Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12](/[CH:16]=[CH:17]/[C:18](=[O:33])[CH2:19][C:20](=[O:32])/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([OH:31])[CH:24]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].CN(C)C1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=C(OC)C=2)=CC=1>>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][CH2:17][C:18](=[O:33])[CH2:19][C:20](=[O:32])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([OH:31])[CH:24]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(/C=C/C(=O)CC(=O)/C=C/c3ccc(OC)c(O)c3)ccc21
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(N(C)C)cc2)ccc1O
Product: CCn1c2ccccc2c2cc(CCC(=O)CC(=O)CCc3ccc(OC)c(O)c3)ccc21

Procedure:
The title compound was synthesized using the same procedure employed for Example 372, but with (1E,6E)-1-(9-ethyl-9H-carbazol-3-yl)-7-(3-hydroxy-4-methoxyphenyl)hepta-1,6-diene-3,5-dione (20 mg, 59 μmol, synthesized in Example 84) as the starting material instead of (1E,6E)-1-(4-dimethylaminophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel column chromatography eluting with hexane/ethyl acetate=75/25 to 65/35. The product was obtained as a solid (13.1 mg, 65%) having the following characteristics.
Reaction SMILES: C([O:8][C:9](=[O:27])[C@H:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:11][C:12]([N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[S:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C@H:10]([C:9]([OH:27])=[O:8])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:13])[CH2:15][CH2:16]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)N1CCSCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCSCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of N-thiomorpholinocarbonyl-L-phenylalanine benzyl ester (526 mg) in a mixture of methanol (10 ml) and water (10 ml) which was cooled to 0° C., was added lN sodium hydroxide solution (4 ml). The mixture was stirred at the same temperature for 1 hour. After evaporation of methanol, remaining aqueous solution was washed with diethyl ether, acidified to pH 2.5 with 3N hydrochloric acid and extracted with ethyl acetate (30 ml×3). The extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give N-thiomorpholinocarbonyl-L-phenylalanine (382 mg) as an oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.Br[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11]>C1COCC1>[CH:3]1([O:7][CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH2:6][CH2:5][CH2:4]1
Reactant: CC(Br)C(N)=O
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(OC1CCC1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 732 mg of sodium hydride in 15 ml THF, 2.0 g of cyclobutanol in 0.5 ml THF were added dropwise and stirred for 30 minutes at 25° C. The reaction mixture was then cooled to 0° C. and 2.11 g of (+/−) 2-bromopropanamide in 0.5 ml tetrahydrofuran were added dropwise and then stirred for 18 hours at 25° C. The reaction mixture was poured onto ice-water and extracted once with 75 ml dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo after filtration. The crude product thus obtained was purified by column chromatography on silica gel with hexane/0-50% ethyl acetate. Yield: 0.79 g of the title compound.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)[CH:16]=1)[CH:11]=2.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:19]([CH:20]=2)=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)[CH:16]=2)[CH:11]=3)[CH2:29][CH2:28]1
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Reactant: CN1CCNCC1
Agent: Cl
Product: CN1CCN(CCCOc2ccc3cc4ccc(OCCCN5CCN(C)CC5)cc4nc3c2)CC1

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and N-methylpiperazine as described in Example 44.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccncc3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[C@@H:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:32]([SH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1>[CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[CH:15]([S:38][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCCCCCCC[C@H](Br)C(=O)Nc1c(SC)ccc2ncccc12
Reactant: CCCCCCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCCCCCCCC(SCCCCCC)C(=O)Nc1c(SC)ccc2ncccc12
Reaction time: 18 h
Yield: 60.3 %

Procedure:
(S)-N-(6-Methylthioquinolin-5-yl)-2-bromodecanoic amide (39 mg, 0.09 mmol) in 1 ml of dry THF was added slowly to a suspension containing cesium carbonate (67 mg, 0.20 mmol) and hexanethiol (13 mg, 0.11 mmol) in 2 ml of THF. After 18 hours, the reaction was quenched with 2 ml of 1N HCl and extracted with ethyl acetate (4×10 ml). The organic phase was purified by silica gel column chromatography (eluent: 100% CHCl3) to yield 25 mg (60% yield) of the desired product. 1H NMR (CDCl3) δ8.85 (1H, d, J=3 Hz), 8.62 (1H, s), 8.05 (1H, d, J=9 Hz), 8.00 (1H, d, J=9 Hz), 7.65 (1H, d, J=9 Hz), 7.40 (1H, dd, J=9, 9 Hz), 3.55 (1 H, t, J=8 Hz), 2.80 (2H, t, J=8 Hz), 2.50 (3H, s), 2.20-1.30 (22H, m), 0.91 (6H, t, J=Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:31][C:32](=[O:51])[NH:33][CH:34]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:13]([NH:15][C@@H:16]([C@H:21]([NH:23][CH2:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH3:22])[C:17]([O:19]C)=[O:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.[OH-].[Na+]>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:31][C:32](=[O:51])[NH:33][CH:34]([C:43]1[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=1)[C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:13]([NH:15][C@@H:16]([C@H:21]([NH:23][CH2:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH3:22])[C:17]([OH:19])=[O:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](NC(=O)[C@H](CC(=O)NC(c1ccc(OC)cc1)c1ccc(OC)cc1)NC(=O)OCc1ccccc1)[C@@H](C)NCCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(NC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H](C(=O)O)[C@@H](C)NCCc2c[nH]cn2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A solution of methyl (2S,3R)-2-[[(2S)-2-benzyloxycarbonylamino-3-[N-[bis(4-methoxyphenyl)methyl]carbamoyl]propionyl]amino]-3-[[2-(4-imidazolyl)ethyl]amino]butyrate (1.40 g) in a mixture of methanol (50 ml) and 1N aqueous sodium hydroxide (25 ml) was stirred for 30 minutes at room temperature and the mixture was adjusted to pH 7 with 1N hydrochloric acid. The precipitate was collected by filtration to give (2S,3R)-2-[[(2S)-2-benzyloxycarbonylamino-3-[N-[bis(4-methoxyphenyl)methyl]carbamoyl]propionyl]amino]-3-[[2-(4-imidazolyl)ethyl]amino]butyric acid (1.16 g) as a white powder.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]O)=[CH:44][CH:43]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C.O>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH2:46][C:45]4[CH:48]=[CH:49][C:42]([Cl:41])=[CH:43][CH:44]=4)=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: OCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(N3CCN(C(=O)OCc4ccc(Cl)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 148 (300 mg, 0.65 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and then added methylene chloride (2 ml) and triethylamine (2 ml). After stirring at room temperature for 5 minutes, the solution was concentrated under reduced pressure, and the residue was dissolved in DMF (15 ml). To the solution, a mixture of 4-chlorobenzyl alcohol (186 mg, 1.31 mmol), 1,1′-carbonyldiimidazole (212 mg, 1.31 mmol) in DMF (5 ml) stirred at room temperature for 3 hours was added followed by stirring at room temperature overnight. The reaction mixture was poured into water, extracted from ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford 4-chlorobenzyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylate (313 mg, yield 91%) as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:1][C:2]2[CH:7]=[C:6]([C@:8]3([CH3:20])[C:14]([F:15])([F:16])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9]3)[C:5]([F:21])=[CH:4][C:3]=2[F:22])=[O:32])=[N:29][CH:30]=1)#[N:24]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)c(F)cc2F)C1(F)F
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC(=O)c3ccc(C#N)cn3)c(F)cc2F)C1(F)F
Yield: 82 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (R)-5-(5-amino-2,4-difluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17C) (70 mg, 0.208 mmol) and commercially available 5-cyano-pyridine-2-carboxylic acid [CAS No. 53234-55-2] (46 mg, 0.312 mmol). The compound was obtained as a light yellow foam (80 mg, 82%). MS (ISP): m/z=467.1 [(M+H)+].
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[C:30]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])=[O:21])[S:17][CH:18]=2)[CH2:7]1)=[O:5])C>[Li+].[OH-]>[CH:32]1([C:30]([C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[NH:22][C:20](=[O:21])[NH:19][C:16]2[S:17][CH:18]=[C:14]([CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[N:15]=2)=[O:31])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)C1CCCN(CCc2csc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)n2)C1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)Nc2nc(CCN3CCCC(C(=O)O)C3)cs2)c(C(=O)C2CCCC2)c1
Yield: 92.9 %

Procedure:
1-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl)-piperidin-3-carboxylic acid (18 mg, 95%) was prepared from 1-(2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl)-piperidin-3-carboxylic acid ethyl ester (0.02 g, 0.04 mmol) and 2.5M LiOH (20 uL) following the general procedure J.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:6]=[CH:7][C:2]([C:38]6[CH:39]=[N:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=6)=[CH:3][CH:4]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:30][CH2:29]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H]3C[C@@]4(C)[C@@H](C[C@@H](C)[C@@H]4C(=O)C4CC4)[C@@H]4CCC5=CC(=O)CCC5=C43)cc2)cn1
Yield: 54 %

Procedure:
Reaction of (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 6-methoxy-3-pyridinylboronic acid using the procedure described in example 1 step h afforded the title compound (54% yield). 1H NMR (400 MHz, CDCl3): δ 0.35 (s, 3H), 0.84-0.99 (m, 6H), 1.08-1.15 (m, 1H), 1.33-1.39 (m, 1H), 1.45-1.54 (m, 1H), 1.62-1.70 (m, 2H), 1.91-1.97 (m, 1H), 2.01-2.08 (m, 1H), 2.24-2.53 (m, 6H), 2.58-2.64 (m, 2H), 2.68-2.85 (m, 3H), 3.98 (s, 3H), 4.44 (d, J=8 Hz, 1H), 5.80 (s, 1H), 6.80 (d, J=8 Hz, 1H), 7.23 (d, J=7 Hz, 2H), 7.44 (d, J=7 Hz, 2H), 7.75-7.79 (m, 1H), 8.36-8.38 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][CH:9](C)CCN>>[CH2:8]([CH:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:1][NH2:7])[CH3:9]
Reactant: CC(C)CCN
Reactant: CCCCCCN
Product: CCCCC(CC)CN

Procedure:
n-hexylamine and/or 3-methyl-butylamine
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22])[CH3:17].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:22][C:21]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:19]([O:18][CH2:16][CH3:17])[CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOc1cc(N)ccc1OC
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOc1cc(Nc2cccc(C(=O)OC)c2C(=O)OC)ccc1OC
Yield: 80 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 3-ethoxy-4-methoxyaniline (0.51 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.90 g of the product at 70:30 hexanes-ethyl acetate, in 80% yield: 1H NMR (CDCl3) δ 1.45 (t, J=7.0 Hz, 1H), 3.86 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 4.05 (q, J=7.0 Hz, 2H), 6.71-6.74 (m, 2H), 6.84 (d, J=7.4 Hz, 1H), 6.96 (dd, J=7.3 Hz, J=1.0 Hz, 1H), 7.13 (dd, J=8.5 Hz, J=1.0 Hz, 1H), 7.24 (t, J=7.4 Hz, 1H), 8.07 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](S(C3C=CC=CC=3)(=O)=O)[CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccc(Cl)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1c[nH]c(-c2ccc(Cl)cc2)n1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of (2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11fb, 440 mg, 1.0 mmol) in THF (12.0 mL) was added 1.0 M tetrabutyl ammonium fluoride (2.0 mL, 2.0 mmol) and stirred overnight. The reaction mixture was diluted by 20 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (60 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was recrystallized from water and methanol to give a white solid. Yield: 83.7%.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]5[CH2:30][CH2:29][N:28]([CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[I-].[Na+]>C(O)(=O)C>[CH3:35][N:34]([CH3:36])[C:32](=[O:33])[CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:8]5[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=5)=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: COc1ncccc1-c1cccn2nc(Nc3ccc(C4CCN(CC(=O)N(C)C)CC4)cc3)nc12
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C(=O)CN1CCC(c2ccc(Nc3nc4c(-c5ccc[nH]c5=O)cccn4n3)cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
A solution of 2-(4-{4-[8-(2-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide (25 mg, 0.052 mmol) in acetic acid (1.3 mL) was added sodium iodide (15.4 mg, 0.103 mmol), and the reaction was stirred at 100° C. for 3 hours. The solvent was evaporated and the residue was diluted with dichloromethane. The dichloromethane solution was washed with 10% sodium thiosulfate solution, brine then dried over sodium sulfate, and concentrated. The product was purified by preparatory TLC (silica gel 10% methanol in dichloromethane) to give the product (13 mg, 54%). MP: >250° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 12.0 (bs, 1H), 9.60 (s, 1H), 8.88 (d, J=6.58 Hz, 1H), 8.75 (d, 1H), 8.45 (d, 1H), 7.70 (d, 2H), 7.50 (m, 1H), 7.20 (m, 2H), 7.05 (t, 1H), 6.45 (t, 1H), 3.25 (s, 2H), 3.05 (s, 3H), 2.90 (m, 2H), 2.78 (s, 3H), 2.45 (m, 1H), 2.10 (m, 2H), 1.85-1.90 (m, 4H). MS=472 (MH)+.
Reaction SMILES: [CH2:1]([C:8]([OH:19])([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CCO>[CH2:1]([C@:8]([OH:19])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)(Cc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@](O)(Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
To diethyl benzyl(hydroxy)propanedioate (6.3 g) in 50 mL of EtOH (anhydrous) was added KOH (1.5 g). The mixture was stirred at rt over night. After removing the solvent in vacuo, the residue was taken up with 100 mL of ethyl acetate and 150 mL of water. The organic layer was removed. To the aqueous layer containing the potassium salt of the desired product was added 0.2 N HCl until pH=2. The mixture was extracted with 200 mL ethyl acetate. The organic layer was dried with magnesium sulfate and concentrated to give the title acid as a colorless oil. The racemic acid was then purified by chrial SFC(OJ-H, 4.6×100 mm, 5% MeOH/0.1% TFA/CO2, 2.5 mL/min, 100 bar) to give the title compound as a single enantiomer. LC/MS 261.1 (M+23).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:11]([CH2:19][CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:11]([CH2:19][CH2:20][CH2:21][NH2:22])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)nn1CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(OCc2ccccc2)nn1CCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
Ethyl 3-(benzyloxy)-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-pyrazole-5-carboxylate (7 g, 17.4 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (50 mL). The mixture was stirred at room temperature for 1 hour and then the solvent was evaporated in vacuo to yield ethyl 3-(benzyloxy)-1-[3-amino-propyl]-1H-pyrazole-5-carboxylate (5.5 g, 95% yield) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]3=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:2]>C1COCC1.CO.[Pt](=O)=O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[C:18]3=[N:19][S:20](=[O:23])(=[O:24])[CH2:21][CH2:22][N:17]3[CH2:16][CH2:15][CH2:14]2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(3-ethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (247 mg) in THF (dry) (20 ml) and MeOH (20 mL). The mixture was stirred at 50° C. under hydrogen for 40 min and at room temperature under hydrogen for 4 h. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (167.0 mg) as colorless crystals.