Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[Cl:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][N:32]=[C:31]4[Cl:37])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: COCCC(C(=O)Nc1ccc2[nH]nc(Cl)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
170 mg (451 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 92.4 mg (purity 90%, 496 μmol, 1.1 eq.) of 5-amino-3-chloro-1H-indazole were reacted according to General Method 1. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 113 mg (48% of theory)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][CH2:11][CH2:12][CH2:13][CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:15]([OH:17])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.Cl.[CH3:42][O:43][C:44]1[CH:45]=[C:46](/[CH:56]=[CH:57]/[C:58]([NH:60][NH2:61])=O)[CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1>C(Cl)Cl.O>[Cl:10][CH2:11][CH2:12][CH2:13][CH:14]([C:15]1[O:17][C:58](/[CH:57]=[CH:56]/[C:46]2[CH:47]=[CH:48][C:49]([N:50]3[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]3)=[C:44]([O:43][CH3:42])[CH:45]=2)=[N:60][N:61]=1)[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1
Reactant: O=C(O)C(CCCCl)c1ccc(Cl)cc1
Reactant: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/c2nnc(C(CCCCl)c3ccc(Cl)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.3 %

Procedure:
IPEA (2.5 mL), 5-chloro-2-(4-chlorophenyl)pentanoic acid (430 mg) and BOPCl (0.44 g) were added to a suspension of (E)-3-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]acrylic acid hydrazide dihydrochloride (500 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 14 hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. A solution of the residue in phosphorus oxychloride (4 mL) was heated under reflux for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 366 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:10])=[O:9])=[C:4](C)[CH:3]=1.BrC1C=CC(S(Cl)(=O)=O)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)NCCN1CCOCC1
Agent: O=S(=O)(Cl)c1ccc(Br)cc1
Product: O=S(=O)(NCCN1CCOCC1)c1ccc(Br)cc1

Procedure:
The title compound was prepared in the same manner as described for 4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide, replacing 4-bromo-2-methyl-benzene sulfonyl chloride with 4-bromobenzene sulfonyl chloride. 1H-NMR (DMSO-d6) δ 7.81 to 7.68 (m, 4H), 7.66 (broad s, 1H), 3.46 (t, J=4.8 Hz, 4H), 2.85 (t, J=6.6 Hz, 2H), 2.28 to 2.21 (m, 6H); MS LC-MS [M+H]+=349 & 351, RT=1.34 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[O:20])[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:30][CH:27]4[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])[CH2:15][CH2:14]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)NC2CCC(C(=O)N3CCNCC3)CC2)cc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1ccc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N3CCN(CC4CC4)CC3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 0.1 g (0.26 mmol) 4-cyano-N-[4-(piperazine-1-carbonyl)-cyclohexyl]-benzenesulfonamide, 0.022 g (0.31 mmol) cyclopropanecarboxaldehyde (commercially available), 0.159 g (2.65 mmol) acetic acid and 0.073 g (0.34 mmol) sodium triacetoxyborohydride in 1 mL THF was stirred at 80° C. for 1 h. The mixture was subjected to purification on preparative HPLC eluting with a gradient formed from acetonitrile and water. Evaporation of the product fractions yielded 3 mg (2.6%) of the title compound. MS (m/e): 431.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C@H:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[O:18])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)C=1>>[O:18]=[C:9]1[C@@H:10]2[C@@H:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:16](=[O:17])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: O=C1[C@H]2CCCC[C@H]2C(=O)N1c1ccc(O)cc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(N2C(=O)[C@H]3CCCC[C@H]3C2=O)cc1)c1ccccc1
Yield: 77.4 %

Procedure:
The title compound (293 mg, 77% yield, white crystals) was prepared from cis-2-(4-hydroxy-phenyl)hexahydroisoindole-1,3-dione (245 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=379 (M+1); Rt=4.08 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(Cl)(Cl)Cl.C(O)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[N:3]=1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cc(-n2ccnc2)nc(Cl)c1C#N
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A solution of 2,6-dichloro-3-cyano-4-methylpyridine (5.6 g) and imidazole (2.04 g) in dimethylformamide (10 mL) was heated at 130° C. for 1.25 hours. After cooling to room temperature the mixture was fractionated directly on silica gel with chloroform/ethanol gradient) to give 1.5 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH3:11][C:12]1([CH3:23])[C:20]2[C:15](=[C:16]([NH2:21])[CH:17]=[CH:18][CH:19]=2)[CH:14]([CH3:22])[CH2:13]1.O>C(Cl)Cl>[CH3:11][C:12]1([CH3:23])[C:20]2[C:15](=[C:16]([NH:21][C:8]([C:4]3[S:3][C:2]([Cl:1])=[N:6][C:5]=3[CH3:7])=[O:10])[CH:17]=[CH:18][CH:19]=2)[CH:14]([CH3:22])[CH2:13]1
Reactant: Cc1nc(Cl)sc1C(=O)O
Reactant: CC1CC(C)(C)c2cccc(N)c21
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Cl)sc1C(=O)Nc1cccc2c1C(C)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
252 mg (1.42 mmol) of 2-chloro-4-methylthiazole-5-carboxylic acid and 442 mg (1.42 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidomethiodide were dissolved in 10 ml of methylene chloride and stirred at room temperature for 1 hour. Then, to the solution was added 249 mg (1.42 mmol) of 1,1,3-trimethyl-4-aminoindan and reaction was effected for 6 hours under reflux. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was concentrated and thereafter was purified by column chromatography (eluent; n-hexane:ethyl acetate=50:50 V/V) to obtain 204 mg of N-(1,1,3-trimethyl-4-indanyl)-2-chloro-4-methylthiazole-5-carboxamide (yield 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[C:4]([F:21])[CH:3]=1.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:28][C@@H:26]([CH3:27])[CH2:25][O:24][NH:23][C:18]([C:17]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:21])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)=[O:20]
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O)CONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a solution of 4-(4-bromo-2-fluorophenylamino)-1H-indazole-5-carboxylic acid (115 mg, 0.33 mmol) and (S)-1-aminooxy-propan-2-ol hydrochloride (63 mg, 0.49 mmol) in DMF (3 mL) was added EDCI (69 mg, 0.36 mmol), HOBt (49 mg, 0.36 mmol) and DIPEA (150 μL, 0.85 mmol). The reaction mixture was stirred at room temperature for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (10-90% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The aqueous fraction was extracted twice with ethyl acetate (2×10 mL) and the combined organic layers washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid (61 mg, 44%). LCMS (Method A): RT=8.45 min, [M+H]+=423/425. 1H NMR (DMSO-d6, 400 MHz) 13.21 (1H, s), 11.63 (1H, s), 9.90 (1H, s), 7.58 (1H, dd, J=10.47, 2.24 Hz), 7.46 (1H, d, J=8.75 Hz), 7.29 (1H, ddd, J=8.59, 2.19, 1.06 Hz), 7.23 (1H, s), 7.08 (1H, t, J=8.80 Hz), 7.02 (1H, d, J=8.78 Hz), 4.77 (1H, d, J=4.15 Hz), 3.84-3.78 (1H, m), 3.70-3.61 (2H, m), 1.03 (3H, d, J=6.33 Hz).
Reaction SMILES: C([O:8][CH2:9][C:10](Cl)=[O:11])C1C=CC=CC=1.[C:13]1([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Si](Cl)(C(C)C)C(C)C)(C)C.N1C=CN=C1>CN(C)C=O.CCCCC>[OH:11][CH2:10][C:9]([O:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C(CO)O[C@@H]1CCCC[C@H]1c1ccccc1
Yield: 95 %

Procedure:
To obtain 1c(-), a solution of (-)-(1R,2S)-2-phenyl-1-cyclohexyl hydroxyacetate (851 mg, 3.63 mmol) was prepared through esterification of benzyloxyacetyl chloride with (-)-(1R,2S)-2-phenyl-1-cyclohexanol followed by hydrogenolysis. Then, triisopropylsilyl chloride (840 mg, 4.36 mmol) and imidazole (618 mg, 9.08 mmol) in dimethylformamide (DMF) (1.7 mL) was stirred at room temperature for 12-20 hours. The mixture was poured into pentane (25 mL), and washed with water and brine. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was subjected to a purification on a short silica gel column using hexane/chloroform (3/1) as the eluant to give pure 1c(-) (1.35 g, 95% yield) as a colorless oil.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C(=O)([O-])[O-].[Na+].[Na+].C(N(CC)CC)C.[ClH:23].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][N:34]([CH:37](Cl)[CH2:38][CH3:39])[CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[ClH:24].[ClH:23].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:32][CH2:33][N:34]([CH2:37][CH2:38][CH2:39][N:3]3[CH2:4][CH:5]4[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[CH2:35][CH2:36]2)[CH:28]=[CH:29][CH:30]=1
Reactant: C1CC2CCC1CNC2
Reactant: CCC(Cl)N1CCN(c2cccc(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1cccc(N2CCN(CCCN3CC4CCC(CC4)C3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-azabicyclo[3.2.2]nonane, (4 g, 0.032 mol), sodium carbonate (4 g, 0.045 mol) and triethylamine 3 mL in 50 mL of dimethylformamide is added 4-(3-chlorophenyl)-1-piperazinylpropylchloride hydrochloride (4 g, 0.0115 mol). The reaction mixture is stirred at room temperature overnight, the solvent is removed under vacuum and the remaining solid is extracted in 3×100 mL methylene chloride. The methylene chloride extracts are collected, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[O:22][C:21]([CH2:23][N:24]5[CH2:27][CH:26]([C:28]([O:30]CC)=[O:29])[CH2:25]5)=[CH:20][CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.O.[OH-].[Li+].C(O)(=O)C>O.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[O:22][C:21]([CH2:23][N:24]5[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]5)=[CH:20][CH:19]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(C5CCCCC5)cc4)n3)o2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4ccc(C5CCCCC5)cc4)n3)o2)C1
Yield: 56.5 %

Procedure:
To a solution of ethyl 1-({5-[5-(4-cyclohexylphenyl)-1,2,4-oxadiazol-3-yl]-2-furyl}methyl)azetidine-3-carboxylate (0.23 g, 0.53 mmol) that was obtained in Example 2 (2d) in a mixed solvent of tetrahydrofuran (0.50 ml), methanol (0.50 ml) and water (0.50 ml) was added lithium hydroxide monohydrate (50 mg, 1.2 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, acetic acid (65 μl, 1.2 mmol) was added to the reaction mixture to quench the reaction. The white solid precipitated was collected by filtration using a Kiriyama funnel, washed with a mixed solvent of water and methanol (3:7) and dried in vacuo to afford the title compound (122 mg) in a yield of 56% as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:16]=3[O:15][CH2:14]2)=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]([O:44][C:45]([NH:47][CH:48](P(OC)(OC)=O)[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:52][O:51][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[O:46])=[CH:23][C:21]1[CH:20]=[CH:19][C:17]2[O:18][C@H:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)=[CH:12][CH:11]=3)[CH2:14][O:15][C:16]=2[CH:22]=1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: O=Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (5.0 g) was dissolved in 25 mL dry DCM under nitrogen at rt and 3.6 mL DBU was added by syringe. 3.8 g of Boc-phosphonoglycine trimethyl ester in 10 mL dry DCM was added by syringe dropwise and the mixture stirred at rt for 14 hours. The residue was purified over silica (hexanes to 8:2 hexanes/EtOAc) 4.9 g desired product after drying under vacuum. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.35 (m, 2H), 7.27 (m, 1H), 7.22-7.19 (m, 2H), 7.11 (m, 1H), 6.98 (m, 2H), 6.93 (d, 1H), 5.10 (m, 1H), 5.04 (s, 2H), 4.32 (m, 1H), 4.02 (m, 1H), 3.84 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=O)[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([NH:24][S@@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: COc1cc(C(C)=O)cnc1OCC(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: COc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)F
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (0.29 g, a white solid) from 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.25 g, 0.99 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: ClC[C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:17]([OH:21])(=[O:20])[CH2:18][OH:19]>C(#N)C>[C:17]([O:21][C:3]1[C:16]2[C:11]([CH:10]=[C:9]3[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]3)=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:20])[CH2:18][OH:19]
Reactant: O=C(O)CO
Reactant: ClCc1c2ccccc2cc2ccccc12
Solvent: CC#N
Product: O=C(CO)Oc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
A suspension of 9-chloromethyl anthracene (1.0 g, 4.4 mmol) in dry acetonitrile (50 ml) is added to a solution of glycolic acid (0.71 g 18.8 mmol) (dried by successive evaporation from dry acetonitrile) in acetonitrile (10 ml). The reaction is stirred for 18 hours at room temperature and refluxed for 2 hours. After evaporation of acetonitrile the residue is redissolved in methylene chloride and extracted with water and 0.5M sodium bicarbonate. The solution is dried and solvent evaporated. The residue is recrystallized from refluxing benzene at 40° C. to yield 0.73 g (2.6 mmol) of yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10])#[N:2].[CH2:12](O)[CH2:13][CH2:14]O>C(Cl)Cl>[O:10]1[CH2:14][CH2:13][CH2:12][O:11][B:9]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccccc1B(O)O
Reactant: OCCCO
Solvent: ClCCl
Product: N#Cc1ccccc1B1OCCCO1
Reaction time: 20 h
Yield: 57.2 %

Procedure:
49.0 g (334 mmol) 2-cyanobenzeneboronic acid and 25.9 g (340 mmol) 1,3-propanediol were dissolved in 1 L CH2Cl2 with stirring in a 2 L round bottom flask for 20 h. The solution was then poured over a filter with suction to remove gummy solids. The filtrate was then dried with anhydrous MgSO4 to remove residual water, filtered and evaporated of solvent to give light-colored oil. The oil was then dissolved in CH2Cl2 and purified on a silica gel plug using CH2Cl2 as eluent. The product fractions were evaporated down to give the product as clear oil (35.7 g, 57.2% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:24](O)=[O:25])[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:36][CH:37]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[CH2:38][CH2:39][NH:40][C:41]([NH2:43])=[O:42]>CN1C(=O)CCC1.CCOC(C)=O>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([CH:37]([NH:36][C:24]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:14][CH2:13][N:12]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH2:11][CH2:10]2)=[O:25])[CH2:38][CH2:39][NH:40][C:41]([NH2:43])=[O:42])=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(=O)NCCC(N)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCNC(N)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluoro-phosphate (378 mg, 0.99 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (240 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.329 mL, 1.99 mmol) in NMP (2 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. 1-(3-amino-3-(4-chlorophenyl)propyl)urea (Intermediate 111) (151 mg, 0.66 mmol) in NMP (2 mL) was then added to the reaction and stirred for 18 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(1-(4-chlorophenyl)-3-ureidopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (379 mg, 100%) as a white solid. m/z (ESI+) (M+H)+=571; HPLC tR=1.88 min.
Reaction SMILES: [OH-].[K+].Br[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:13][C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1.O>C(O)C>[Br:13][C:14]1[CH:15]=[C:16]([S:20][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Sc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(CSc1cccc(Br)c1)c1ccccc1
Reaction time: 16 h
Yield: 101 %

Procedure:
Add potassium hydroxide (4.89 g, 87.3 mmol) and 2-bromoacetophenone (15.8 g, 79.3 mmol) to a solution of 3-bromobenzenethiol (15 g, 79.3 mmol) in ethanol (200 mL, 70% in water) at 0° C. After stirring 16 h, add water to precipitate a yellow solid. Filter to obtain the desired intermediate (24.6 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[N:18]1([C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[O:10])=[N:4][C:5]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(NC(=O)c2nc(Br)ccc2N)cn1
Reactant: OB(O)c1cccc(N2CCCCC2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Cn1cc(NC(=O)c2nc(-c3cccc(N4CCCCC4)c3)ccc2N)cn1
Temperature: 25 °C

Procedure:
To a microwave reaction vial was added 317 from Example 317 (150 mg, 0.51 mmol), 3-(piperidin-1-yl)phenylboronic acid (312 mg, 1.52 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (41 mg, 0.051 mmol), a 1M solution of Na2CO3 (0.76 mL), a 1M solution of potassium acetate (0.76 mL) and acetonitrile (11 mL). The mixture was irradiated to 120° C. with a microwave for 30 min and cooled to room temperature. It was filtered through Celite and thoroughly washed with methylene chloride. The filtrate was concentrated and the residue was purified via flash chromatography, 0 to 7% methanol in methylene chloride (with 1% ammonium hydroxide). The product was further purified via reverse phase HPLC to afford 318. 1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.07 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.71 (s, 1H), 7.59-7.43 (m, 2H), 7.34-7.17 (m, 2H), 7.03-6.84 (m, 3H), 3.83 (s, 3H), 3.26-3.18 (m, 4H), 1.73-1.48 (m, 7H). MS (ESI) m/z: 377.2 [M+H+].