Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8]1.[C:17]([O-])(=[O:19])C.[Na+]>CN(C=O)C>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[CH:17]=[O:19]
Reactant: Cc1cn(C)c2ccccc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)n(C)c2ccccc12
Temperature: 99 °C
Yield: 97 %

Procedure:
Phosphorous oxychloride (0.0.93 mL, 9.7 mmol) was added dropwise with stirring to DMF (5 mL) at 10° C. over 20 min. 1,3-dimethyl-1H indole (1.3 g mg, 8.9 mmol) in DMF (5 mL) was added slowly with stirring and the mixture was heated for 3 h at 98-100° C. Excess concentrated aqueous solution of sodium acetate was added. The mixture was stirred for 30 min at 28° C. and extracted with ethyl acetate, dried and evaporated. The crude mixture was chromatographed over silica gel eluting with hexane/ether to afford the title compound (1.5 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 3.99 (s, 3H), 2.60 (s, 3H)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)=[O:28]>CN1C(=O)CCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:31]3[CH2:32][CH2:33][CH2:34][C@@H:29]([C:27]([NH:26][CH3:25])=[O:28])[CH2:30]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CNC(=O)[C@@H]1CCCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: CNC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)C1
Temperature: 25 °C
Yield: 12.6 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 76 mg, 0.220 mmol) and (R)-N-methylpiperidine-3-carboxamide (62.7 mg, 0.441 mmol) in NMP (1.1 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (30-30% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (12.5 mg, 13%); ESI-MS: m/z 451.3 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=Cc1ccc2nnn(O)c2c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=Cc1ccc2nnn(OS(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: 10 °C
Yield: 64.5 %

Procedure:
In dry benzene (300 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (4.83 g) and triethylamine (3.2 g) under stirring, and thereto is added dropwise a solution of p-toluenesulfonyl chloride (5.8 g) in benzene (50 ml) under cooling at 10° C. The mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto ice-water (200 ml) and extracted with ethyl acetate (60 ml, three times). The combined extracts are washed with an aqueous sodium hydrogen carbonate and then water, dried over anhydrous magnesium sulfate, treated with charcoal and then concentrated under a reduced pressure. The resulting residue is recrystallized from ethyl acetate-n-hexane to give colorless crystals of 1-(p-toluenesulfonyloxy)-6-vinyl-1,2,3-benzotriazole (6.1 g), melting point: 90°-91° C. The filtrate is further concentrated, and the resulting residue is recrystallized from benzene-n-hexane to give additionally the desired product (1.9 g).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C@H:19]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH2:20][CH:21]=C)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].C[N+]1([O-])CC[O:35]CC1.S([O-])([O-])(=O)=S.[Na+].[Na+].I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.CO.ClCCl.O1CCCC1.O.CC(C)=O.C(O)(C)(C)C.O>[CH3:1][N:2]([CH2:18][C@H:19]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH2:20][CH:21]=[O:35])[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(-n2cnnn2)ccc1OC)c1ccc(Cl)c(Cl)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N(C)C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
Combine (S)-N-methyl-N-(2-(3,4-dichlorophenyl)pent-4-enyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide (5.12 g, 11.5 mmol), acetone/t-butanol/water (2/1/1, 120 mL), and a solution of N-methylmorpholine N-oxide (3.3 g 50% in water). Add a solution of osmium tetraoxide (4.4 g, 4% in water, 13.8 mmol). After 2 hours, evaporate in vacuo to remove most of the acetone and partition the evaporated reaction mixture between dichloromethane and an aqueous 10% solution of sodium thiosulfate. Separate the layers, extract the organic layer with brine, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Combine the residue and tetrahydrofuran/water (4/1 150 mL). Add sodium meta-periodate (2.95 g, 13.8 mmol). After 1.5 hours, filter the reaction mixture, rinse the solids with tetrahydrofuran, and evaporate the filtrate to remove most of the tetrahydrofuran. Dilute the evaporated reaction mixture with dichloromethane. Extract with water, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 1% methanol/dichloromethane, 2% methanol/dichloromethane, and 3% methanol/dichloromethane to give the title compound: Rf=0.20 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [ClH:1].C([N:15]1[CH2:18][C:17]([CH:20]2[CH2:22][CH2:21]2)([F:19])[CH2:16]1)(C1C=CC=CC=1)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[CH:20]1([C:17]2([F:19])[CH2:18][NH:15][CH2:16]2)[CH2:22][CH2:21]1
Reactant: FC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: FC1(C2CC2)CNC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To wet 10% palladium on carbon (Degussa catalyst) under nitrogen was added ethanol (100 ml). A solution of 1-Benzhydryl-3-cyclopropyl-3-fluoroazetidine hydrochloride (6.74 g, 21.23 mmol) in ethanol (50 ml) was added to the catalyst and the mixture hydrogenated at 60 psi on the Parr shaker hydrogenation apparatus for 5 hrs. The reaction was filtered through celite and concentrated to an oil. Ether (50 ml) was added and the mixture cooled to 0° C. and stirred until a precipitate formed. The suspension was filtered and the filter cake washed with ether (20 ml) and the solid dried under vacuum. This furnished the product as an off white solid (3.00 g, 93%). 1H NMR d6-DMSO δ 0.52-0.56 (2H, m), 0.59-0.64 (2H, m), 1.35-1.40 (1H, m), 3.91-4.10 (4H, m), 4.01-4.23 (4H, m), 9.50 (1H, brs), 9.63 (1H, brs).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([CH2:18][NH:19][C:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([O:30][C:31](=[O:45])[NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:26][CH2:25]3)=[O:21])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[NH2:50][CH2:51][C@@H:52]([C:61]1[CH:70]=[CH:69][C:68]([OH:71])=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:72])[NH:66]2)[O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[Si:54]([O:53][C@H:52]([C:61]1[CH:70]=[CH:69][C:68]([OH:71])=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:72])[NH:66]2)[CH2:51][NH:50][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([CH2:18][NH:19][C:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([O:30][C:31](=[O:45])[NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:26][CH2:25]3)=[O:21])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:7][CH:8]=1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=Cc1ccc(NC(=O)c2cccc(CNC(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccc(NC(=O)c2cccc(CNC(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)c2)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-formylphenylcarbamoyl)-phenyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (151 mg, 0.250 mmol) and 5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one acetic acid salt (98.6 mg, 0.250 mmol) in 1:1 MeOH:DCM (2.0 mL) was stirred at room temperature for 3 h. Sodium triacetoxyborohydride (159 mg, 0.750 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. LC-MS (Method 10-90) showed product was present (Rt 3.32 min; m/z 923.6 [M+H]+. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]2[C:6]([CH:7]=[C:8]([C:20]([OH:22])=O)[C:9](=[O:19])[NH:10]2)=[CH:5][CH:4]=1.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:20]([C:8]2[C:9](=[O:19])[NH:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=3[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:22])=[CH:25][CH:24]=1
Reactant: NCCc1ccncc1
Reactant: CCCCCOc1c(OC)ccc2cc(C(=O)O)c(=O)[nH]c12
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCOc1c(OC)ccc2cc(C(=O)NCCc3ccncc3)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (30.0 mg) obtained in Example 2-1, 2-pyridine-4-ylethylamine (36.0 mg), and 1-hydroxybenzotriazole hydrate (17.3 mg) were dissolved in dimethylformamide (2 ml), and 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (24.5 mg) was successively added to this solution while being cooled with ice. After the reaction solution was stirred at room temperature for 5 hours, ethyl acetate (3 ml) and a saturated aqueous solution of sodium hydrogencarbonate (3 ml) were added to this solution. The organic layer was separated and dried over anhydrous sodium sulfate, filtered to remove the desiccating agent, and concentrated under reduced pressure. The resultant residue was purified through column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 25:1) to obtain the title compound (35 mg) as colorless crystals (Table 8).
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([N:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:23]
Reactant: C1COCCOCCOCCOCCOCCN1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCNCC1
Reactant: OCCCCCCCCCCCCBr
Product: NC(=O)C1CCN(CCCCCCCCCCCCO)CC1
Yield: 68.7 %

Procedure:
Prepared from isonipecotamide (2.0 g, 15.6 mmol), 12-bromododecanol (4.15 g, 15.6 mmol) potassium carbonate and (2.16 g, 15.6 mmol) according to procedure used for Example 8 (Step A) to give 3.35 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.[N+]([O-])(O)=[O:13]>CO.CC(C)=O.O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:13])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Yield: 119 %

Procedure:
5.0 g. of Acetonine was dissolved in a mixed solvent comprising 10 g. of acetone and 10 g. of methanol. The solution was added dropwise with a solution of 2.1 g. of nitric acid containing 0.63 g. of water in 10 g. of acetone and 10 g. of methanol at 15°-20°C. After completion of the addition, the mixture was maintained at room temperature for 24 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 5 to obtain triacetonamine in a yield of 119%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[C@@H:7]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:22]=[N:23][C:24]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[CH:25][C:26]=3[C:27]3[S:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=3)=[CH:18][CH:19]=2)[C:14](=[O:42])[C:13]([C:43]([O:45]CC)=O)=[CH:12]1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:49][NH2:50].C(O)C>>[CH2:40]([NH:39][C:37](=[O:38])[NH:36][C:24]1[N:23]=[CH:22][C:21]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[N:11]([C@@H:7]([CH:8]([CH3:9])[CH3:10])[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:48])[CH:12]=[C:13]([C:43](=[O:45])[NH:50][CH3:49])[C:14]3=[O:42])=[C:26]([C:27]2[S:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=2)[CH:25]=1)[CH3:41]
Reactant: CN
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](C(=O)OC(C)(C)C)C(C)C)cn1
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NC)cn3[C@H](C(=O)OC(C)(C)C)C(C)C)cn1

Procedure:
A solution of (S)-ethyl 1-(1-tert-butoxy-3-methyl-1-oxobutan-2-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline -3-carboxylate (Example 137, 0.100 g, 0.15 mmol) in 33 wt. % methylamine solution in absolute ethanol (3 mL, 24.1 mmol) was heated in the microwave to 80° C. for 15 min. The mixture was conconcentrated in vacuo and purified by column chromatography (silica, 95:5 methylene chloride/methanol) to provide the desired product.
Reaction SMILES: ClC1C=C(C(N)C)C2OCCOC=2C=1.FC1C=C(F)C=CC=1S(C)(=O)=O.C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[CH:46]=[C:45]([CH:47]([NH:49][C:50]2[CH:55]=[C:54](F)[CH:53]=[CH:52][C:51]=2[S:57]([CH3:60])(=[O:59])=[O:58])[CH3:48])[C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1.[NH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C)C=O.C(#N)C.O>[Cl:36][C:37]1[CH:46]=[C:45]([CH:47]([NH:49][C:50]2[CH:55]=[C:54]([N:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)[CH:53]=[CH:52][C:51]=2[S:57]([CH3:60])(=[O:59])=[O:58])[CH3:48])[C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1
Reactant: CC(Nc1cc(F)ccc1S(C)(=O)=O)c1cc(Cl)cc2c1OCCO2
Reactant: C1CNCCN1
Agent: CC(N)c1cc(Cl)cc2c1OCCO2
Agent: CS(=O)(=O)c1ccc(F)cc1F
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O)c1cc(Cl)cc2c1OCCO2
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of 1-(6-chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethanamine (130 mg, 0.61 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (116 mg, 0.61 mmol) and diisopropylethylamine (314 mg, 2.43 mmol) in N,N-dimethylformamide (2 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The solvent was concentrated in vacuo to collect 53.4 mg of the desired product, which was used for the next reaction without further purification. A solution of N-(1-(6-chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (53.4 mg, 0.14 mmol), piperazine (239 mg, 2.76 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.38 mmol) in acetonitrile (2 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo. The crude product was purified by silica chromatography (10% ethyl acetate in hexanes) to yield 50 mg (80%) of desired product. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, 1H), 6.82 (d, 1H), 6.76 (d, 1H), 6.60 (d, 1H), 6.23 (d, 1H), 5.87 (d, 1H), 4.73 (m, 1H), 4.28 (m, 4H), 3.24 (m, 4H), 3.05 (s, 3H), 3.03 (m, 4H), 1.54 (d, 3H); MS (ESI) m/z: 452.3 (M++1).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:8]2[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]2)[S:6][CH:7]=1)#[N:2].[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>C(#N)C>[C:18]([S:20][C@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[S:6][CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)[CH2:9]1)(=[O:21])[CH3:19]
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2nc(C#N)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@H]1CCN(c2nc(C#N)cs2)C1
Yield: 49.2 %

Procedure:
To a solution of (3R)-1-(4-cyano-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (300 mg, 1.10 mmol) (obtained as described in Reference Example 18(7)) in acetonitrile (9 ml) was added potassium thioacetate (376 mg, 3.30 mmol) at room temperature. The mixture was heated under reflux for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (5:1→1:1) as the eluant to afford (3S)-3-acetylthio-1-(4-cyano-1,3-thiazol-2-yl)pyrrolidine (137 mg, yield 50%) as a pale brown solid.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=2[O:40][CH3:41])[N:15]=1.[NH2:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[C:45](=[O:60])[C:46]([CH3:59])=[CH:47][N:48]2[CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55]>>[CH2:57]([O:56][C:54](=[O:55])[CH2:53][N:48]1[C:49]2[C:44](=[C:43]([NH:42][C:14]3[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:37])=[CH:27][C:26]=4[O:40][CH3:41])[N:15]=3)[CH:52]=[CH:51][CH:50]=2)[C:45](=[O:60])[C:46]([CH3:59])=[CH:47]1)[CH3:58]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCOC(=O)Cn1cc(C)c(=O)c2c(N)cccc21
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOC(=O)Cn1cc(C)c(=O)c2c(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)cccc21

Procedure:
The title compound was prepared according to Compound 102A using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (50.0 mg, 0.110 mmol) and ethyl (5-amino-3-methyl-4-oxoquinolin-1(4H)-yl)acetate (Example 301A, 31.5 mg, 0.121 mmol). 1H NMR (CD3OD, 400 MHz): δ=1.24-1.32 (m, 9H), 2.12 (s, 3H), 3.29 (d, J=21.2 Hz, 2H), 4.05-4.16 (m, 6H), 4.84 (s, 2H), 6.91 (dt, J=2.8, 8.4 Hz, 1H), 7.04 (t, J=2.0 Hz, 1 H), 7.40 (d, J=8.8 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.37 (s, 1H), 8.66 (d, J=7.6 Hz, 1H). MS (ES+): m/z 678.17 [MH+]. HPLC: tR=1.50 min (UPLC TOF, polar—3 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[N:36]=CO[C:39]=1[C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].Cl>C(O)(C)C>[NH2:36][CH:35]1[CH2:39][C:40]2[C:46](=[CH:45][CH:44]=[C:42]([NH:43][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=6[F:32])[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:41]=2)[CH2:34]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Cc1ncoc1-c1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Product: NC1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1

Procedure:
The title compound was prepared by heating N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (180 mg, 0.39 mmol) (prepared according to a procedure similar to that described in Example 27, Step C), 3-(4-methyl-1,3-oxazol-5-yl)aniline (75 mg, 0.43 mmol), hydrochloric acid (40 μL, 0.040 mmol, 1M HCl/Et2O) and isopropanol (2 mL) at 160° C. for 15 min in a microwave synthesizer. The reaction was cooled and concentrated and purified by silica gel column chromatography (20-100% gradient EtOAc (0.5% TEA)/hexanes (0.5% TEA)). Purification yielded 60 mg (25%) of a yellow powder. ESIMS (M+H)+=601.17.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:14]([O:22][CH2:23][CH3:24])=[O:21])[CH3:20]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
2,5-Dibromonitrobenzene (41.5 g, 148 mmol) was dissolved in anhydrous DMF (500 ml) and sodium hydride (17.7 g of a 60% suspension in mineral oil, 443 mmol) was added under argon. Diethyl malonate (49.6 g, 295 mmol) was added dropwise over 10 minutes giving a strong exotherm (mixture rose to 60° C.). The reaction mixture was maintained at 60° C. for 6 hours then left to cool to ambient temperature and stirred for 18 hours. The resulting dark red solution was poured slowly into 2M hydrochloric acid (1500 ml) and extracted with ether (500 ml×4). The organic phases were combined, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The crude oil was purified by flash chromatography eluting with isohexanes/ethyl acetate (100/0, then 95/5 and finally 80/20) to give diethyl(4-bromo-2-nitrophenyl)malonate (51 g, 96%).