Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1
Yield: 99.4 %

Procedure:
10.6 g (0.071 mol) of p-tertiarybutylaniline was dissolved in 19 ml of glacial acetic acid. 8.0 g (0.078 mol) of acetic anhydride was then added dropwise to the solution at a temperature of 30° C. After the completion of dropwise addition, the reaction mixture was then allowed to undergo reaction at a temperature of 40° C. for 3 hours. The reaction solution was then poured into 200 ml of water. The resulting crystal was filtered off, washed with water, and then dried to obtain 13.5 g (yield: 99.9%) of p-tertiarybutylacetanilide. The melting point of the crystal was from 172.5° C. to 173.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]Br>ClCCl.CCOC(C)=O>[Br:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(O)c(C=O)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
Ex-62A: A solution of 2-hydroxy-4-methoxybenzaldehyde (3.03 g, 20 mmol) in 25 mL of dichloromethane was cooled to 0° C. and treated dropwise with a solution of bromine (3.41 g, 21 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at 0° C. for 1.5 hours. The solvent was removed by rotary evaporation to give a residue. The residue was taken up in EtOAc and washed with 3 portions of water. The organic layer was dried over MgSO4. The drying agent was removed by filtration, and solvent was removed by rotary evaporation to give 3.9 g of the desired 5-bromo-2-hydroxy-4-methoxybenzaldehyde as a solid, m.p. 111-115° C.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[C:12]([CH2:13]Cl)=[N:11][C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[N:8]3[N:9]=[C:10]([C:15]([OH:17])=[O:16])[N:11]=[C:12]3[CH2:13]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1nc(CCl)n(-c2cccnc2Cl)n1
Product: O=C(O)c1nc2n(n1)-c1cccnc1N(c1ccc(Cl)cc1)C2

Procedure:
using 8.91 g (0.033 mol) of 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 20.90 g (0.164 mol) of p-chloroaniline there is obtained 5-(4-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid and the methyl ester thereof which, after recrystallisation from methylene chloride/ethyl acetate, melts at 234°-237° with decomposition;
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>COC1C=C([Mg]Br)C=CC=1OC>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:26]3[CH:27]=[CH:26][C:30]([O:29][CH3:28])=[C:28]([O:29][CH3:30])[CH:27]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: COc1ccc([Mg]Br)cc1OC
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1OC

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 3,4-dimethoxyphenylmagnesium bromide. Yield: 55 mg of a white solid. LC-MSD, m/z for C24H19BrN2O4 [M+H]+=479.0, 481.0; HPLC retention time: 2.1 min.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.[CH3:29][C:30]([CH3:36])([CH2:34][OH:35])[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C:30]([CH3:36])([CH3:29])[C:31]([N:26]1[CH2:25][CH:24]=[C:23]([C:21]2[NH:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]5[N:6]=[CH:5][S:4][C:8]=5[CH:9]=4)[C:15]=3[CH:22]=2)[CH2:28][CH2:27]1)=[O:32]
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: CC(C)(CO)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine trihydrochloride (50.0 mg, 0.11 mmol) in DMF (3 mL) was added 2,2-dimethyl-3-hydroxypropionic acid (150 mg, 1.3 mmol), TBTU (42.0 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.50 mmol). The reaction mixture stirred at rt for 16 h. The mixture was concentrated in vacuo and purified via MDP, which afforded the title compound as yellow solid. MS (ES+): m/z: 448.96 (100) [MH+]. HPLC: tr=2.35 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, DMSO-d6): δ=1.20 (s, 6H), 3.19 (s, 1H), 3.46 (s, 2H), 3.79-3.81 (m, 2H), 4.21 (s, 2H), 4.59 (bs, 1H), 6.43 (s, 1H), 6.84 (d, J=1.6 Hz, 1H), 7.87 (dd, J=1.6, 8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.34 (s, 1H), 8.91 (d, J=2.0 Hz, 1H), 9.23 (s, 1H), 9.62 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:7]=1.C(OO)(C)(C)C.[NH4+:23].[OH-]>N.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:23])=[N:13]2)[CH:7]=1
Reactant: CC1(c2cc(Br)ccc2F)COCC(=S)N1
Reactant: [NH4+]
Agent: CC(C)(C)OO
Agent: N
Agent: [OH-]
Solvent: CO
Product: CC1(c2cc(Br)ccc2F)COCC(N)=N1
Temperature: 25 °C

Procedure:
To a suspension of 5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholine-3-thione (14.0 g, 46 mmol) in 7N NH3/MeOH (308 ml) was added tBuOOH (72.8 ml of a 70% aq. soln.) and NH4OH (131.6 ml of a 25% aq. soln.). The reaction mixture was stirred over night at rt, quenched with aq. Na2S2O3 soln., concentrated and extracted with EtOAc to give the title compound that was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]([CH:11]=1)[CH2:7][NH:8][CH2:9][CH3:10].[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]([CH:11]=1)[CH2:7][N:8]([CH2:9][CH3:10])[C:16]([CH:13]1[CH2:15][CH2:14]1)=[O:17]
Reactant: CCNCc1cc(Br)ccc1I
Reactant: O=C(Cl)C1CC1
Product: CCN(Cc1cc(Br)ccc1I)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-bromo-2-iodo-benzyl)-ethyl-amine and cyclopropanecarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ncccn1

Procedure:
The title compound, MS: m/e=296.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[N+:10]([C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]2)([O-:12])=[O:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ccc([N+](=O)[O-])cc1C=O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O

Procedure:
A solution of 10.0 g (46 mmol) of 1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, ethyl ester [J. Chem. Soc., 2518 (1962)] and 50 ml of sulfuric acid is stirred in an ice bath and a cold mixture of 9.75 ml of 70% nitric acid and 9.75 ml of sulfuric acid is added dropwise over 10 minutes. The reaction solution is stirred with ice bath cooling for 1 hour and then is poured into ice and water with stirring. The resulting solid is collected by filtration and washed with water and ethanol. After drying, 10.7 g of the requisite ester is obtained, mp>310° C. The structure is assigned by an unequivocal synthesis from the condensation of 2-amino-5-nitro-benzaldehyde and diethyl malonate to give the same 1,2-dihydro-6-nitro-2-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: [ClH:1].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:12][O:13][CH3:14])[CH:11]=1)[C:7]#[N:8].[CH2:15]([OH:17])[CH3:16]>>[ClH:1].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:12][O:13][CH3:14])[CH:11]=1)[C:7](=[NH:8])[O:17][CH2:15][CH3:16]
Reactant: COCc1cc(C#N)cc(CO)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cc(CO)cc(COC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Hydrogen chloride gas was passed through a solution of 3-hydroxymethyl-5-methoxymethyl-benzonitrile (720 mg, 4.063 mmol) in anhydrous ethanol (25 mL) at 0° C. After 1 h, hydrogen chloride gas was stopped and the reaction vessel was sealed with a septum. After stirring at room temperature for 1 d, the reaction vessel was cooled to 0° C. and the septum was removed. The solvent was evaporated in vacuo to afford ethyl 3-hydroxymethyl-5-methoxymethyl-benzimidate hydrochloride as a white solid (1.05 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].[NH:10]1[CH2:18][CH2:17][CH:13]([C:14](O)=O)[CH2:12][CH2:11]1.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:14]([CH:13]3[CH2:17][CH2:18][NH:10][CH2:11][CH2:12]3)[O:9][C:3]=2[CH:4]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Nc1ccc(Br)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc2nc(C3CCNCC3)oc2c1
Temperature: 190 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
2-amino-5-bromophenol (1.3 g, 6.9 mmol) and isonipecotic acid (893 mg, 6.91 mmol) were dissolved in polyphosphoric acid (39 g). This mixture was heated to 190° C. for 3 h. After 3 h, reaction mixture cooled to rt and basified with 10% aqueous NaOH solution to pH 8. Work up (EtOAc/H2O) followed by removal of EtOAc afforded the title compound (500 mg) as a black solid. It was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:3]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=1[NH:1][C:7](=[O:8])[CH3:6])(=[O:4])[CH3:2]
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1CO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Cl)ccc1Oc1ccccc1COC(C)=O
Reaction time: 16 h

Procedure:
0.026 Part of 2-(2-amino-4-chlorophenoxy)benzyl alcohol is dissolved in 0.5 part pyridine and 0.5 part by volume acetic anhydride and allowed to stand at room temperature for 16 hours. The solvent is removed by evaporation under a nitrogen atmosphere and the resultant residue chromatographed on 0.6 part silicic acid. Elution with a 5:95 mixture of ethyl acetate-benzene and recrystallization from a mixture of ethyl acetate and benzene affords 2-(2-acetamido-4-chlorophenoxy)benzyl acetate. This compound melts at about 83° - 84° C. and is represented by the following structural formula. ##STR6## Elemental analysis shows C, 61.71%; H, 5.30%; Cl, 10.73%; N, 4.01%. The calculated values are C, 61.17%; H, 4.83%, Cl, 10.62%; and N, 4.20%.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:20][CH:21]=1.[CH3:27][C:28]1[N:29]=[C:30]([S:33](Cl)(=[O:35])=[O:34])[S:31][CH:32]=1.COC(C)(C)C>N1C=CC=CC=1>[CH3:27][C:28]1[N:29]=[C:30]([S:33]([NH:4][C:5]2[CH:13]=[C:12]3[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][C:6]=2[O:14][CH2:15][C:16]2[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:20][CH:21]=2)(=[O:35])=[O:34])[S:31][CH:32]=1
Reactant: CCOC(=O)c1cnc(COc2cc3c(cc2N)CCC3)cn1
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(COc2cc3c(cc2NS(=O)(=O)c2nc(C)cs2)CCC3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 712 mg of ethyl 5-{[(6-amino-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyrazine-2-carboxylate trihydrochloride were added 35.6 mL of pyridine and 35.0 mL of a 0.21 M 4-methyl-1,3-thiazole-2-sulfonyl chloride/tert-butyl methyl ether solution, followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added a 5% w/v aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 95:5) to obtain 256 mg of ethyl 5-{[(6-{[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyrazine-2-carboxylate.
Reaction SMILES: [NH:1]1[CH:6]=[C:5]([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:9][N:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=23)[CH:4]=[CH:3][C:2]1=[O:22].[H-].[Na+].I[CH3:26].[Na+].[Cl-]>CN(C=O)C>[CH3:26][N:1]1[CH:6]=[C:5]([C:7]2[C:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=23)[CH:4]=[CH:3][C:2]1=[O:22]
Reactant: CI
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccncc23)c[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2c(-c3ccccc3)nn3ccncc23)ccc1=O
Reaction time: 0.17 h

Procedure:
To a suspension of 3-(2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (120 mg) in DMF (3 mL) was added NaH (60% oil suspension, 25 mg) at room temperature and the mixture was stirred at the same temperature for 10 min. To the mixture was added iodomethane (0.039 mL). After stirring at room temperature for 15 h, the reaction mixture was poured into 10% NaCl solution, extracted with EtOAc, washed with 10% NaCl solution and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc to CH2Cl2-MeOH 10:1) to give 3-(1-methyl-2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (114.5 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[O:19][CH3:20])[NH:5][C:6](=[O:10])[C:7]=1[N:8]=O.C(N(CC)CC)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[O:19][CH3:20])[NH:5][C:6](=[O:10])[C:7]=1[NH2:8]
Reactant: COc1c(Cl)cc(Cl)cc1-c1nc(N)c(N=O)c(=O)[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(Cl)cc1-c1nc(N)c(N)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
4-Amino-2-(3,5-dichloro-2-methoxyphenyl)-5-nitrosopyrimid-6-one (6.8 g.) was suspended in a solution of triethylamine (10 ml.) in water (100 ml.). Sodium dithionite (7.5 g.) was added, in portions, to the mixture with stirring, and stirring was continued for a further 30 minutes. A further quantity (2 g.) of sodium dithionite was added, and stirring was continued for a further 30 minutes, after which the mixture was allowed to stand overnight. The solid was filtered off and washed with water to give crude 4,5-diamino-2-(3,5-dichloro-2-methoxyphenyl)pyrimid-6-one (6 g.), m.p. 145°-150° C. (with decomposition), pure enough for use in the next stage of the preparation.
Reaction SMILES: I[C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:12]B1OB(C)OB(C)O1>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH3:12][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1scc(C)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1scc(C)c1C

Procedure:
A solution of methyl 3-iodo-4-methylthiophene-2-carboxylate (400 mg, 1.418 mmol), trimethylboroxine (793 μL, 5.67 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (92 mg, 0.142 mmol) in THF (2363 μL) was degassed by bubbling N2 through the solution. 1N aq. K2CO3 (2363 μL) was added and N2 was bubbled through the mixture for 30 s. The mixture was subjected to microwave irradiation in a sealed tube at 120° C. for 30 min. The reaction mixture was filtered through a plug of silica, eluted with EtOAc and the filtrate was washed with 1N aq. NaOH (2×), dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 10% EtOAc in hexanes over 1140 mL) to afford methyl 3,4-dimethylthiophene-2-carboxylate.
Reaction SMILES: [FH:1].[K].[O:3]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4]1>C(Cl)Cl>[F:1][CH2:4][C:5]1([OH:3])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: F
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Agent: [K]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(O)(CF)CC1
Temperature: 120 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
3.2 g of potassium hydrogen fluoride and 610 mg tetra-n-butyl ammonium dihydrogen trifluoride were added to 5 g of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate, and it was stirred at 120° C. for 7 hr. After cooling, methylene chloride was added thereto and it was filtered through Celite. The filtrate was evaporated, and the resulting residue was subjected to silica gel column chromatography to give 4.7 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6](=[O:21])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(F)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 82.1 %

Procedure:
A mixture of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.400 mmol), 4-fluoro-phenyl boronic acid (67 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (120 mg, 82%). ESI-MS m/z: 366 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[Cl:1][C:2]1[C:7]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: CN(C(=O)c1ccccc1)c1cccnc1Cl
Temperature: 25 °C
Yield: 110.1 %

Procedure:
5.0 g N-(2-chloro-pyridin-3-yl)-benzamide (18.6 mmol), 7.7 g potassium carbonate (K2CO3) (56 mmol), and 60 mL ethanol were added and stirred in a round-bottomed flask. 3.97 g methyl iodide (MeI) (27.9 mmol) was then added and reacted for 12 hr. After cooling to room temperature, the reaction was quenched by water. After extraction three times by ethyl acetate, removal of water by magnesium sulphate (MgSO4), concentration, and purification by column, 5.05 g white solid was obtained, with a yield of 96%.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH2:7][CH2:6]1.[Cl:18]CCl.S(Cl)(Cl)=O>O1CCCC1>[Cl:18][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH2:7][CH2:6]1
Reactant: ClCCl
Reactant: O=c1ccc(N2CCC(CCCO)CC2)n[nH]1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=c1ccc(N2CCC(CCCCl)CC2)n[nH]1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice bath) mixture of 2.8 parts of 6-[4-(3-hydroxypropyl)-1-piperidinyl]-3(2H)-pyridazinone, 65 parts of dichloromethane and 45 parts of tetrahydrofuran were added dropwise 2.8 parts of thionyl chloride. Upon complete addition, stirring was continued overnight at room temperature. The whole was evaporated and the residue was taken up in methylbenzene. The organic layer was evaporated again, yielding 3 parts (100%) of 6-[4-(3-chloropropyl)-1-piperidinyl]-3(2H)-pyridazinone as a residue (int. 100).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:6]1)=O.[NH3:23]>CO.CCOCC>[CH3:20][N:15]1[C:14]2[CH:21]=[CH:22][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18][CH2:17][C:16]1=[O:19]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)OCC(=O)N3C)C(=O)O1
Reactant: N
Solvent: CO
Solvent: CCOCC
Product: CN1C(=O)COc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reaction time: 16 h
Yield: 81 %

Procedure:
To a stirred solution of (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (Step 2, 2.41 g, 7.87 mmol) in MeOH (25 mL) is added 2M NH3 in MeOH (25 mL, 50 mmol). The resulting clear solution becomes turbid after ˜10 min. This mixture is stirred for 16 h at which time the reaction is diluted with ether (20 mL) and the resulting white solid filtered off. This white solid is washed with several portion of ether (50 mL) and dried under high vacuum to give the title compound (1.87 g, 81%), 1H NMR (300 MHz, DMSO) δ 7.85 (br s, 1H), 7.60 (br s, 1H), 7.31-7.14 (m, 3H), 5.00 (dd, 1H), 4.65 (s, 2H), 4.21 (t, 1H), 3.97 (dd, 1H), 3.32 (s, 3H); MS for C14H13N3O5 m/z 292.5 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][N:17]=[C:16](Cl)[C:15]=3[Cl:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(OCC)(=O)C>CS(C)=O>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:15]=3[Cl:21])=[O:22])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccnc(Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1nccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Yield: 72.9 %

Procedure:
N-(1-Adamantylmethyl)-2,3-dichloroisonicotinamide (0.4 g) and tert-butyl 3-aminopropylcarbamate (0.4 g) in DMSO (4 ml) were heated in a sealed tube at 160 C for 5 hrs. Ethyl acetate was added and the solution was washed with NaHCO3 solution, water, KHSO4 solution and water. The solution was dried and the solvent was evaporated. The resulting oil was subjected to flash chromatography, using ethyl acetate/hexane as eluant, to give the title compound as a colourless oil (0.41 g).