Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])(=[O:20])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:21][C:22]([OH:24])=[O:23])(=[O:20])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)CS(=O)(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfonyl}acetate (0.10 g, 0.24 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred f or 0.5 hr. Diisopropyl ether was added to the mixture. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.048 g, 55%) as pale yellow crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][F:32])=[N:25][C:21]=3[CH:20]=[C:19]([C:41]#[N:42])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][F:32])=[N:25][C:21]=3[CH:20]=[C:19]([C:41](=[N:2][OH:3])[NH2:42])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (108 mg, 1.56 mmol), sodium bicarbonate (196 mg, 2.34 mmol), and water (1.56 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (364 mg, 0.78 mmol) dissolved in ethanol (3.6 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C25H31ClFN7O [M+H]+ 500. found 500.
Reaction SMILES: C1CCCCC=1.C1(O)C=CC=CC=1.C1(OC2C=CC=CC=2)CCCCC1.[CH:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[OH:39])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[OH:39])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Oc1ccccc1C1CCCCC1
Agent: c1ccc(OC2CCCCC2)cc1
Solvent: Oc1ccccc1
Solvent: C1=CCCCC1
Product: Oc1ccccc1-c1ccccc1

Procedure:
The alkylation of Example 1A is repeated except the reaction is run at 140° C. The product contains 3.2 percent cyclohexene, 23.3 percent phenol, 13.7 cyclohexylphenyl ether, 57.7 percent ortho cyclohexyl phenol, and about 0.7 percent di-adduct. This product is then distilled in a POPE™ 2-inch wiped film still at 170° C., 1.7 psig (0.11 atm.) and 500 rpm (revolutions per minute). The heavies stream (distillation product which is not volatilized off) has about 0.7 percent cyclohexene, 44.3 percent phenol, 15.5 percent cyclohexylphenyl ether, 38 percent ortho cyclohexylphenol and 0.2 percent di-adduct. The heavies stream is reacted under the same conditions as Example 1A, except the reaction temperature is about 235° C. resulting in a product having about 0.05 percent cyclohexene, about 42.7 percent phenol, about 0.05 percent cyclohexylphenyl ether, about 53 percent orthocyclohexyphenol and about 0.4 percent di-adduct. This product from the heavies stream is then reacted under the same conditions as described by Example 1B. Example 1B resulted in essentially the same conversion and selectivity as described in Example 1B.
Reaction SMILES: [NH:1]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[N:15]=[C:14]([C:24](OCC)=[O:25])[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[C:11]([C:10](=[O:30])[CH:9]=1)=[CH:12][C:13]([F:29])=[C:14]([CH2:24][OH:25])[N:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(CO)c(F)cc12
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
To a 0° C. suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (100.0 mg, 0.25 mmol) in THF (2.5 mL) was added LAH (0.750 mmol, 1M in THF) dropwise over 10 min. After 5 min. the reaction was slowly quenched with EtOAc (10 mL), was left to stir for 15 min and was concentrated in vacuo. The residue was taken up in CH2Cl2 (10 mL) and 1N HCl (5 mL) and was left to stir for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. Trituation with Et2O provided 2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (55.2 mg, 61%) as a tan solid: LCMS RT: 2.01 min, MH+: 362.3.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:39])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: O=C(Cl)N1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)N5CCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 68.7 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and pyrrolidine-1-carbonyl chloride (25 mL, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(pyrrolidine-1-carbonyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (84 mg, 70%). MS(ESI) m/z 532.3 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[Cl:33][C:34]1[O:38][C:37]([CH:39]=O)=[CH:36][CH:35]=1.[Si]([O:48][CH2:49][CH:50]([SH:72])[CH2:51][N:52]1[C:60]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([F:67])[CH:62]=2)=[C:59]2[C:54]([N:55]([CH3:71])[C:56](=[O:70])[N:57]([CH3:69])[C:58]2=[O:68])=[CH:53]1)(C(C)(C)C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.[OH-].[Na+]>[Cl:33][C:34]1[O:38][C:37]([CH:39]2[C:53]3=[C:54]4[N:55]([CH3:71])[C:56](=[O:70])[N:57]([CH3:69])[C:58](=[O:68])[C:59]4=[C:60]([C:61]4[CH:66]=[CH:65][CH:64]=[C:63]([F:67])[CH:62]=4)[N:52]3[CH2:51][CH:50]([CH2:49][OH:48])[S:72]2)=[CH:36][CH:35]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(S)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Reactant: O=Cc1ccc(Cl)o1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)SC(CO)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (161 μl, 2.094 mmol) was added to a solution of bismuth triflate (41.2 mg, 0.063 mmol), 5-chlorofuran-2-carbaldehyde (30.1 mg, 0.230 mmol) and 6-(3-((tert-butyldimethylsilyl)oxy)-2-mercaptopropyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg, 0.209 mmol) in toluene (2094 μL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (10 mL) and 1M NaOH(aq) (10 mL). The phases were separated and the aqueous phase was extracted with DCM (3×10 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-50% EtOAc/hexane, afforded the title compound as a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[N:46]=[CH:45][C:44]([NH2:47])=[N:43]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:44]4[CH:45]=[N:46][S:42][N:43]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: Nc1cnsn1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3cnsn3)ccc12
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 45 mg, 0.074 mmol), 1,2,5-thiadiazol-3-amine (8.21 mg, 0.081 mmol), and THF (0.5 mL) to give a clear solution. The vial was cooled in an ice-water bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (162 μl, 0.162 mmol) was added drop wise. After 10 min, the mixture was diluted with a small amount of methanol to give a solution which was purified directly by chromatography on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM) to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,5-thiadiazol-3-yl)isoquinoline-6-sulfonamide (22.2 mg, 0.042 mmol, 57.1% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=12.50 (br. s., 1H), 8.81-8.69 (m, 2H), 8.50 (s, 1H), 8.18 (d, J=5.4 Hz, 1H), 8.00 (dd, J=1.9, 8.9 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.65-7.52 (m, 2H), 7.48-7.39 (m, 2H), 7.35-7.29 (m, 1H), 7.27 (s, 1H), 3.70 (s, 3H). m/z (ESI) 527.2 (M+H)+.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH:25][CH2:26][C:27]([CH2:32]O)([CH2:30][OH:31])[CH2:28][OH:29]>>[C:1]([O:24][CH2:32][C:27]([CH2:30][OH:31])([CH2:28][OH:29])[CH2:26][OH:25])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)(CO)CO
Temperature: 130 °C

Procedure:
A four-necked rounded bottom flask equipped with a stirrer, a thermocouple, and a nitrogen inlet tube was charged with 4 mol of behenic acid per mol of pentaerythritol, and the contents were heated to 130° C. for 5 hours in a nitrogen atmosphere to carry out an esterification reaction. A reaction product was purified with methyl ether to provide pentaerythritol behenate. Here, the acid value was 0.4 mgKOH/g, and the hydroxyl value was 1.6 mgKOH/g.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone and 2-chloro-5-trifluoromethylpyrimidine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[O:2].S(Cl)([Cl:14])=O>C1C=CC=CC=1.CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
In a suspension of 1.00 g of 4-formyl benzoic acid in 15 ml of benzene, 0.87 g of thionyl chloride and 2 drops of N,N-dimethylformamide were added, and stirred under reflux with heat for 2 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain 1.14 g of crude 4-formyl benzoic acid chloride as white crystal. In a solution of 0.66 g of 2,2,2-trifluoroethylamine and 0.81 g of triethylamine in 6 ml of chlororform, the solution of 1.14 g of the crude 4-formyl benzoic acid chloride in 6 ml of chloroform was added dropwise under cooling with ice and with stirring, after the completion of the addition dropwise, continued to stir at room temperature for further 18 hours. After the completion of the reaction, the reaction mixture was added in 30 ml of water, extracted with chloroform (20 ml×3). The organic phase was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residual solid was washed with hexane to obtain 1.32 g of the aimed product as white crystal.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=O)[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[CH2:29]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=C)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1>>[CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=[CH2:29])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1
Reactant: C[C@]12CCCCC1CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C=C1CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Yield: 85 %

Procedure:
The 3,3:17,17-Bis(ethylendioxy)-7-methyleneandrostane was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)androstane-7-one by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.67 (1H, m), 4.60 (1H, m), 3.86 (8H, m), 2.20-1.10 (20H, m), 0.97 (3H, s), 0.86 (3H, s).
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Br.C(=O)([O-])O.[Na+].[NH2:14][C:15]1[C:16](=[O:24])[N:17]([CH3:23])[C:18]([S:21][CH3:22])=[N:19][N:20]=1>CC(O)C.CO.O>[CH3:23][N:17]1[C:16](=[O:24])[C:15]2=[N:14][CH:3]=[CH:4][N:20]2[N:19]=[C:18]1[S:21][CH3:22]
Reactant: CSc1nnc(N)c(=O)n1C
Reactant: COC(CBr)OC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: CSc1nn2ccnc2c(=O)n1C
Temperature: 25 °C
Yield: 47.4 %

Procedure:
Bromoacetaldehyde dimethyl acetal (2.57 g, 13.1 mmol), 48% hydrobromic acid (1.06 g, 13.1 mmol) and water (1.5 ml) were heated at 95° C. for 1.5 h. The mixture was allowed to cool to ambient temperature, diluted with propan-2-ol (20 ml) then treated with sodium hydrogen-carbonate (1.46 g, 17.4 mmol) added in portions over 5 min. The mixture was filtered and the filtrate was added to 6-amino-4-methyl-3-methylsulfanyl-4H-[1,2,4]triazin-5-one (1.50 g, 8.71 mmol). The resulting suspension was heated at 95° C. for 18 h. The mixture was allowed to cool to ambient temperature, diluted with methanol (100 ml) and evaporated onto silica. The product was purified by flash column chromatography on silica eluting with dichloromethane (+0.1% 0.880 ammonia) on a gradient of methanol (3-6%). Collecting appropriate fractions gave 3-methyl-2-methylsulfanyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one (0.81 g, 47%) as a pale yellow solid: δH (400 MHz, CDCl3) 2.61 (3H, s), 3.58 (3H, s), 7.49 (1H, d, J1), 7.52 (1H, d, J1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].[Na].[F:13][C:14]([F:22])([F:21])[CH2:15]CS([O-])(=O)=O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:15][C:14]([F:22])([F:21])[F:13]
Reactant: O=S(=O)([O-])CCC(F)(F)F
Reactant: Oc1ccc(Cl)cc1Br
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Cl)cc1Br

Procedure:
To a stirred cold (0° C.) suspension of oil free NaH (0.12 mol, 4.8 g of 60% NaH in mineral oil) in anhydrous DMF (50 mL), a solution of 2-bromo-4-chlorophenol in DMF (50 mL) was added over 30 minutes under nitrogen. The resultant gray suspension of the sodium salt of 2-bromo-4-chlorophenol was treated with neat 2,2,2-trifluoroethylmethane sulfonate (21.4 g, 0.12 mol). The stirred mixture was heated at reflux temperature for 2-3 days. The mixture was cooled in an ice water bath and extracted with diethyl ether (2×100 mL). The combined ether extract was washed with 1N NaOH (3×100 mL), 1N HCl, brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to provide a golden-yellow oil (18.4 g) which was then distilled in vacuo to afford the title compound as a colorless oil (14.7 g): bp 100-103° C. @ 0.5 torr.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]2[CH:3]1[CH2:1][CH3:2])=[O:22]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CCC1Nc2cc(F)ccc2-n2cccc21
Product: CCC1c2cccn2-c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC

Procedure:
5-(2,4-Dimethoxybenzoyl)-4-ethyl-7-fluoro-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 17 and 2,4-dimethoxy benzoyl chloride according to the procedure of Example 106, Step 2, mp 131-132° C. MS (ESI) m/z 381; Anal. Calcd for C22H21FN2O3: C, 69.46; H, 5.56; N, 7.36. Found: C, 69.22; H, 5.63; N, 7.32.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1.[C:14]([O:18][C:19](=[O:37])[NH:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:22]=1[F:36])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:37])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=3)[N:4]([CH3:13])[N:3]=2)=[CH:23][C:22]=1[F:36])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: CSc1ncc2c(Br)nn(C)c2n1
Product: CSc1ncc2c(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)nn(C)c2n1

Procedure:
Following the procedure of Example 15, 3-Bromo-1-methyl-6-methylsulfanyl-1H -pyrazolo[3,4-d]pyrimidine and [2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester gave the title compound as an off white solid; LC/MS(m/e) at 390.2 (MH+), Rt=2.56 min.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1(C(OCC)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[C:7]1=[O:16])C.Cl.C(O)(=O)C>>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:16])[CH:6]([CH2:5][C:4]([OH:22])=[O:3])[CH2:14]2
Reactant: CCOC(=O)CC1(C(=O)OCC)Cc2cc(F)ccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CC1Cc2cc(F)ccc2C1=O
Yield: 84.1 %

Procedure:
Ethyl 2-(2-ethoxy-2-oxo-ethyl)-5-fluoro-1-oxo-indane-2-carboxylate (500 mg, 1.6 mmol) was suspended in 1.4 ml mixture of 6 N HCl: acetic acid (1:1) and heated to reflux for 3 h. Reaction was monitored by TLC. Reaction mass was evaporated to dryness, 10 ml water was added and extracted with ethyl acetate (40 ml×3). Organic layer was washed with sat brine, dried over sodium sulphate. Crude product was washed with hexane to obtain a desired product (280 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH2:11][OH:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]1>C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH:11]=[O:12])=[CH:4][C:3]=1[N:13]1[CH2:14][CH2:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18]1
Reactant: CCOc1cc(CO)cc(N2CCS(=O)(=O)CC2)c1Cl
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCOc1cc(C=O)cc(N2CCS(=O)(=O)CC2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a solution of [4-chloro-3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-5-ethoxy-phenyl]-methanol (0.089 g, 0.28 mmol, 1.0 equiv) in THF (20 mL) was added activated MnO2 (0.242 g, 2.78 mmol, 10.0 equiv). After stirring at rt for 4 h, the reaction mixture was filtered and the solvent removed by evaporation under reduced pressure providing 0.084 g (95%) of the title compound in sufficient quality for the reductive alkylation step. MS (ISP): 318.0 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]2[CH:7]([CH2:24][C:25]([OH:27])=O)[CH2:8][O:9][C:10]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:14][C:11]=3[C:12]=2[N:13]=1)(=[O:3])[NH2:2].Cl.[CH3:29][NH:30][CH3:31].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:29][N:30]([CH3:31])[C:25]([CH2:24][CH:7]1[C:6]2[S:5][C:4]([C:1]([NH2:2])=[O:3])=[N:13][C:12]=2[C:11]2[CH:14]=[C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)=[O:27]
Reactant: CNC
Reactant: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(CC(=O)O)CO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)CC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(N)=O)sc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a mixture of [2-Carbamoyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-4-yl]-acetic acid (60 mg, 0.155 mmol) in DCM (20 mL) were added Dimethylamine Hydrochloride (31.7 mg, 0.388 mmol), HOBt (31.5 mg, 0.233 mmol), EDCI (44.7 mg, 0.233 mmol) and DIPEA (60.3 mg, 0.466 mmol). The mixture stirred in autoclave at 60° C. overnight. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc and hexane (1:1) to afford 4-Dimethylcarbamoylmethyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (30 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 8.61 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 7.85 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 5.45 (s, 1H), 4.5 (m, 1H), 4.10 (m, 1H), 3.93 (m, 1H), 2.90 (d, J=16 Hz, 6H), 2.82 (m, 1H), 2.69 (m, 1H), 1.47 (s, 6H); LC-MS (ESI & APCI): 414.5 (M+1).