound was prepared in accordance with Example 1(b) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 4-bromo-1-cyclopentoxy-2-nitrobenzene (see step (a) above), followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[N:15]3)=[O:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>C(Cl)Cl>[CH2:23]([S:26]([N:1]([C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[N:15]3)=[O:11])[C:3]=1[F:22])[S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])(=[O:28])=[O:27])[CH2:24][CH3:25]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3nccnc3c2)c1F
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3nccnc3c2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(quinoxalin-6-yl)methanone (300 mg, 1 mmol, 1 eq.) in DCM (30 mL) was added TEA (1.0 g mg, 10 mmol, 10 eq.), followed by propane-1-sulfonyl chloride (713 mg, 5 mmol, 5 eq.). After the resulting mixture was stirred at rt for 1 h, the mixture was washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(propylsulfonyl)-N-(2,4,5-trifluoro-3-(quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (170 mg, 33.0%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14](=[O:15])[NH:13][C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:7]2[C:6]=1[OH:16])=[O:4].[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[C:14](=[O:15])[NH:13][C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:7]2[C:6]=1[O:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[O:4]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1c(O)c2nccnc2[nH]c1=O
Solvent: ClCCCl
Product: COC(=O)c1c(OC(=O)C(C)C)c2nccnc2[nH]c1=O
Temperature: 25 °C

Procedure:
To a suspension of 8-hydroxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester (Example 7.1) in 1,2-dichloro-ethane (9 ml) was added powdered molecular sieves (4A) followed by dropwise addition of isobutyryl chloride (0.048 ml). The reaction mixture was heated to reflux for 5 hours, cooled to ambient temperature and filtered. The filtrate was concentrated to give 8-isobutyryloxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester as a light brown solid (0.166 g) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[N:11]=[CH:12][C:13]([C:16]#[N:17])=[C:14](O)[C:9]2=[CH:8][CH:7]=1)=[O:5])[CH3:2].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[O:29]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O=P(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[N:11]=[CH:12][C:13]([C:16]#[N:17])=[C:14]([NH:42][C:39]3[CH:38]=[CH:37][C:36]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:41][CH:40]=3)[C:9]2=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(O)c(C#N)cnn12
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Compound 406E (110 mg, 0.476 mmol) was heated in POCl3 (1 ml) at 83-100° C. for 2 h. Excess POCl3 was removed on a rotary evaporator, and the residue was stripped with CH2Cl2 (2 ml). To the solid residue was added DMF (5 ml), K2CO3 (690 mg, 5 mmol) and 4-phenoxy-phenylamine (353 mg, 1.91 mmol) at 0° C. The reaction mixture was degassed and stirred at rt overnight. Solid was filtered off and the filtrate was concentrated, the residue was purified by silica gel flash column chromatography to give the 406 (147 mg, 78%) as a yellow solid (25% EtOAc—Hexanes). LCMS Found: (M+H)+=398.6
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-:20].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([OH:20])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12

Procedure:
A solution of 2,4-dichloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidine (0.76 g, 2.58 mmol) and sodium hydroxide (2.6 ml, 1N) in THF (30 mL) was heated at 50° C. for 1 hour. 1N HCl (3 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to provide 0.73 g of 2-chloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4-ol which was characterized by its mass spectrum as follows: MS (m/z) 276 [M+H]+.