Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:5][C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])([CH3:6])[C:3]#[N:4]
Reactant: CC(C)(N)C#N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)NS(C)(=O)=O
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
To a stirred mixture of 8.4 g (0.1 mole) 2-amino-2-methylpropionitrile (the product of Example 1), and 10.1 g (0.1 mole) triethylamine in 125 ml methylene chloride, 11.5 g (0.1 mole) methanesulfonyl chloride in 25 ml methylene chloride were added dropwise over about 20 minutes in an exothermic addition reaction. The reaction mixture was stirred 15 minutes, then washed once with 100 ml water, washed twice with 50 ml water, dried over magnesium sulfate, and stripped to give 8.9 g of a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][O:36]C2CCCCO2)=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][OH:36])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CCOC4CCCCO4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(-c2csc3c(/C=C/CCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.5 %

Procedure:
A suspension of N-(4-{4-amino-7-[(1E)-4-(tetrahydro-2H-pyran-2-yloxy)but-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.05 g, 0.09 mmol) in methanol (3 mL) was treated with p-toluene sulfonic acid monohydrate (0.002 g, 0.0095 mmol). The reaction mixture was stirred for 15 hours at room temperature. Solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane to give 0.033 g (77%) of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.00–7.98 (m, 1H), 7.93 (s, 1H), 7.71–7.69 (m, 1H), 7.61–7.58 (m, 2H), 7.35–7.33 (m, 2H), 7.20 (m, 1H), 7.15–7.15 (m, 1H), 709–7.07 (m, 1H), 6.59–6.55 (m, 1H), 6.35–6.20 (m, 1H), 5.58 (brs, 2H), 4.65 (m, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.57–3.54 (m, 2H), 2.42 (m, 2H); LCMS (conditions a) Rt 3.42 min (96%), M+ 499.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH:7]([CH2:13]CC(O)=O)[CH2:6]2.C(C1C(=O)C(Cl)=C(Cl)[C:22](=[O:23])[C:21]=1C#N)#N.CC([O:36]C)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:23][CH2:22][CH3:21])=[O:36])=[CH:6]2
Reactant: COc1ccc2c(c1)CC(CCC(=O)O)CN2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COC(C)(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-methoxy-3-carboxyethyl-1,2,3,4-tetrahydroquinoline (Step C, 17.6 g, 0.074 mol) in CH2Cl2 (330 mL) cooled at 5° C., was added DDQ (42.2 g, 0.186 mol) portion-wise. The reaction was stirred at RT for 2 h, then diluted with MTBE (600 mL), washed twice with 1N NaOH and twice with water. Flash chromatography in 20% EtOAc/Hexane yielded 6-methoxy-3-ethoxycarbonylquinoline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH3:2].[C:21](O)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:21](=[O:23])[CH3:22])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(N)cc2)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)Cc1ccc(Oc2ccc(NC(C)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 6.8 g of ethyl[p-(p-aminophenoxy)phenyl]acetate, 7.5 ml of acetic acid, 5.4 ml of water and 8.75 g of crushed ice, maintained at 0°-5° C. is added 2.8 g of acetic anhydride. The temperature immediately rises to 15° C. The stirring is continued for two hours, and extracted with two 50 ml portions of ether. The combined extracts are washed with 50 ml of H2O, 50 ml of saturated NaHCO3, 50 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent affords the product as a tan solid, mp 95°-102° C. A portion is recrystallized from ethanol-hexane to give the product, mp 105°-107° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([N:19]([CH3:43])[C:20]([N:22]([C:31]2[C:36]([Cl:37])=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([O:40][CH3:41])[C:32]=2[Cl:42])COCC[Si](C)(C)C)=[O:21])[CH:14]=1.[C:44](O)([C:46](F)(F)F)=[O:45].[CH2:51](Cl)Cl>>[Cl:42][C:32]1[C:33]([O:40][CH3:41])=[CH:34][C:35]([O:38][CH3:39])=[C:36]([Cl:37])[C:31]=1[NH:22][C:20](=[O:21])[N:19]([C:15]1[N:16]=[CH:17][N:18]=[C:13]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][N:9]([CH3:10])[CH3:11])=[CH:7][C:2]=2[NH:1][C:44](=[O:45])[CH:46]=[CH2:51])[CH:14]=1)[CH3:43]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(CN(C)C)cc3N)ncn2)c1Cl
Reactant: ClCCl
Reactant: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cc(CN(C)C)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a stirred solution of 1-[6-(2-amino-4-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-urea in anhydrous DCM (10 mL) was added TFA (10 mL) at room temperature. The solution was stirred at room temperature for 3 hours. LCMS showed major product peak. The solution was evaporated to dryness, diluted with DCM (40 mL) and washed with 10% saturated Na2CO3 (10 mL). The DCM layer was dried over anhydrous Na2SO4. Concentration under vacuum gave crude product, which was purified by silica gel column chromatography (10% MeOH/DCM with 0.5% Et3N) to afford the title compound (45 mg, yield: 58% in two steps). MS (ESI): 520 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]#[N:12].C([S:23]P([O-])(OCC)=S)C.O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]([NH2:12])=[S:23]
Reactant: CCOP([O-])(=S)SCC
Reactant: C[C@@H](C#N)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A mixture of (2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyronitrile (30.5 g, 0.110 mol), diethyldithiophospate (235 ml) and H2O (110 ml) was stirred at 80° C. for 2 hrs. The reaction mixture was cooled down to r.t. n-Hexane (400 ml) and water (200 ml) was added. The whole was shaken well and the aqueous layer was separated. The remaining organic layer was further extracted with H2O (100 ml×3). All the aqueous layer was combined. Cooled down to 0° C. and neutralized and basified (PH8) with NaHCO3. This basic(PH8) aqueous layer was extracted with EtOAc (300 ml+100 ml×3). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give dark brown syrup. By addition of CH2Cl2 (100 ml) to this crude syrup, precipitate was formed. The precipitate was filtered and washed with CH2Cl2-hexane (5:1 mixture) to give (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyramide (19.2 g, 56%) as white powder. On the other hand, the filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (Wako-gel C-300, CH2Cl2:MeOH=20:1) to give additional (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyramide (7.46 g, 22%) as pale brown amorphous powder. Physical form: White solid; FAB-MS: m/z 313 (M+H)+; 1H-NMR (CDCl3): 1.12(3H,d,J=7.3 Hz),3.74(1H,q,J=7.3 Hz), 4.55,5.12 (2H,ABq,J=14.5 Hz), 5.84(1H,s),6.85˜7.02(2H,m),7.15˜7.22(1H,m),7.80 (1H,s),7.89(1H,s), 7.89(1H,brs),8.43(1H,brs).
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11](Cl)=[O:12].S(=O)(=O)(O)O.[CH3:19]COCC>>[CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11](=[O:12])[CH3:19]
Reactant: CCOCC
Reactant: C[C@@H]1c2ccccc2C[C@@H]1C(=O)Cl
Agent: O=S(=O)(O)O
Product: CC(=O)[C@H]1Cc2ccccc2[C@H]1C
Yield: 92 %

Procedure:
cis-1-(2,3-Dihydro-1-methyl-1H-inden-2-yl)ethanone is prepared by the treatment of cis-2,3-dihydro-1-methyl-1H-indene-2-carboxylic acid chloride with ethoxymagnesiummalonic acid ethyl ester in dry ether and thereafter by the treatment of sulfuric acid according to the publication (Reynolds G. A. and Hauser, C. B., Org. Synth. 30 (1957) 70). The yield is 92%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4OC)[N:23]=3)=[C:14]3[C:18]=2C[N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.N[C:51]1C=CC(C2C=NN(CCCO)C=2)=CC=1C(NCC)=O>>[CH2:19]([NH:16][C:15]([C:14]1[CH:18]=[C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=2)[CH:11]=[CH:12][C:13]=1[NH:21][C:22]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:37][P:38](=[O:45])([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])=[CH:46][CH:47]=2)[N:23]=1)=[O:20])[CH3:51]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CCNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CCNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1Nc1nc(Nc2ccc(CP(=O)(OCC)OCC)cc2)ncc1C(F)(F)F
Yield: 81 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 2-amino-N-ethyl-5-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]benzamide (Compound 9C, 455 mg, 1.07 mmol) to afford 589 mg of the title compound (81%). 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=8.8 Hz, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.68 (dd, J=2.2, 8.7 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 7.23 (dd, J=2.6, 8.7 Hz, 2H), 4.31 (d, J=13.6 Hz, 2H), 3.97-4.08 (m, 4H), 3.57 (t, J=6.2 Hz, 2H), 3.38-3.42 (m, 2H), 3.18-3.25 (m, 2H), 2.10 (quin, J=6.5 Hz, 2H), 1.17-1.26 (m, 9H). MS (ESI): m/z 676.78 [M+H]+. UPLC: tR=1.18 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH2:10])=[N:8][NH2:9])=[CH:5][CH:4]=[N:3][CH:2]=1.O=[C:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[O:19]=[C:18]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][NH:8][C:7]([C:6]2[CH:5]=[CH:4][N:3]=[CH:2][CH:1]=2)=[N:10]1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: NN=C(N)c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1n[nH]c(-c2ccncc2)nc1=O
Reaction time: 13 h
Yield: 56 %

Procedure:
In ethanol (20 ml), 4-pyridinecarboxyamidrazone (1.48 g) was dissolved. To the resulting solution, diethyl ketomalonate (1.65 ml) was added dropwise at room temperature, followed by stirring for 13 hours. After heating under reflux for 4 hours, the reaction mixture was cooled. Yellow crystals thus precipitated were collected by filtration and dried, whereby the title compound (1.50 g, 56%) was obtained.
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[P:18](Cl)([O:35][C:36]1[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][C:39]([CH3:46])=[CH:38][C:37]=1[C:47]([CH3:50])([CH3:49])[CH3:48])[O:19][C:20]1[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]([CH3:30])=[CH:22][C:21]=1[C:31]([CH3:34])([CH3:33])[CH3:32].Cl>O1CCCC1.C(#N)C>[P:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:9]2[CH:14]=[CH:13][C:12]([O:15][P:18]([O:35][C:36]3[C:37]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:38][C:39]([CH3:46])=[CH:40][C:41]=3[C:42]([CH3:45])([CH3:44])[CH3:43])[O:19][C:20]3[C:21]([C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:22][C:23]([CH3:30])=[CH:24][C:25]=3[C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:11][CH:10]=2)=[CH:3][CH:4]=1)([O:35][C:36]1[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][C:39]([CH3:46])=[CH:38][C:37]=1[C:47]([CH3:50])([CH3:49])[CH3:48])[O:19][C:20]1[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]([CH3:30])=[CH:22][C:21]=1[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Reactant: Cc1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(C(C)(C)C)c(OP(Oc2ccc(Sc3ccc(OP(Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 0.65 gram of 4,4'-thiobisphenol (0.003 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-thiobisphenol solution under nitrogen, 0.14 gram (0.006 mol) of sodium hydride, as a 50 weight percent dispersion in mineral oil was added to the 4,4'-thiobisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,6-di-t-butyl-4-methylphenyl) phosphorochloridite (3.0 grams, 0.006 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,6-di-t-butyl-4 -methylphenyl) 4,4'-thiobisphenyl diphosphite was 1.19 grams. The molecular weight, FD/MS was 1154. NMR data obtained was, (CDCl3): 1.44 (S, 72H), 2.24 (S, 12H), 6.06 (d, J=8.4, 4H), 6.85 (d, J=8.4, 4H), 7.30 (S, 8H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1.C(O)C.C(O)(=O)C.[OH-].[Na+]>[Fe].O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COc1cc(N)ccc1-n1cnc(Cl)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Step A (2): Iron powder-325 mesh (4.6 g, 82 mmol) was added to a 500 mL round bottom flask charged with a mixture of 4-chloro-1-(2-methoxy-4-nitrophenyl)-1H-imidazole (5.2 g, 20.5 mmol), absolute ethanol (100 mL), and glacial acetic acid (50 mL). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 100° C. with vigorous stirring for 30 min. The reaction mixture allowed to cool to rt and was added to a chilled and stirred solution of 3 M NaOH (291 mL). The resulting mixture was poured into a separatory funnel and extracted with EtOAc (3×250 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (4.57 g, 97% yield) as a solid. LC-MS (M+H)+ 224.0. 1H NMR (500 MHz, chloroform-d) δ ppm 7.47 (d, J=1.22 Hz, 1 H) 7.00 (d, J=8.24 Hz, 1 H) 6.99 (d, J=1.53 Hz, 1 H) 6.32 (d, J=2.44 Hz, 1 H) 6.29 (dd, J=8.24, 2.44 Hz, 1 H) 3.88 (br. s., 2 H) 3.78 (s, 3 H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=2[C:17]([OH:19])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:21][CH:22]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:23]1=[O:24]>N1C=CC=CC=1>[O:24]=[C:23]1[CH:22]([N:21]2[C:17](=[O:19])[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]2=[O:13])[CH2:28][CH2:27][C:26](=[O:29])[NH:25]1
Reactant: O=C(O)c1cccc(Nc2ccccc2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(Nc4ccccc4)c3C2=O)C(=O)N1
Yield: 83 %

Procedure:
A mixture of 3-phenylaminophthalic acid (0.52 g, 2.0 mmol) and rac-α-aminoglutarimide hydrochloride (0.33 g, 2.0 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.60 g of the product at 4:6 hexanes-ethyl acetate, in 83% yield: mp 214-216° C.; 1H NMR (DMSO-d6) δ 1.99-2.09 (m, 1H), 2.53-2.64 (m, 2H), 2.84-2.97 (m, 1H), 5.13 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 7.11-7.16 (m, 1H), 7.25 (d, J=7.0 Hz, 1H), 7.31-7.45 (m, 5H), 7.61 (t, J=7.8 Hz, 1H), 8.45 (s, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.7, 112.0, 113.4, 119.4, 121.9, 124.0, 129.4, 132.5, 136.2, 139.4, 142.8, 167.0, 168.3, 170.0, 172.8; Anal. calcd for C19H15N3O4: C, 65.32; H, 4.33; N, 12.03. Found: C, 64.93; H, 4.33; N, 11.79.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][N:6]=[C:7]1[N:12]=[CH:11][C:10]([CH3:14])([CH3:13])[CH2:9][S:8]1.[C:19](=[S:21])=[S:20].[H-].[Na+].[CH3:24]I>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][N:6]=[C:7]1[N:12]([C:19]([S:21][CH3:24])=[S:20])[CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][S:8]1
Reactant: CI
Reactant: COc1ccccc1CN=C1N=CC(C)(C)CS1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1CN=C1SCC(C)(C)CN1C(=S)SC
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a mixture of 2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine (0.27 g), carbon disulfide (0.09 g) and N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Methyl iodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-methoxybenzyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine (0.20 g, yield: 57%) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:18]([C:34]([F:37])([F:36])[F:35])=[CH:17][N:16]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH3:40])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:18]([C:34]([F:37])([F:35])[F:36])=[CH:17][N:16]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2C)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C)CC3)cc2C)ncc1C(F)(F)F

Procedure:
Methyl 2-(2-(2-(2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (54) (1.10 g, 2.15 mmol) was dissolved in dry MeOH (20 mL) and formaldehyde solution (37% aq; 348 μL, 4.29 mmol) was added. Sodium triacetoxyborohydride (2.27 g, 10.7 mmol) was added under nitrogen and the resultant mixture was stirred at room temperature for 16 hours. Ethyl acetate (50 mL) was added and the mixture was washed with 10% NaHCO3 solution (20 mL). The organic layer was separated, dried (MgSO4) then the volatiles removed by evaporation under reduced pressure. Chromatography (SiO2, 0-50% MeOH/DCM) gave the title compound (I55) (480 mg, 42%) as a cream solid; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.83-7.73 (m, 1H), 7.35 (s, 1H), 7.32-7.19 (m, 3H), 7.19-7.09 (m, 2H), 7.07-6.97 (m, 1H), 3.76 (s, 2H), 3.70 (s, 3H), 3.23 (d, J=11.5 Hz, 2H), 3.17-3.04 (m, 4H), 2.61-2.51 (m, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 2.33-2.24 (m, 2H), 2.02-1.84 (m, 4H). LCMS Method C: rt 5.25 min; m/z 527.2 [M+1]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[C:8](=[O:16])[NH:9][C:10]2[C:15]\1=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH2:17]=O.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CCO>[N:19]1([CH2:17][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[CH:6][C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)[C:8]2=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1Nc2ccccc2/C1=C/c1ccc[nH]1
Reactant: C=O
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C1C(=Cc2ccc[nH]2)c2ccccc2N1CN1CCCCC1
Temperature: -20 °C
Yield: 77.6 %

Procedure:
A solution of Z-(1H-Pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one (0.60 g, 2.85 mmol), paraformaldehyde (0.13 g, 4.28 mmol) and piperidine (0.24 g, 2.85 mmol) in EtOH (5 mL) was heated to 60-70° C. for 14 h. The reaction mixture was cooled to −20° C. for 1 h and the fine yellow solid present was collected by filtration. The solid collected was dried under vacuum to give the title compound as a yellow solid (0.68 g, 77%).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][OH:7])(=[O:3])[CH3:2].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[C:1]([NH:4][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][O:7][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)(=[O:3])[CH3:2]
Reactant: C1CCOCC1
Reactant: COC(=O)[C@H](CO)NC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](COC1CCCCO1)NC(C)=O
Reaction time: 7 h

Procedure:
To a solution of about 4.50 g of N-acetyl-L-serine, methyl ester in about 100 ml of dry methylene chloride was added about 2.93 ml of distilled tetrahydro-2H-pyran and about 0.34 ml of borontrifluoroetherate. The mixture was stirred under argon for about 7 hours, then washed with saturated sodium bicarbonate and brine, dried and the solvent removed under reduced pressure, giving about 6 g of the desired title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][CH:39]=[N:40][CH:41]=2)=[CH:32][CH:31]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13])=O.O1CCCC1>CO>[OH:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[N:40][CH:39]=[N:38][CH:37]=2)=[CH:34][CH:35]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13]
Reactant: O=CO[C@H](CCc1ccc(-c2cncnc2)cc1)[C@H](CCn1nnc2ccccc2c1=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H](CCn1nnc2ccccc2c1=O)[C@H](O)CCc1ccc(-c2cncnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.081 g) was added to a solution of the compound obtained from step n above (0.25 g) in methanol (5 mL) and tetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. Solvents were evaporated and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 60% ethyl acetate in hexane as eluant to afford the title compound (0.030 g).