Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>CN(C)C=O>[NH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[N:10]=2)[N:7]=1
Reactant: Nc1cccc(O)c1
Reactant: COCC(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Yield: 51.1 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methoxyacetamide (0.60 g, 1.81 mmol), N,N-dimethylformamide (6.0 mL), potassium carbonate (499 mg, 3.61 mmol) and 3-aminophenol (296 mg, 2.71 mmol) as starting materials and in the same manner as in Example 91, the title compound (0.29 g, 51%) was obtained as a dark brown powder.
Reaction SMILES: [F:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1.Cl>CS(C)=O>[F:1][C:2]1[C:11]([O:12][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:13]([OH:15])=[O:14]
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Reactant: O=C(O)c1cccc2c(F)c(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc4c(C(=O)O)cccc4c3F)ccnc2cc1OCCCN1CCOCC1
Reaction time: 0.25 h

Procedure:
In a microwave tube, 5-fluoro-6-hydroxy-1-naphthoic acid (300 mg, 1.48 mmol) and Cs2CO3 (1.45 g, 4.44 mmol) in DMSO (1.5 mL) were stirred for 3 min at RT. 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (500 mg, 1.48 mmol) was added and the vessel sealed. The mixture was subjected to the microwave (Personal Chemistry) at 160° C. for 15 min, then 30 min. The vessel was opened and the mixture stirred with a spatula, resealed and heated another 5 minutes. The reaction mixture made pH 7 with 1 N HCl and evaporated. The residual solid was taken up into MeOH and filtered and evaporated. The solid was then taken up into and CH2Cl2/MeOH mixture and filtered. The filtrate was evaporated to dryness and triturated with ethyl acetate/hexanes and the title compound collected as a yellow solid.
Reaction SMILES: [O:1]([CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)O.[O:14]([CH:16]=[CH:17][CH2:18][CH2:19][CH3:20])O>>[OH:1][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[OH:14][CH:16]=[CH:17][CH2:18][CH2:19][CH3:20]
Reactant: OOCCCC=Cc1ccccc1
Reactant: CCCC=COO
Product: CCCC=CO
Product: OCCCC=Cc1ccccc1

Procedure:
reacting a mixture of 1-hydroperoxy-5-phenyl-4-pentene as a hydroperoxypentene and a reducing substrate in the presence of a peroxidase in a solvent for the reaction to produce 1-hydroxy-5-phenyl-4-pentene as a hydroxypentene;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:2]1=2.[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:25](Cl)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:25]([NH:11][C:8]3[CH:9]=[CH:10][C:2]4[O:1][CH2:6][CH2:5][O:4][C:3]=4[CH:7]=3)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: CC#N
Product: c1ccc(CN2CCc3c(ncnc3Nc3ccc4c(c3)OCCO4)C2)cc1

Procedure:
The title compound was prepared using the general procedure set forth in Example 2, above, using 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.32 mL, 2.63 mmol) and 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.621 g, 2.39 mmol) in acetonitile (3 mL).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:49]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[O:42][CH3:41])(=[O:51])=[O:50])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: COc1ccccc1S(=O)(=O)NCCc1c(CCN(C)c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
The intermediate from example 147 step 7 was treated with 2-methoxy-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 95% yield.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:24][C:25]2[N:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21].COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:27][C:26]2[C:25]([NH:24][C:16]3[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=3)=[N:32][CH:31]=[CH:30][CH:29]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: COc1cc(Nc2ncccc2C=O)cc(OC)c1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2cccnc2Nc2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
To a solution of 4-methoxy acetophenone (104.16 mg, 0.694 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 2-(3,4,5-trimethoxyphenylamino)nicotinaldehyde (200 mg, 0.694 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6z) (266 mg, 91% yield).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][C:16](OCC)=[O:17].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][OH:17]
Reactant: CCOC(=O)C=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCC=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 85.1 %

Procedure:
7-(3',5'-bistrifluoromethylbenzyloxy)heptan-1-al (See Example 2, 4.97g, 13.96 mmol) was reacted with carboethoxymethylene triphenylphosphorane (4.86g, 13.96 mmol, Lancaster Synthesis Ltd., U.K.) in dry dichloromethane to give ethyl 9-(3',5'-bistrifluoromethylbenzyloxy)nona-2- enoate (5g). The ester (5g, 13.55 mmol) was reacted with diisobutylaluminium hydride (27 mmol) in toluene-dichloromethane at -30°. After conventional work-up, 9-(3',5'-bistrifluoromethylbenzyloxy)nona-2-en-1-ol (4.43g) was obtained. The alcohol was converted into 9-(3',5'-bistrifluoromethylbenzyloxy)nona-2-en-al by Swern oxidation (oxalyl chloride-dimethylsulphoxide, see EP-A-164 187).
Reaction SMILES: CC1C(=C)C(C(C(C(NC)CC2C=CC=CC=2)=O)C)CC(=O)NCCCC(C(C)=O)CC(=C)C(CC2N=CNC=2)C(C)C(=O)C(CC2C=CC=CC=2)CC(=[O:5])C1CCCCN.[C:62]([O-:65])(=[O:64])[CH3:63].[N+:66]([C:69]1[CH:74]=[CH:73][C:72](CC([O-])=O)=[CH:71][CH:70]=1)([O-:68])=[O:67]>CN(C)C=O>[C:62]([O:65][C:72]1[CH:73]=[CH:74][C:69]([N+:66]([O-:68])=[O:67])=[CH:70][CH:71]=1)(=[O:64])[CH3:63].[N+:66]([C:69]1[CH:74]=[CH:73][C:72]([OH:5])=[CH:71][CH:70]=1)([O-:68])=[O:67]
Reactant: CC(=O)[O-]
Reactant: C=C1CC(C(C)=O)CCCNC(=O)CC(C(C)C(=O)C(Cc2ccccc2)NC)C(=C)C(C)C(CCCCN)C(=O)CC(Cc2ccccc2)C(=O)C(C)C1Cc1c[nH]cn1
Reactant: O=C([O-])Cc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 10 mg of calcitonine M acetate in 2 ml of absolute dimethylformamide is treated with 0.5 ml of a 1% solution of para-nitrophenylacetate in dimethylformamide, rinsed with nitrogen, and allowed to stand in the closed test tube at 40° C. for 30 minutes. 5 ml of 2N-acetic acid are then added, the excess para-nitrophenyl acetate and the para-nitrophenol formed are extracted with ethyl acetate (2 × 30 ml), the aqueous phase is evaporated to dryness under reduced pressure, the residue dissolved in 0.5 ml of 95% acetic acid, and the solution lyophilized. The product consists of a mixture of mono- and diacetyl derivative and some starting material. The monoacetyl derivative itself is a mixture of the Nα - and Nε -derivatives as evidenced by electrophoresis at pH 8.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:15][CH:16]=[CH:17][C:18](Cl)=O)C>C(Cl)Cl.[OH-].[Na+]>[NH:12]1[C:9]2[C:10](=[CH:11][C:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:7]=3[CH:8]=2)[CH:18]=[CH:17][C:16]1=[O:15]
Reactant: Nc1ccc2c(c1)NCCCC2
Reactant: CCOC=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=c1ccc2cc3c(cc2[nH]1)NCCCC3
Temperature: 50 °C

Procedure:
A solution of 2,3,4,5-tetrahydro-1H-1-benzazapin-8-amine (0.6 g, 3.4 mmol) and 3-ethoxyacryloyl chloride (0.45 g, 3.4 mmol) in CH2Cl2 (50 mL) and 3N NaOH (10 mL) was stirred for 1 h at ambient temperature. The reaction was partitioned between CH2Cl2 and water. The organic layer was concentrated and the remaining brown oil was dissolved in 70% aq. H2SO4 (20 mL) and heated gently (50° C.) for 2 h. The reaction was cooled and neutralized with aq. NH4OH and partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMF (1 mL) and purified on a GILSON automated system affixed with a YMC COMBIFLASH 50 mm×20 mm reverse phase column eluted 5–95% CH3CN in water at 30 mL/min over 10.5 min to provide pure desired product. HRMS m/z (M+1) calcd 215.1179; found 215.1186.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O)[OH:2].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17]([O-:20])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:9]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:20][CH2:17][C:1]1[CH:3]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1ccc(COc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
A mixture of catechol (11.0 g, 0.10M), benzylbromide (25.0 ml, 0.21M) and finely powdered anhydrous K2CO3 (44.2 g, 0.32M) in DMF (60 ml) was stirred at room temperature under N2 for 72 hours. The mixture was then diluted with Et2O and filtered. The ether solution was washed with three portions of distilled water, one portion of saturated NaCl solution, dried (K2CO3) and concentrated in vacuo. The residue was recrystallized from hexane to give dibenzyloxybenzene (27.04 g, 93% yield) as white crystal, mp 58°-59° C. (literature: Page et al., J. Org. Chem. 27, 218 (1962), mp 58°-59° C.).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:22]([Cl:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 10.2 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.04 g, 3.03 mmol) in 25 mL of dichloromethane and 3,4-dichloroaniline (0.982 g, 6.06 mmol) in 8 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes to yield 0.184 g of the title compound, mp 230-233° C.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:13])[C:11]=1[CH3:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:14](=O)([O-])[O-].[K+].[K+].IC.Cl>CC(C)=O.O>[CH3:12][C:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3][C:2]=1[S:1][CH3:14]
Reactant: Cc1c(S)oc2ccccc2c1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: CSc1oc2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a solution containing 2-mercapto-3-methyl-chromen-4-one (2.26 g, 11.76 mmol) and potassium carbonate (1.62 g, 11.76 mmol) in acetone (120 mL) was added iodomethane (807 μL, 12.93 mmol). The reaction stirred under nitrogen atmosphere at room temperature for 16 hours before being concentrated to yield a crude oil. The residue was taken up in water and adjusted to pH 7 with 5% HCl. The resulting aqueous layer was washed with ethyl acetate. The organic layer was then washed with water and brine, dried over sodium sulfate, filtered, and concentrated to obtain the desired product as a yellow solid (1.95 g, 80% yield), which was taken on to the next step without further purification. 1H NMR (600 MHz, CDCl3): δ 8.21 (d, 1H, J=6.6 Hz), 7.61 (m, 1H), 7.38 (m, 2H), 2.66 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[N:11]1[CH:12]=[CH:13][N:14]2[CH:19]=[C:18]([CH2:20][C:21]3[N:25]4[N:26]=[C:27]([C:30]5[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=5)[CH:28]=[CH:29][C:24]4=[N:23][CH:22]=3)[CH:17]=[CH:16][C:15]=12>O>[CH3:35][N:33]1[CH:34]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]3[N:25]([C:21]([CH2:20][C:18]4[CH:17]=[CH:16][C:15]5[N:14]([C:13]([CH:4]=[O:5])=[CH:12][N:11]=5)[CH:19]=4)=[CH:22][N:23]=3)[N:26]=2)[CH:31]=[N:32]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)cn1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(C=O)n5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (2 mL) was cooled down to 0° C. and then POCl3 (0.130 mL, 1.397 mmol) was added slowly. The solution was stirred for 10 min then it was warmed up to rt and the 3-(imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (Example 10, 200 mg, 0.607 mmol) was introduced. The RM was warmed up to 120° C. and stirred for 2 h. It was cooled down to rt and water was added. It was extracted twice with EtOAc. Combined organic layers was washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM) to afford after evaporation of the solvent the title compound as a yellow solid (tR 0.7 min (conditions 2), MH+=358).
Reaction SMILES: [NH2:1][C:2]1[C:9](Br)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17]>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:9]([C:17]#[C:16][C:15]([CH3:19])([CH3:18])[CH3:14])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C#CC(C)(C)C
Reactant: N#Cc1cc([N+](=O)[O-])cc(Br)c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cc([N+](=O)[O-])cc(C#N)c1N
Temperature: 80 °C
Reaction time: 10 h
Yield: 69.9 %

Procedure:
To a stirred solution of 2-amino-3-bromo-5-nitrobenzonitrile (2.4 g, 10 mmol) in dry Et3N (60 mL) was added CuI (380 mg, 5% mol) and Pd(PPh3)2Cl2 (470 mg, 5% mol) at room temperature. 3,3-dimethyl-but-1-yne (2.1 g, 25 mmol) was added dropwise to the mixture at room temperature. The reaction mixture was stirred at 80° C. for 10 h. The reaction mixture was filtered and the filtrate was poured into ice (60 g), extracted with ethyl acetate. The phases were separated and the organic phase was dried over Na2SO4. The solvent was removed under vacuum to obtain the crude product, which was purified by column chromatography (2-10% EtOAc in petroleum ether) to obtain 2-amino-3-(3,3-dimethylbut-1-ynyl)-5-nitrobenzonitrile (1.7 g, 71%). 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.7 Hz, 1H), 8.27 (d, J=2.7 Hz, 1H), 5.56 (br s, 2H), 1.37 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:36])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(OCC2C=CC=CC=2)=O)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.ClCCl.[OH-].[OH-].[Pd+2]>[CH2:10]([O:11][C:12](=[O:36])[CH3:13])[CH3:9].[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:36])[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCN)cc1
Yield: 137.5 %

Procedure:
A solution of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid 2-tert-butoxycarbonylaminoethyl ester 44a (162 mg, 0.32 mmol) and acetic acid (3 drops) in ethyl acetate (3 mL) and dichloromethane (6 mL) was stirred at room temperature for 16 h under hydrogen atmosphere in the presence of palladium hydroxide on activated charcoal (80 mg, 60% wet). The catalyst was removed by suction filtration and the liquid filtrate was concentrated in vacuo to give [4-(4-aminobutyl)phenoxy]acetic acid 2-tert-butoxycarbonylaminoethyl ester ethyl acetate 45a as an off-white solid (100 mg, 84% yield) which was used directly without purification. m/z (ESI) 367 [C19H30N2O5+H]+.
Reaction SMILES: [S:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13])[C:2]#[N:3].[CH2:14]([Cl:23])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>C(#N)C.CN(C)C=O>[ClH:23].[S:1]([C:4]1[C:12]2[C:7]([N:8]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[CH:9]=[CH:10][CH:11]=2)=[N:6][C:5]=1[CH3:13])[C:2]#[N:3]
Reactant: O=C(CCl)c1ccccc1
Reactant: Cc1[nH]c2ncccc2c1SC#N
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccccc3)cccc-2c1SC#N
Product: Cl
Temperature: 25 °C

Procedure:
A solution of 100 mg (0.53 mmol) of 3-thiocyano-2-methyl pyrrolo [2,3-b]pyridine and 122 mg (0.79 mmol) of phenacyl chloride in 3 ml acetonitrile: dimethylformamide 2:1 was warmed at 70° C. for 36 h. The reaction mixture was cooled to room temperature and the acetonitrile was evaporated. To the residue was added 10 ml diethyl ether. The precipitated product was filtered off and washed with acetonitrile giving 37 mg (23%) of the title compound.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH2:9]([NH:11][C:12]1[C:17]([CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=2)=[CH:16][N:15]=[C:14]([N:30]([O:32][CH3:33])[CH3:31])[CH:13]=1)[CH3:10].CCN(CC)CC>>[CH2:9]([N:11]1[C:12]2[CH:13]=[C:14]([N:30]([O:32][CH3:33])[CH3:31])[N:15]=[CH:16][C:17]=2[CH2:18][N:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=2)[C:4]1=[O:3])[CH3:10]
Reactant: CCNc1cc(N(C)OC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(N(C)OC)cc21
Yield: 79.9 %

Procedure:
Diphosgene (2.4 mL, 20 mmol), N4-ethyl-5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2-methylpyridine-2,4-diamine (5.6 g, 16 mmol) and Et3N (4.3 g, 40 mmol) were combined by the procedure of Example A4 to provide 1-ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (4.8 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.14 (m, 1 H), 7.96 (s, 1 H), 7.79 (m, 1 H), 7.61 (m, 1 H), 6.57 (s, 1 H), 4.78 (s, 2 H), 3.88 (d, J=7.2 Hz, 2 H), 3.71 (s, 3 H), 3.15 (s, 3 H), 1.20 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 376.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13](OC)=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[NH2:20][NH2:21]>CO>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:20][NH2:21])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Temperature: 65 °C

Procedure:
Methyl 3-(morpholinosulfonyl)benzoate (120 mg, 0.421 mmol) was added to hydrazine (17.52 mg, 0.547 mmol) in methanol and refluxed for 12 h at 65° C. The reaction was monitored by TLC. Upon completion of the reaction and cooling the reaction mixture, the solvent was removed by vacuum and then compound was purified by column chromatography to yield the title compound as an off white solid (90 mg). 1H NMR (400 MHz, CDCl3): δ 8.16 (m, 1H), 8.12 (m, 1H), 8.04 (m, 1H), 7.85 (m, 1H), 7.63 (t, 1H, J=8.0 Hz), 4.19 (m, 2H), 3.71 (m, 4H), 2.97 (m, 4H). ESI-MS: 286.1 [M+H]+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1([CH2:11][C:12]2[N:17]=[C:16](O)[C:15]3[CH2:19][CH2:20][CH2:21][C:14]=3[N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>>[Cl:3][C:16]1[C:15]2[CH2:19][CH2:20][CH2:21][C:14]=2[N:13]=[C:12]([CH2:11][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(CC2CCCC2)nc2c1CCC2
Product: Clc1nc(CC2CCCC2)nc2c1CCC2
Yield: 77 %

Procedure:
Phosphorus oxychloride (4.6 mL, 51 mmol) was added to 2-cyclopentylmethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (3.7 g, 17 mmol) and the mixture was heated at reflux for 2 hours. Thereafter, volatiles were evaporated under reduced pressure and the mixture was poured over ice-water. The mixture was extracted with dichloromethane (3×60 mL). The combined organic extracts were washed with water, treated with activated charcoal, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid (3.1 g, 78% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][CH2:21][C:22](O)=[O:23])[CH3:19].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH2:18]([O:20][CH2:21][C:22]([NH:17][NH:16][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:15])=[O:23])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: CCOCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOCC(=O)NNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (WO 2000039125, prep 27) (3 g, 12.33 mmol), ethoxyacetic acid (1.28 mL, 13.56 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.6 g, 13.56 mmol), 1-hydroxybenzotriazole hydrate (1.83 g, 13.56 mmol) and triethylamine (2.1 mL, 14.8 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous sodium carbonate solution. The layers were separated, the organic phase was dried over MgSO4 and evaporated under reduced pressure to provide the title compound as an oil, that crystallised on standing.