Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48](=[O:65])[NH:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[C:52]([C:57]#[C:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:51]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[C:43]([O:47][C:48](=[O:65])[NH:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:9])=[C:52]([C:57]#[C:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:51]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(C#Cc2ccccc2)n1
Reactant: O=C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of oxane-4-carboxylic acid (45 mg, 0.34 mmol), HATU (162 mg, 0.43 mmol) and DIPEA (43 μl, 0.25 mmol) in DMF (1 ml) is stirred at RT for 30 minutes. Tert-butyl-N-[5-amino-6-(2-phenylethynyl)pyridin-2-yl]carbamate B5a (60 mg, 0.19 mmol) is added and stirring continued for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 40 mg (49%). HPLC-MS: M+H=422; tR=1.73 min (*Method—5).
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][CH2:30][F:31])[CH:25]=1)=O)(C)(C)C>CO>[ClH:1].[NH:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][CH2:30][F:31])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CCF)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: FCC[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M HCl (anhydrous)/ether (2.0 mL) was added to a stirred solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1S,2R)-2-(2-fluoroethyl)cyclopropyl]pyridine (160 mg, 0.45 mmol) in dry MeOH (2.0 mL) at 0° C. The mixture was stirred at room temperature for 12 h. The above solution was concentrated and purified by HPLC to give the title compound (97 mg). 1H NMR (CD3OD, 400 MHz) δ 8.38 (s, 1H), 8.28 (s, 1H), 7.71 (s, 1H), 4.92-4.86 (m, 1H), 4.61-4.48 (m, 4H), 4.18-4.04 (m, 2H), 2.75-2.61 (m, 2H), 2.03-1.97 (m, 1H), 1.91-1.77 (m, 2H), 1.46-1.35 (m, 1H), 1.25-1.19 (m, 1H), 1.16-1.09 (m, 1H). MS (ESI) m/z 273 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>C(O)C>[Cl:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C=NCCCl
Solvent: CCO
Product: O=C(NCCCl)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of 2 g of 6-aminoindazole in 125 mL of anhydrous ethanol is added, in a dropwise manner, 1.25 g of 2chloroethyl isocyanate. This solution is stirred for 16 h at room temperature, cooled at -20° C., and filtered. A white solid separated and was recrystallized from ethanol, yield 30%, mp 253°-258° C. 1H NMR (DMSO-d6 : CDCl3): 8.12 ppm, 7.56 ppm, 7.44 ppm, 7.25 ppm, 7.12 ppm, 7.08 ppm, 6.43 ppm, 6.39 ppm, 6.01 ppm, 5.98 ppm, 5.96 ppm, 3.42 ppm, 3.4 ppm, 3.39 ppm, 3.54 ppm, 3.26 pm, 3.23 ppm, 3.2 ppm, 3.17 ppm, 3.14 ppm, 3.12 ppm, 3.09 ppm, 3.05 ppm, 3.04 ppm, 3.04 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19](=[O:21])(=[O:20])[NH2:22])[CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Yield: 20.2 %

Procedure:
A solution of 4-bromobenzenesulfonyl chloride (1.34 g, 5.25 mmol), 3-aminobenzenesulfonamide (860 mg, 5.0 mmol) and DIPEA (1.29 g, 10 mmol) in THF (10 mL) was stirred overnight at room temperature. The solvent was then evaporated and the residue purified by chromatography on the SP4 (70 g Silica Isolute II, 0-100% EtOAc/hexane) to and the title compound obtained as a white solid (395 mg).
Reaction SMILES: N[C:2]1[N:7]([CH2:8][C:9]2C=CC(Cl)=CC=2)[C:6](=[O:16])[NH:5][C:4](=O)[C:3]=1NC(=O)C(C)C.CC(C)([O-:27])C.[K+].C(Br)C.Cl>CN(C=O)C>[CH2:8]([N:7]1[C:2](=[O:27])[CH:3]=[CH:4][NH:5][C:6]1=[O:16])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C(=O)Nc1c(N)n(Cc2ccc(Cl)cc2)c(=O)[nH]c1=O
Agent: Cl
Agent: [K+]
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCn1c(=O)cc[nH]c1=O
Reaction time: 1.5 h

Procedure:
13.47 g (40 mM) of 6amino-1-(4-chlorobenzyl)-5-isobutyrylaminouracil were dissolved in 130 ml of DMF, treated at 5° C. with 4.57 g (40.8 mM) potassium t-butoxide and after dissolution, 3.28 ml (44 mM) of ethylbromide added. After 3 hr another 1.14 g of t-BuOK and 1.64 ml of ethylbromide were added. After a further 1.5 hr, 1.64 ml of ethylbromide were supplemented. After a total of 22 hr the solution was neutralized with 1N HCl to pH 7 and the solvents evaporated in vacuo. The residue was taken up in dichloromethane-water and the organic phase collected giving 17.66 of crude 3-ethyl uracil, which was dissolved in 17.6 ml of 1N NaOH and heated under reflux for 1 hr. The solution was treated twice with 1 g of charcoal, filtered and neutralized with 5N HCl to pH 7. The solid was diluted with water, collected, and dried. The crude material was recrystallized from methanol to give 7.42 g (49.2%) of 3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-xanthine, mp 221-2° C.
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O-])=[O:13])=[CH:5][CH:4]=1.Cl.[NH2:26][CH2:27][C:28]#[N:29]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:29][CH2:28][C:27]#[N:26])=[O:13])=[CH:7][CH:8]=1
Reactant: N#CCN
Reactant: CC(C)CC(OC(c1ccncc1)c1ccc(Br)cc1)C(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccncc1)c1ccc(Br)cc1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 17, step 3, 2-[(4-bromophenyl)(pyridin-4-yl)methoxy]-4-methylpentanoic acid potassium salt from step 3 (312 mg, 0.75 mmol) was coupled with aminoacetonitrile HCl Salt. The crude residue obtained was chromatographed on silica gel using 10% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]3C=C4C(C=CC=C4)=C3)[CH:15]=2)[CH:10]=1)[CH2:2][CH3:3].O.NN>CO>[NH2:19][CH2:18][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:28][CH2:29][CH3:30])[CH2:1][CH2:2][CH3:3])[CH2:17]2)=[CH:12][CH:13]=1
Reactant: CCCN(CCC)CCCCC1=Cc2ccc(Cn3cc4ccccc4c3)cc2C1
Agent: NN
Solvent: CO
Solvent: O
Product: CCCN(CCC)CCCCC1=Cc2ccc(CN)cc2C1
Yield: 65.2 %

Procedure:
The compound (82.0 mg) obtained in Example 11-12 was dissolved in methanol (4.1 ml) and added with hydrazine monohydrate (0.082 ml) and the whole was refluxed under heating for 3 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was added with water and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (40.1 mg) as a yellow oily substance.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][C@@H:25]2[C@:20]([CH3:31])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:29][OH:30])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:33])([C@@H:17]([OH:32])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:26][C@H:25]2[C@:20]([CH3:31])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:29][O:30][S:40]([C:37]3[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:33])([C@@H:17]([OH:32])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCOS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 8 h

Procedure:
The compound of Example 1B (1.50 g, 3.2 mmol) was dissolved in 15 ml of chloroform and 15 ml of pyridine; p-toluenesulfonyl chloride (920 mg, 4.83 mmol) was added, and the mixture was stirred overnight. Chloroform (250 ml) was added, the resultant solution was washed with 5% HCI solution and sat. Na2SO4. After solvent removal in vacuo, the crude product was purified by column chromatography on silica gel (40%->60% ethyl acetate/hexanes. The yield of the title compound was 1.40 g (71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43]C)[N:38]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Li+]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]3[NH:38][C:39](=[O:43])[CH:40]=[CH:41][CH:42]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1cccc(-c2cc3nc(N4CCOC[C@H]4c4ccccc4)n(C[C@H]4CC[C@H](C)CC4)c3c(-c3cncc(Cl)c3)n2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(-c4cccc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-(5-chloropyridin-3-yl)-6-(6-methoxypyridin-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine (63.0 mg, 0.104 mmol), p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol), and lithium chloride (44.1 mg, 1.04 mmol) in DMA (1.0 mL) was heated at 100° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (2×10 mL), and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 10% CH2Cl2/MeOH) afforded 6-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}pyridin-2(1H)-one. 1H NMR (400 MHz, CDCl3) δ 10.69 (br s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.50 (m, 1H), 8.02 (s, 1H), 7.86 (m, 1H), 7.50 (dd, J=9.0, 6.8 Hz, 1H), 7.32-7.41 (m, 2H), 7.23-7.31 (m, 3H), 6.79-6.86 (m, 1H), 6.58 (d, J=9.0 Hz, 1H), 4.66 (m, 1H), 4.08-4.14 (m, 2H), 3.92-4.07 (m, 2H), 3.62-3.74 (m, 1H), 3.36-3.54 (m, 3H), 1.39-1.51 (m, 2H), 1.02-1.18 (m, 1H), 0.80-0.94 (m, 1H), 0.75 (d, J=6.4 Hz, 3H), 0.55-0.71 (m, 4H), 0.36-0.52 (m, 2H). MS ES calc'd. for C34H35ClN6O2 [M+H]+ 595. found 595.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Product: CN1CCN(C(=O)c2cc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to 1-methylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 34.5 mg of 122. MS (Q1) 464.2 (M)+.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:7][S:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C.C(OCC)(=O)C>[CH3:1][NH:2][S:17]([C:13]1[CH:12]=[C:11]([S:8]([NH:7][C:3]([CH3:6])([CH3:5])[CH3:4])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cccc(S(=O)(=O)NC(C)(C)C)c1
Reaction time: 2 h

Procedure:
5 ml of a 33% solution of methylamine in ethanol was added to a solution of 1.8 grams (7 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. The mixture was stirred for 2 hours. The ethyl acetate layer was separated and concentrated in vacuo. The residue was purified on silica gel eluting 5% methanol in diochloromethane to give 1.32 grams of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])[CH:4]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1.[CH3:22]C(C)([O-])C.[K+].CCOC(C)=O>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]1[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:9])([CH3:12])([CH3:16])[CH3:22]
Reactant: O=C(Oc1ccccc1)N1C=CC(Cl)=CC1C1CCCC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C=CC(Cl)=CC1C1CCCC1
Temperature: -42 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a stirred solution of 4-Chloro-1-(phenoxycarbonyl)-2-cyclopentyl-1,2-dihydropyridine (5.52 g, 17.3 mmol) in 200 ml of THF at −42° C. was added dropwise over 15 minutes a 1.0M solution of potassium t-butoxide (50 mL, 50 mmol). The resulting orange solution was stirred for 1 h at −42° C. The cooling bath was removed, and the reaction mixture was allowed to stir for 20 min while being slowly warmed to room temperature. Water (50 ml) and ether (70 ml) were added and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with cold 1.0 N NaOH (2×35 ml), and brine. The organic phase was dried over MgSO4, filtered through Celite, and concentrated in vacuo to give the crude product. Column chromatography with 5% EtOAc in hexanes afforded 3.71 g (75.7%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 6.89-6.67 (dd, 1H), 5.58 (br s, 1H), 5.27-5.23 (m, 1H), 4.92-4.62 (m, 1H), 2.21 (m, 1H), 1.892-1.25 (m, 17H).
Reaction SMILES: ClC(C[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[O:13][CH3:14])C=O.[NH2:15]C(N)=S>C(O)C>[F:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH3:14])=[C:6]([NH2:15])[CH:11]=1
Reactant: NC(N)=S
Reactant: COc1ccc(F)cc1CC(Cl)C=O
Solvent: CCO
Product: COc1ccc(F)cc1N

Procedure:
A mixture of 2-chloro-3-(5-fluoro-2-methoxy-phenyl)-propionaldehyde (crude from above) and thiourea (29.2 g, 0.384 mol) in ethanol (400 mL) was heated to reflux for 15 hours. The solvent was removed and the residue was diluted with dichloromethane (300 mL), sodium hydroxide (10% aqueous solution, 150 mL) and water (200 mL). The aqueous phase was extracted twice with dichloromethane (150 mL). The combined organic layer was washed with water, a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude product was recrystallized from a mixture of ethyl acetate and hexanes to give the pure product (6.5 g, 0.027 mol, 6.2% from 5-fluoro-2-methoxy-phenylamine). ESI-MS m/z calc. 238.1. found 239.2 (M+1)+ 1H NMR (CDCl3): δ 6.90-6.81 (m, 2H), 6.79-6.76 (m, 2H), 4.75 (br, 2H), 3.91 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:8]=[C:7]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:6]=1)=O.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[C:30]2[CH3:37].C[Al](C)C>C1(C)C=CC=CC=1>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([C:30]=1[CH3:37])=[CH:28][C:27]([NH:26][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:8]=[C:7]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:6]=1)=[O:2])=[CH:35][CH:34]=2
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Reactant: COC(=O)c1cc(OCCN2CCOCC2)nc(N2CCOCC2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ccc(NC(=O)c3cc(OCCN4CCOCC4)nc(N4CCOCC4)n3)cc2c1C
Temperature: 25 °C

Procedure:
To a stirred mixture of compound (I) (1.02 g, 2.9 mmol) and 5-amino-2,3-dimethyl indole (488 mg, 3.04 mmol) in toluene (6.9 mL) that was heated briefly until components partly dissolved and cooled to ambient temperature, was added 2 M solution of trimethylaluminum in toluene (2.32 mL, 1.6 eq) drop-wise under nitrogen purge. Reaction mixture was stirred until bubbling (gas evolution) completed, and then heated at 115° C. (oil bath) for 15 minutes. To a cooled reaction mixture chloroform and 1 N NaOH were added, chloroform layer was separated, washed twice with water, brine and dried over anhydrous sodium sulfate. Flash column chromatography on silica gel (eluent dichloromethane-acetone-methanol (3:1:01)) and recrystallization from chloroform-ethyl acetate mixture afforded target amide, 2-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (2,3-dimethyl-1H-indol-5-yl)-amide, as a pale yellow solid (1.1 g, 79%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3F)[C:11](=[O:26])[C:10]([C:27]([OH:29])=[O:28])=[CH:9]2)[CH2:7][CH2:6]1>C(O)C>[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3[O:2][CH3:1])[C:11](=[O:26])[C:10]([C:27]([OH:29])=[O:28])=[CH:9]2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: COc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
To the solution of sodium methoxide prepared from sodium (0.2 g) and absolute ethanol (9 ml) was added 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (0.5 g) and the mixture in sealed tube was heated for 72.5 hours at 140° to 150° C. After cooling, the reaction mixture was concentrated, water (4 ml) was added to the residue, and the solution was adjusted to pH 7 with acetic acid. The insoluble materials were filtered off and the filtrate was allowed to stand in a refrigerator. The resulting precipitate was collected by filtration and recrystallized from dichloromethane-methanol (2:1; 6 ml) to give the title compound (0.12 g) as colorless prisms, mp 185°-187.5° C. (decompd.).
Reaction SMILES: Cl.[O:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:27]([C:30]1[S:31][C:32]([C:35](O)=[O:36])=[CH:33][N:34]=1)([CH3:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH:27]([C:30]1[S:31][C:32]([C:35]([N:5]2[CH2:6][C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[O:2][CH2:3][CH2:4]2)=[O:36])=[CH:33][N:34]=1)([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: CC(C)c1ncc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.694 g) in DMF (13 mL) was treated with triethylamine (1.3 mL), followed by 2-isopropylthiazole-5-carboxylic acid (example 55, step b) (0.406 g) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.26 g). The resulting mixture was stirred at RT for 16 h. DMF was removed in vacuo. The residue was taken up in EtOAc (40 mL) and washed with saturated sodium bicarbonate solution (2×40 mL), water (40 mL) and brine (40 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The viscous orange oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM to give the subtitled compound as a viscous orange oil. Yield 0.765 g.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH3:19][CH:20]1[N:25]([CH2:26][CH2:27][NH2:28])[CH:24]([CH3:29])[CH2:23][O:22][CH2:21]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:28][CH2:27][CH2:26][N:25]1[CH:24]([CH3:29])[CH2:23][O:22][CH2:21][CH:20]1[CH3:19])=[O:18]
Reactant: CC1COCC(C)N1CCN
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: CC1COCC(C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and 2-(3,5-dimethylmorpholino)ethylamine [see Preparation 12]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 95:5, by volume, dichloromethane:methanol to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[2-(3,5-dimethylmorpholino)ethyl]-2-piperidinecarboxamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27]>CC(O)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:29]/[N+:26]([O-:28])=[O:27])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
To a solution of 4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzaldehyde (13 g, 43.2 mmol) and ammonium acetate (1.67 g, 21.62 mmol) in HOAc (40 mL), was added nitromethane (6.99 mL, 130 mmol). The reaction mixture was stirred at 120° C. for 5 h, and concentrated. The residue was dissolved in DCM (150 mL), washed with sat. aqueous NaHCO3 (100 mL×2), brine and then, dried over anhydrous Na2SO4 and concentrated to afford the title compound as a brown solid (14.3 g, 63% yield).