Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](C)[N:3]=1.[CH2:10]([NH2:12])[CH3:11]>O>[NH2:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([NH:12][CH2:10][CH3:11])[N:7]=1
Reactant: CCN
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: O
Product: CCNc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 3-necked 3-L flask, that was equipped with an overhead stirrer, was added in order 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 100 g, 0.696 mol, 1 equiv.), ethylamine (70% ethylamine in water, Lancaster, 625 mL), 625 mL H2O, and 125 mL TEA (0.889 mol, 1.28 equiv.). The mixture was stirred and heated at reflux for 20 h, during which time the reaction turned homogeneous. The reaction was allowed to cool to room temperature. The volatile ethylamine was removed on a rotary evaporator. A precipitate formed. The aqueous mixture containing the precipitate was allowed to stand at room temperature for 2 h and then filtered. After drying under vacuum, 106 g (100% yield) of 2-amino-6-ethylaminopyrimidine was obtained as a colorless solid. This material was used as such in the following reaction.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[N:10]1[CH3:26])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[N:10]1[CH3:26]
Reactant: Cc1c(N2C(=O)C(CNC(=O)OC(C)(C)C)N(C)C2=O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N2C(=O)C(CN)N(C)C2=O)ccc(C#N)c1Cl
Yield: 180.1 %

Procedure:
A solution of the N-Boc-protected amine 13B (260 mg, 0.662 mmol) in CH2Cl2 (3 mL) and TFA (3 mL) was stirred at rt for 1.5 h. The solution was then concentrated under reduced pressure to afford the title compound (349 mg) as a brown foam as the TFA salt. 1H NMR (CD3OD) δ 2.32, 2.33 (s, 3H), 3.07, 3.09 (s, 3H), 3.49-3.64 (m, 2H), 4.50-4.52 (m, 1H), 4.63-4.65 (m, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.79, 7.80 (d, J=8.23 Hz, 1H); HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 1.50, 1.65 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 0.90, 1.11 min retention time (90%); MS (ES) m/z 293 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:15])[O-])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.N12CCCN=C1CCCCC2.O>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([C:13]([NH:12][C:9]2[C:10]3[CH2:11][CH:2]([OH:1])[CH2:3][CH2:4][C:5]=3[CH:6]=[CH:7][CH:8]=2)=[O:15])[CH2:26][CH2:25]1
Reactant: O=C([O-])Nc1cccc2c1CC(O)CC2
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c1CC(O)CC2)N1CCN(c2ccccc2Cl)CC1
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
To a mixture of (7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (141 mg, 0.50 mmol) and 2-chlorophenyl piperazine hydrochloride (155 mg, 0.66 mmol) in tetrahydrofuran (15 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (228 mg, 1.50 mmol) at room temperature, and the mixture was stirred for 30 minutes. Water was added and the mixture was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/1) to provide 4-(2-chlorophenyl)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)piperazine-1-carboxamide (103 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(OC)c(Cl)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncccc2-c2nc(C)nc(N)n2)cc1Cl
Temperature: 25 °C
Yield: 24 %

Procedure:
A solution of 4-(2-(5-chloro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.3068 g, 0.525 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature, and concentrated to about 50% of the original volume. The remaining mixture was pipetted carefully into a saturated solution of NaHCO3, which had been cooled in an ice bath. The resulting precipitate was removed by filtration and washed with water. The solid was dissolved in DCM and MeOH, and dry packed with silica gel. Purification using an ISCO Combiflash Companion (12 g column, 1-6% MeOH in DCM over 40 min, product eluted with 4% MeOH) gave 4-(2-(5-chloro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.0434 g, 0.126 mmol, 24.03% yield) as a tan amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 11.89 (s, 1H); 8.80 (dd, J=7.8, 2.0 Hz, 1H); 8.51-8.56 (m, 2H); 8.35 (dd, J=4.7, 2.0 Hz, 1H); 7.92 (br. s., 1H); 7.76 (br. s., 1H); 6.94 (dd, J=7.8, 4.7 Hz, 1H); 3.93 (s, 3H); 2.43 (s, 3H). m/z (ESI, +ve ion) 344.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([N:6]2[C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[C:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:8][C:7]2=[O:9])[CH:21]=[CH:20][CH:19]=1
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Reactant: OB(O)c1cccc(Cl)c1
Product: CCC1(CC)OC(=O)N(c2cccc(Cl)c2)c2ccccc21

Procedure:
Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-chlorophenyl boronic acid according to Procedure A. White solid: mp 150-151° C. 1H-NMR (CDCl3) δ8.52 (s, 1H, D2O exchangeable), 7.50 (s, 1H), 7.31-7.44 (m, 4H), 7.16 (d, 1H, J=1.5 Hz), 6.89 (d, 1H, J=8.2 Hz), 2.03 (m, 4H), 0.94 (t, 6H, J=7.4 Hz); MS (EI) m/z 315(M+, 53%). Anal. Calc. For C18H18ClNO2: C, 68.46, H, 5.75, N, 4,44. Found: C, 68.16, H, 5.81, N, 4.32.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[N:11][C:10]([NH:13][C:14](=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[CH:9][CH:8]=1)#[N:2].N[NH:29][C:30]([NH2:32])=[S:31].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:32][C:30]1[S:31][C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[N:12]=[N:11][C:10]([NH:13][C:14](=[O:27])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=3)=[CH:9][CH:8]=2)=[N:2][N:29]=1
Reactant: N#CCCCCc1ccc(NC(=O)Cc2cccc(OC(F)(F)F)c2)nn1
Reactant: NNC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Nc1nnc(CCCCc2ccc(NC(=O)Cc3cccc(OC(F)(F)F)c3)nn2)s1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
1118 (1.0 equiv., 0.154 mol, 58.2 g) was charged into a 500 mL round bottom flask along with thiosemicarbazide (1.2 equiv., 0.184 mol, 16.8 g). TFA (5 vol., 291 mL) slowly added to reaction vessel while stirring. The reaction slurry was heated in a 65° C. bath with an open top reflux condenser. The reaction usually goes to completion after 5 hours (determined by LC/MS). Toluene (10 vol., 582 mL) added to deep red solution, azeotroped by rotary evaporation (bath≦30° C.) to a red oil. Slowly transferred oil to a well stirred 6000 mL Erlenmeyer flask containing 7.5% sodium bicarbonate solution (69 vol., 4.0 L) cooled in a 0° C. bath. The crystals were filtered through a Büchner funnel and rinsed twice with diethyl ether (5 vol., 2×250 mL). Dried under high vacuum to a constant weight to afford N-(6-(4-(5-amino-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 657; yield of 55.7 g (80%). 1H NMR (300 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.51-7.26 (m, 4H), 6.99 (s, 2H), 3.88 (s, 2H), 2.87 (m, 4H), 1.71 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][O:11]2)=[CH:6][C:5]=1[NH2:14])([O-])=[O:2].[N:15]#[C:16][NH2:17].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:14]=[C:16]([NH2:17])[N:15]=1)[CH2:8][CH2:9][CH2:10][O:11]3
Reactant: N#CN
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCCC2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)OCCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A mixture of nitroaniline 238 (2.05 g, 10.6 mmol) and cyanamide (1.78 g, 42.3 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (10 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (200 mL), filtered, washed with water (3×50 mL) and dried. The aqueous fraction was extracted with CHCl3 (3×50 mL), dried and the solvent evaporated. The combined solids were purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give amine 239 (1.30 g, 56%) as a yellow powder: mp (MeOH/DCM) 280-283° C.; 1H NMR [(CD3)2SO] δ 7.32 (s, 1H, H-10), 7.31 (s, 1H, H-5), 6.96 (br s, 2H, NH2), 4.22 (dd, J=5.3, 5.2 Hz, 2H, H-8), 2.95 (br t, J=6.3 Hz, 2H, H-6), 1.92-1.98 (m, 2H, H-7); 13C NMR [(CD3)2SO] δ 159.1, 152.2, 143.4, 135.8, 128.7, 125.7, 102.6, 66.5, 25.0, 21.0. Anal. calcd for C10H10N4O2: C, 55.0; H, 4.6; N, 25.7. Found: C, 55.1; H, 4.6; N, 25.5%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)[CH3:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)=O>CO>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)[CH3:15])[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: CC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(c2ncc(F)cn2)CC1
Agent: O=C=O
Solvent: CO
Product: C[C@@H](Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(c2ncc(F)cn2)CC1

Procedure:
The racemic 5-fluoro-2-{4-[1-({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)ethyl]-1-piperidinyl}pyrimidine (prepared as in Example 153) was subjected to Chiral HPLC [column: OJ-H, column mobile phase: 70% CO2: 30% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 254 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as an off-white solid with Tr of 30.59 min (second eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.[Br:12]Br>ClCCl>[Br:12][C:6]1[C:7]([NH2:9])=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1
Reactant: BrBr
Reactant: Nc1cccc(C(F)(F)F)n1
Solvent: ClCCl
Product: Nc1nc(C(F)(F)F)ccc1Br

Procedure:
A solution of 6-(trifluoromethyl)pyridin-2-amine (200 mg, 1.23 mmol) in dichlormethane (2.47 mL) was cooled to 0° C. and bromine (197 mg, 63.4 μL, 1.23 mmol) was slowly added within 30 minutes. After 25 hours at 0° C. the reaction mixture was extracted with saturated Na2S2O3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using CH2Cl2/MeOH (with 10% ammonia) as eluent. The title compound was obtained as a white solid (711 mg, 24%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[N:7]=1>C(O)C.[Pd]>[NH2:12][C:8]1[N:7]=[C:6]([CH2:5][C:4]([N:3]([O:2][CH3:1])[CH3:16])=[O:15])[CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)Cc1cccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: CON(C)C(=O)Cc1cccc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxy-N-methyl-2-(6-nitropyridin-2-yl)acetamide (200 mg, 0.88 mmol) in 4 ml ethanol was added palladium on carbon (25 mg) and the resulting mixture set under hydrogen atmosphere and stirred vigorously at room temperature for 2 hours. The catalyst was filtered off using a 0.45 mM Oilmen PTFE syringe filter washing the solid with 10 mL of methanol. The filtrate was concentrated to dryness under reduced pressure and used for the next reaction without further purification (84.4 mg, 53%). LC-MS: C9H13N3O2 calculated 195.22 found m/z (ES) 196 (MH)+.
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=2)[CH:13]=O)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[ClH:18].Cl.[C:20]1([C@H:26]2[C@@H:31]([NH2:32])[CH2:30][CH2:29][CH2:28][NH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.Cl.C(C1(C2C=CC(OC)=C(C=2)CN[C@H]2CCCN[C@H]2C2C=CC=CC=2)CC1)#N>>[ClH:18].[ClH:18].[C:1]([C:3]1([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=2)[CH2:13][NH:32][C@H:31]2[CH2:30][CH2:29][CH2:28][NH:27][C@H:26]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1ccc(C2(C#N)CCCC2)cc1C=O
Agent: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C2(C#N)CCCC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 51 and Compound 3 in the same manner of Compound 5.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][CH2:11][C:12](Cl)=[O:13].O>ClCCl>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1C=O
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccccc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-Aminobenzaldehyde (650 mg) was dissolved in dichloromethane (20 ml) to prepare a solution. Chloroacetyl chloride (728 mg) was added to the solution, and the mixture was stirred at room temperature overnight. Water was added thereto, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give 2-chloro-N-(2-formylphenyl)-acetamide (1.05 g, yield 99%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][N:17]([CH3:30])[CH2:18][CH2:19][C@@H:20]([NH2:29])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:30][N:17]([CH3:16])[CH2:18][CH2:19][C@@H:20]([NH:29][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13])[CH2:21][S:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1C(F)(F)F

Procedure:
The title compound was prepared from 4-fluoro-3-(trifluoromethyl)-benzenesulfonamide and (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine using the procedure described for Intermediate 4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[CH2:12]Cl>C1COCC1>[CH3:18][O:17][C:15]1[CH:14]=[C:11]([CH2:12][N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)[CH:10]=[C:9]([O:8][CH3:7])[CH:16]=1
Reactant: COc1cc(CCl)cc(OC)c1
Reactant: C1CSCCN1
Solvent: C1CCOC1
Product: COc1cc(CN2CCSCC2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Thiomorpholine (3.4 g) was added to a solution of 3,5-dimethoxybenzyl chloride (2 g) in THF (25 mL) and the mixture was stirred overnight at room temperature. The solid material was removed by filtration and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1/2) to yield 2 g of 3,5-dimethoxy-1-(thiomorpholino-methyl)benzene. ESMS: m/z 253 (M).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:10]O)[C:4]=2[CH:3]=[CH:2]1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1>[N:26]([CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[N+:27]=[N-:28]
Reactant: OCc1cccc2[nH]ccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cccc2[nH]ccc12
Reaction time: 5 h
Yield: 1810.1 %

Procedure:
To a solution of 1H-indole-4-methanol (Example 17; 71 mg, 0.48 mmol) in tetrahydrofuran (1 mL) at 0° C. was added diphenylphosphoryl azide (156 μL, 0.72 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (87.4 μL, 0.58 mmol). The cooling bath was removed and the solution was allowed to stir for 5 h. After the solvent was evaporated, ethyl acetate was added and the solution was washed with 1N hydrochloric acid solution and brine, dried (MgSO4), filtered and concentrated. The residual material was chromatographed over silica gel (12% ethyl acetateihexanes) to give 4-(azidomethyl)-1H-indole (1.496 g, 88% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=[C:4]2[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH:37]([C:39]1[CH:40]=[C:41]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:42]=[CH:43][C:44]=1[N+:45]([O-:47])=[O:46])=[O:38]>C(N(CC)CC)C.CN(C)C=O>[CH:37]([C:39]1[CH:40]=[C:41]([N:48]2[CH2:53][CH2:52][N:51]([C:11]([C:9]3[N:10]=[C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]4[CH:8]=3)=[O:13])[CH2:50][CH2:49]2)[CH:42]=[CH:43][C:44]=1[N+:45]([O-:47])=[O:46])=[O:38]
Reactant: Cc1ccn2cc(C(=O)O)nc2c1
Reactant: O=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccn2cc(C(=O)N3CCN(c4ccc([N+](=O)[O-])c(C=O)c4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of 7-methylimidazo[1,2-a]pyridine-2-carboxylic acid (10.56 g), 1-hydroxybenzotriazole (8.1 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.46 g) and N,N-dimethylformamide (360 ml) was stirred for 1 hour at ambient temperature. 1-(3-Formyl-4-nitrophenyl)piperazine hydrochloride (16.2 g) and triethylamine (9.1 g) were added thereto and the mixture was stirred for 1 hour. The resulting precipitates were collected, washed with ethyl acetate (100 ml×2) and water (100 ml×2), and dried to give 1-(3-formyl-4-nitrophenyl)-4-(7-methylimidazo[1,2-a]pyridine-2-carbonyl)piperazine (23.0 g).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([O:33][CH3:34])[CH:27]=3)[S:25][C:18]=12.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49]O)[CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:13][C:14]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:49][CH2:48][N:45]4[CH2:46][CH2:47][O:42][CH2:43][CH2:44]4)=[C:28]([O:33][CH3:34])[CH:27]=3)[S:25][C:18]=12
Reactant: COc1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)ccc1O
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)ccc1OCCN1CCOCC1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
DEAD (0.96 mL, 6.07 mmol) was added to a solution of the compound 137 (1.78 g, 4.33 mmol), 2-morpholinoethanol (0.74 mL, 6.07 mmol) and triphenylphosphine (1.59 g, 6.07 mmol) in THF (43 mL). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was quenched with a saturated aqueous solution of ammonium chloride then extracted three times with ethyl acetate and 3 times with dichloromethane (with a bit of methanol inside). The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was triturated with diethyl ether, filtered and dried on a vacuum pump to afford title compound 138 as a yellow-brown solid (1.80 g, 79% yield). MS (m/z): 526.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1/[CH:22]=[CH:23]/[O:24]C.[H-].[Na+].[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C@H:7]([CH2:22][CH:23]=[O:24])[C@H:8]([N:11]([CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]1=[O:10]
Reactant: CO/C=C/[C@@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N(Cc3ccc(OC)cc3OC)[C@@H]2CC=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((E)-2-methoxyvinyl)-4-oxoazetidin-3-yl)carbamate (example 82, step 1, 1.44 g, 3.38 mmol) in DMF (33.8 ml) at −10° C. (salt-ice bath) was addeds sodium hydride (60%, 162 mg, 4.05 mmol). After stirring for 30 min, p-methoxybenzylchloride (506, μL, 3.71 mmol) was added. After warming to 0° C. and stirring for an additional 30 min, it was quenched with NH4Cl (aq, satd) then diluted with EtOAc and LiCl (5% aq). The layers were separated and aqueous layer was extracted with EtOAc (2×). The combined organic layers washed with LiCl (5% aq), brine, dried over Na2SO4 and concd in vacuo. The crude material was subjected to conditions described in example 82, step 2 then purified via silica gel chromatography (EtOAc-Hept, 0-70%) to afford the title compound (684 mg, 38%). LCMS: Rt=0.97 min, m/z=533.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:10])[CH2:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(O[CH:15](OC(C)C)[N:16]([CH3:18])[CH3:17])(C)C>C(Cl)Cl>[CH2:1]([C:5]1[NH:6][C:7](=[O:10])[C:8](=[CH:15][N:16]([CH3:18])[CH3:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NCC(=O)N1
Reactant: CC(C)OC(OC(C)C)N(C)C
Solvent: ClCCl
Product: CCCCC1=NC(=CN(C)C)C(=O)N1
Yield: 77.1 %

Procedure:
A solution of 5.00 g (35.67 mmol) of 2-butyl-2-imidazolin-5-one and 7.02 g (39.24 mmol) of N,N-dimethylformamide diisopropyl acetal in 25 ml of methylene chloride was stirred at room temperature for 2.5 hours. Then, the solvent was removed on a Rotavapor, and the residue was treated with 40 ml of methylene chloride. The solution thus obtained was washed twice, each time with 10 ml of water, and dried (MgSO4) and concentrated on the Rotavapor. The residue was then dried in a high vacuum. 5.37 g of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one was obtained; the product had a content of greater than 90 percent, according to H-NMR. This corresponds to a yield of about 71 percent, based on the 2-butyl-2-imidazolin-5-one.