Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH2:5]([N:7]([C:15]1[S:27][C@@H:26]2[C@@H:17]([C@@H:18]3[C@@H:23]([C@@H:24]([CH2:28][OH:29])[O:25]2)[O:22][C:21]([O:31][CH3:32])([CH3:30])[C:20]([O:34][CH3:35])([CH3:33])[O:19]3)[N:16]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C(N(CC)CC)C>ClCCl>[CH2:5]([N:7]([C:15]1[S:27][C@@H:26]2[C@@H:17]([C@@H:18]3[C@@H:23]([C@@H:24]([CH:28]=[O:29])[O:25]2)[O:22][C:21]([O:31][CH3:32])([CH3:30])[C:20]([O:34][CH3:35])([CH3:33])[O:19]3)[N:16]=1)[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH3:6]
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H]3OC(C)(OC)C(C)(OC)O[C@@H]3[C@@H](CO)O[C@@H]2S1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H]3OC(C)(OC)C(C)(OC)O[C@@H]3[C@@H](C=O)O[C@@H]2S1
Temperature: -30 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
A solution of DMSO (40 g, 0.52 mol) in anhydrous dichloromethane (1.5 L) was treated with oxallyl dichloride (49 g, 0.39 mol) at −78° C. for 1 hour, followed by addition of 123 (30 g, 65 mmol). The resulting solution was stirred for 4 hours at −30° C. and then cooled down to −78° C. again at which time triethylamine (86 g, 0.85 mol) was added. After 1 hour at −50° C., the reaction mixture was quenched by H2O (500 mL), washed with brine (3×100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a short silica gel column, eluted with 30% ethyl acetate in petroleum ether to give 124 as a brown syrup (18 g, 60%). (ES, m/z) [M+H]+ 461.0; 1H NMR (300 MHz, CDCl3) δ 8.93 (s, 1H), 8.90 (s, 1H), 6.15-6.18 (m, 2H), 4.41-4.45 (m, 1H), 4.28-4.30 (m, 1H), 3.76-4.09 (m, 13H), 3.38 (s, 3H), 3.32 (s, 3H), 3.28 (s, 3H), 3.26 (s, 3H), 1.58 (s, 9H), 1.47 (s, 3H), 1.43 (s, 3H), 1.39 (s, 3H), 1.37 (s, 3H), 1.14-1.21 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:41][CH2:42][CH2:43][OH:44])=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:27][CH2:28]3)=[CH:18][CH:19]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:41][CH2:42][CH2:43][O:44][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3c(c2)N(CCCO)CCC3)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)C1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was reacted with methanesulfonyl chloride to yield the crude (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester which was used without further purification or characterization.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C:31](=[O:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3].[CH3:20][C@@H:19]1[C@:21]2([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]2)[O:22][C@H:17]2[CH2:16][C@@H:15]3[C@@:29]([CH3:39])([C@@H:18]12)[C:30](=[O:38])[C@H:31]([OH:37])[C@H:32]1[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@:33]1([CH3:36])[CH2:34][CH2:35][C@H:9]([OH:8])[CH2:10]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)C(=O)[C@]3(C)[C@H]1[C@@H]2C
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α, 12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-12-ol-11-one (see procedure G8) was converted into the title compound via reduction with lithium aluminum hydride in THF at room temperature according to the procedure described in J. Am. Chem. Soc., 1951, 73, 1777.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:32]=[CH:31]C(C#N)=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O.[C:35]([OH:38])(=[O:37])[CH3:36]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:32]=[CH:31][C:36]([C:35]([OH:38])=[O:37])=[CH:27][CH:26]=5)[CH2:23][CH2:24]4)[CH2:15][CH2:14]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(N2CCC(N3CCN(c4ccc(C5CCCCC5)cc4)CC3)CC2)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(N2CCC(N3CCN(c4ccc(C5CCCCC5)cc4)CC3)CC2)cc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a solution of 4-[4-[4-(4-cyclohexylphenyl)piperazin-1-yl]piperidin-1-yl]benzonitrile (1.95 g) in acetic acid (10 ml) was added concentrated hydrogen chloride (20 ml) and the mixture was stirred at 120° C. for 10 hours. The reaction mixture was added to water and the resulting precipitate was collected by filtration to give 4-[4-[4-(4-cyclohexylphenyl)piperazin-1-yl]piperidin-1-yl]benzoic acid (959 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: CSc1ccc(B(O)O)c(C)c1
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CSc1ccc(-c2cnc(N)cn2)c(C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A mixture of [2-methyl-4-(methylthio)phenyl]boronic acid (prepared as in Example 185, Step 2, 253 mg, 1.390 mmol), 5-bromo-2-pyrazinamine (242 mg, 1.390 mmol), Pd(PPh3)2Cl2 (195 mg, 0.278 mmol), DME (5 mL) and 2M Na2CO3 (8 mL) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, charged with CH2Cl2 and water, and stirred at ambient temperature for 30 min. The mixture was filtered, the organics were separated, and the aqueous layer was washed with CH2Cl2. The organics were pooled, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 50% EtOAc/hexane to give 190 mg (59%) of 5-[2-methyl-4-(methylthio)phenyl]-2-pyrazinamine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 8.05 (s, 1H), 7.29 (d, 1H, J=8.5 Hz), 7.17-7.12 (m, 2H), 4.97-4.82 (m, 2H), 2.50 (s, 3H), 2.36 (s, 3H); LRMS (ESI), m/z 232 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:42])[C@@H:4]([NH:8][C:9](=[O:41])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[N:26]=[C:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:28][C:29]=3[C:30]([F:33])([F:32])[F:31])=[O:24])=[CH:18][N:17]=2)=[C:12]([Cl:40])[CH:11]=1)[CH:5]([CH3:7])[CH3:6].CO.O.O.[OH-].[Li+]>O1CCCC1>[Cl:40][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[N:26]=[C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:28][C:29]=2[C:30]([F:31])([F:33])[F:32])=[O:24])=[CH:18][N:17]=1)[C:9]([NH:8][CH:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:42])=[O:2])=[O:41]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1)C(=O)O
Yield: 92 %

Procedure:
A solution of (S)-2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid methyl ester (30 mg, 0.05 mmol) in a mixture of tetrahydrofuran, methanol and water (3:1:1, 2 mL) was treated with lithium hydroxide monohydrate (6 mg, 0.15 mmol) at 50° C. for an hour. The reaction mixture was concentrated, diluted with water and the pH was adjusted to 1-2 with dilute hydrochloric acid (1N). The white precipitate was collected by centrifugation, and then was dried under vacuum to give 2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid (27 mg, 93%) as a white solid. LCMS calcd for C28H22ClF3N4O5 (m/e) 586, obsd 587 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(S(C)(=O)=O)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Nc3ccc(S(C)(=O)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
N-tert-butyl-2-(4-(methylsulfonyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 174 μmol) was dissolved in dichloromethane (3 mL) and treated with trifluoroacetic acid (396 mg, 268 μL, 3.48 mmol). After stirring at room temperature for 16 h, the mixture was concentrated in vacuo then re-dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.35 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then diluted with water, triturated and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(4-(methylsulfonyl)phenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (65 mg, 168 μmol, 97%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.55 (s, 1H), 10.12 (s, 1H), 8.19 (d, J=2.8, 1 H), 8.16 (s, 1H), 7.95 (d, J=8.8, 2 H), 7.88 (d, J=8.8, 2 H), 7.75 (s, 1H), 3.22 (s, 3H), 1.54 (s, 9H); MS (EI/CI) m/z: 388.2 [M+H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=6)=[C:23]([C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35]C)=[O:34])[C:22]([CH3:42])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=6)=[C:23]([C@H:32]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[C:33]([OH:35])=[O:34])[C:22]([CH3:42])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c1-c1ccc(Cl)cc1
Solvent: CO
Solvent: O
Product: Cc1cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
The solution of crude (S)-methyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate from the previous reaction was treated directly with LiOH monohydrate (60 mg, 1.42 mmol), H2O (500 μL), and MeOH (500 μL). The reaction was heated to 50° C. for 15 h. The reaction failed to reach completion (LCMS analysis). The reaction was then heated to 100° C. for 30 min and reached completion. The system was cooled to 23° C. and filtered (0.45 micron Teflon® filter). The filtrate was purified directly on a C-18 Gemini column using a Gilson liquid handler (Eluent H2O/CH3CN gradient with both mobile phase components spiked 0.1% v/v with TFA). The title compound was obtained as a mono-trifluoroacetic acid salt. LCMS-ESI+: calc'd for C32H27ClN4O3S: 583.2 and 585.2 (M+H+); Found: 583.3 and 585.3 (M+H+). 1H NMR (400 MHz, CD3OD) S: 8.78 (d, J=5.5 Hz, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 8.11 (dd, J=8.6, 1.2 Hz, 1H), 8.04 (dd, J=5.4, 1.2 Hz, 1H), 7.99 (s, 1H), 7.74-7.70 (m, 2H), 7.65-7.60 (m, 3H), 5.23 (s, 1H), 2.65 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([N:7]([CH3:27])[C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][C:31]=1[CH3:38]>C(O)C>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([N:7]([CH3:27])[C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:28])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:26])[C:18]=2[OH:25])=[O:23])=[CH:32][C:31]=1[CH3:38]
Reactant: COC(=O)c1nc2n(c(=O)c1O)CC1CCC2(N(C)C(=O)C(=O)N(C)C)CC1
Reactant: Cc1cc(CN)ccc1F
Solvent: CCO
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC2CCC3(N(C)C(=O)C(=O)N(C)C)CC2)ccc1F
Temperature: 90 °C
Yield: 65.4 %

Procedure:
To a mixture of methyl 10-(((dimethylamino)(oxo)acetyl)(methyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (3 g, 7.65 mmol) in ethanol (80 mL) was added (4-fluoro-3-methylphenyl)methanamine (2.90 mL, 22.94 mmol) and the mixture was heated at 90° C. for 18 h. The reaction mixture was cooled, concentrated, diluted with ethyl acetate and washed twice with 0.2N NaOH (2×100 mL). The organic layer was discarded and the aqueous layer acidified with conc. HCl and extracted with dichloromethane (2×150 mL), dried (Na2SO4), filtered and concentrated. The crude product was recrystallized from methanol to afford the title compound (2.5 g, 66% yield) as a crystalline white solid. 1H NMR (500 MHz, CDCl3) δ: 12.13 (1 H, s), 9.56 (1 H, brs), 7.20-7.23 (1 H, m), 7.15-7.20 (1 H, m), 6.88-6.93 (1 H, m), 4.83 (1 H, dd, J=15.56, 7.02 Hz), 4.55-4.62 (1 H, m), 4.39-4.45 (1 H, m), 3.60 (1 H, d, J=15.56 Hz), 3.33-3.47 (2 H, m), 3.01 (3 H, s), 2.99 (3H, s), 2.97 (3 H, s), 2.49 (1 H, brs), 2.23 (3 H, d, J=1.83 Hz), 1.97-2.09 (4 H, m), 1.74-1.84 (2 H, m). LCMS (M+H)=500.69. HPLC purity: >95%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([F:36])[CH:27]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:24][C:20]2[CH:21]=[N:22][CH:23]=[C:18]([C:16]3[CH:15]=[CH:14][C:10]4[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:9]=4[N:17]=3)[CH:19]=2)(=[O:33])=[O:34])=[C:28]([F:36])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.050 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 4-bromo-2-fluorobenzene-1-sulfonyl chloride (0.051 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1 N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 4-bromo-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.028 g, 32%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.10-4.16 (2H, m), 5.66-5.71 (1H, m), 7.38-7.41 (2H, m), 7.79-7.83 (1H, m), 8.25 (1H, d, J=8.8 Hz), 8.40 (1H, d, J=8.8 Hz), 8.72 (1H, s), 8.85 (1H, s), 9.20 (1H, m). m/z=562.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Nc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cc(F)ccc2[nH]c2c([N+](=O)[O-])ccc(Cl)c12
Yield: 87.1 %

Procedure:
A mixture of 6-chloro-2-[(4-fluorophenyl)amino]-3-nitrobenzoic acid (12.39 g, 0.04 mol), chloroform (100 ml), and POCl3 (60 ml, 0.64 mol) was stirred at reflux for 8 h. Solvents were removed under reduced pressure. To the residue was added 200 ml of a mixture of 1,4-dioxane and water (8:1), and the mixture was acidified with concentrated hydrochloric acid and stirred at reflux for 2 h. Water was added (200 ml) and the precipitate was collected by filtration and crystallized from N,N-dimethylformamide—water to give 10.2 g (87%) of 1b as orange needles: mp 287-291° C. Anal. (C13H6N2O3ClF) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1>[C].[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of ethyl 3-[(4-nitrobenzoyl)amino]propanoate (26.6 g) synthesized above, 5% palladium-carbon (8.9 g), tetrahydrofuran (150 mL) and ethanol (150 mL) was stirred at room temperature overnight under a hydrogen atmosphere. 5% Palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure to give a white solid. Recrystallization from ethyl acetate-diisopropyl ether gave the title object compound (22.6 g, 95%) as white crystals.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([CH:41]([CH2:45][CH:46]=[CH2:47])[C:42](O)=[O:43])[CH:39]=[CH2:40]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:42](=[O:43])[CH:41]([CH2:45][CH:46]=[CH2:47])[CH2:38][CH:39]=[CH2:40])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: C=CCC(CC=C)C(=O)O
Product: C=CCC(CC=C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 75.8 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and mg (4.0 mmol) of 2-allyl-4-pentenoic acid, to provide 1.02 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(Cl)(Cl)Cl>O>[Br:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:3]([C:4](=[O:5])[N:6]([CH3:7])[CH3:8])[CH:9]=1
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Br)ccc1NC(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
2-Amino-5-bromo-N,N-dimethyl-benzamide (2.00 g, 8.22 mmol), diisopropylethylamine (6.5 ml, 37.32 mmol), 4-morpholinecarbonyl chloride (4.3 ml, 37.46 mmol), and chloroform (20 ml) were combined and stirred for 18 hours at 50° C. Water was added to the mixture, and the organic layer was extracted. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the crude material was purified by flash chromatography (50% to 100% ethyl acetate in hexanes) to give 1.13 g (39%) of morpholine-4-carboxylic acid (4-bromo-2-dimethylcarbamoyl-phenyl)-amide. 1H-NMR (250 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.56-7.45 (m, 2H), 7.42 (t, J=9.3 Hz, 4H), 3.35-3.28 (m, 4H), 2.96-2.86 (m, 6H); MS: m/z 356.0+358.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 91.7 %

Procedure:
[1-(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid benzyl ester (1.3 g, 3.5 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (0.48 g, 9.1 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (1.25 g, 99% yield) as a brown solid. Tr=1.81 min, m/z (ES+) (M+H)+ 390.