Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=3)([F:13])[F:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[CH2:31][NH2:32].C([O-])(O)=O.[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:13])([F:12])[C:14]3[N:15]=[N:16][C:17]([NH:32][CH2:31][C:24]4[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:23]=4[O:22][CH3:21])=[CH:18][CH:19]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: FC(F)(c1ccc(Cl)nn1)c1nnc2ccc(Br)cn12
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(CNc2ccc(C(F)(F)c3nnc4ccc(Br)cn34)nn2)c(OC)c1
Temperature: 140 °C
Yield: 88 %

Procedure:
A reaction mixture of 6-bromo-3-((6-chloropyridazin-3-yl)difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (0.5 g, 1.387 mmol), (2,4-dimethoxyphenyl)methanamine (0.696 g, 4.16 mmol) and NaHCO3 (0.58 g, 7.0 mmol) in IPA (10 mL) was heated at 140° C. in a microwave for 1 hr. The solvent was removed via rotary evaporation and the resulting residue was reconstituted in EtOAc. The organic solution was washed with water, separated and passed through a short silica plug to provide the title compound, 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-N-(2,4-dimethoxybenzyl)pyridazin-3-amine 45G (0.6 g, 1.22 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.71-3.76 (s, 3 H) 3.79 (s, 3 H) 3.85-3.89 (m, 2 H) 6.46 (dd, J=8.34, 2.53 Hz, 1 H) 6.57 (d, J=2.27 Hz, 1 H) 6.61-6.66 (m, 1 H) 7.08 (d, J=9.35 Hz, 1 H) 7.14 (d, J=8.34 Hz, 1 H) 7.81 (d, J=9.35 Hz, 1 H) 7.99 (dd, J=9.60, 1.01 Hz, 1 H) 8.70 (s, 1 H). ESI-MS:m/z 491.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[Br:18][CH2:19][C:20]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:21]
Reactant: COc1ccc(CO)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)CBr)cc1
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a -78 ° C. solution of p-methoxybenzyl alcohol (6.91 g, 50 mmol) and triethylamine (6.95 mL, 50 mmol) in anhydrous CH2Cl2 (50 mL) was added a solution of bromoacetyl bromide (10.1 g, 50 mmol) in CH2Cl2 at -78° C. under nitrogen, over a period of 10 min. The cooling bath was removed, and the reaction mixture was stirred for 2 h. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to provide 12 g (93% yield) of p-methoxybenzyl bromoacetate as a dark colored oil which was used in the next reaction without purification. A portion was purified by column chromatography on silica gel (elution with 20% ethyl acetate/hexanes) to give a clear, colorless oil. 1H NMR (300 MHz, CDCl3 ) δ3.79 (s, 3 H), 3.83 (s, 2 H), 5.12 (s, 2 H), 6.87 (m, 2 H), and 7.30 (m, 2 H); IR (film) 1738 cm-1 ; MS (ESI/NH4OAc) M+NH4+ =276.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10]C)[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>ClC(Cl)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(F)ccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: N#Cc1ccc(F)cc1O
Yield: 86 %

Procedure:
To a solution of 1 g of 4-fluoro-2-methoxy-benzonitrile in 15 mL of dichloroethane was added 1.1 g of aluminum trichloride. The resulting mixture was refluxed for 1 day then poured slowly into water and extracted with ethyl acetate. The organic extracts were washed twice with 10% aqueous solution of sodium hydroxide. The combined basic layers were washed twice with ethyl acetate, acidified with concentrated aqueous solution of hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with water, with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.78 g of 4-fluoro-2-hydroxy-benzonitrile as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([Br:26])=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].Cl>CO.C1COCC1.O>[Br:26][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]2[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
5-Bromo-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (65 mg, 0.15 mmol, 1.0 equiv) was dissolved in 10 mL of 1:1 methanol/THF. To this was added a solution of lithium hydroxide hydrate (200 mg, 4.8 mmol, 31 equiv) in 5 mL water. The reaction was heated at 50° C. for 15 min and then stirred at ambient temperature overnight. The reaction was cooled to 0° C. and acidified to pH˜2 with concentrated HCl. The product was extracted with ethyl acetate (2×25 mL). The solution was dried over anhydrous sodium sulfate, filtered, and evaporated to give 55 mg of 5-bromo-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid (55 mg, 91%). This material was used without further manipulation.
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[N+:20]([O-])=O)[CH2:4][CH:3]=1>CCOC(C)=O.[Pd]>[NH2:20][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:4][CH2:3][CH:2]([F:1])[CH2:7][CH2:6]1
Reactant: CC(=O)Nc1ccc(NCC2CC=C(F)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NCC2CCC(F)CC2)c(N)c1

Procedure:
N-(4-{[(4-Fluorocyclohex-3-en-1-yl)methyl]amino}-3-nitrophenyl)acetamide (340 mg, 1.11 mmol) was dissolved in 25 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H2 atmosphere (40 psi) using a Parr hydrogenation apparatus at rt for 48 h. The solution was filtered through Celite and the solvent was evaporated. Yield: 308 mg (99%). MS (ESI) (M+H)−=279.95.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([Br:15])[C:12]([CH2:16]Br)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CC(C)=O.C(OCC)(=O)C>[Br:15][C:13]1[C:12]([CH2:16][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:4])[CH:14]=1
Reactant: COC(=O)c1cc(CBr)c(Br)cc1OC(C)=O
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1cc(CN2CCOCC2)c(Br)cc1O
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(acetyloxy)-4-bromo-5-(bromomethyl)benzoate (may be prepared as described in Description 16; 741 mg, 2.03 mmol) in acetone (5 ml) was added triethylamine (0.56 ml, 4.05 mmol) and morpholine (0.23 ml, 2.63 mmol). The mixture was stirred for 1 hour, then the solvent was removed in vacuo to give a residue. The residue was redissolved in ethyl acetate (10 ml) and washed with water (10 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give oil. Purification by column chromatography (SiO2, 3:1-1:1 cyclohexane/ethyl acetate) gave the product as oil. 580 mg.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][OH:13])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([OH:27])(=[O:9])=[O:26].[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][OH:13])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Agent: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a stirred mixture of 31.2 parts of 3-[(2-amino-4,5-dichlorophenyl)amino]-1-propanol hydrochloride in 200 parts of water is added dropwise, during a 15 minute-period, a solution of 10.6 parts of potassium cyanate in 50 parts of water at a temperature between 15° and 20° C. Upon completion, stirring is continued first for 20 minutes at room temperature and further for 20 hours at reflux. The reaction mixture is allowed to cool over week-end to room temperature. The precipitated product is filtered off and boiled in trichloromethane. The undissolved part is filtered off and boiled in 4-methyl-2-pentanone. After cooling, the product is filtered off and dried, yielding 14.5 parts (48%) of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp. 174.7° C. To a stirred mixture of 13.3 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 8 parts of N,N-diethylethanamine and 260 parts of dichloromethane are added dropwise 7.4 parts of methanesulfonyl chloride. Upon completion, stirring is continued for one hour at reflux temperature. The reaction mixture is washed with water, dried, filtred and evaporated. The solid residue is shaken with acidified water and 4-methyl-2-pentanone. The whole is filtered (the filtrate is set aside) and the filter-cake is dried, yielding a first fraction of 6.2 parts of 5.6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate. The 4-methyl-2-pentanone-phase is separated from the filtrate, dried, filtered and evaporated, yielding a second fraction of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate as an oily residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([NH:12][NH2:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:15]([C:17]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20])[CH3:16].OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([NH:12][NH:13][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[C:25]([CH3:26])[C:17]=2[CH2:15][CH3:16])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCc1c(C(=O)O)ccc(OC)c1C
Reactant: NNC(=O)C(O)c1cc(F)cc(F)c1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C(=O)NNC(=O)C(O)c2cc(F)cc(F)c2)ccc(OC)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
106.0 g of 3,5-difluorophenylhydroxyacetohydrazide (B2) are dissolved in 820 ml of N,N-dimethylformamide. 104.9 g of 2-ethyl-4-methoxy-3-methylbenzoic acid (B1), 153.9 g of N-3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (DAPECI) and 42.8 g of hydroxybenzotriazole (HOBt) are subsequently added. The reaction mixture is cooled in an ice bath during the addition of the compounds enumerated above. The solution is then stirred at room temperature for 24 hours. For work-up, the reaction mixture is diluted with 3.5 litres of water. The resultant suspension is stirred for one hour, subsequently filtered off and washed with additional water. The filter cake is recrystallised from 2.5 litres of methanol, giving 129.0 g of the title compound as colourless solid having a melting point of 197.1° C. (MS: 401 (MNa+)).
Reaction SMILES: [NH2:1][C:2]1C(O)=NC=[N:6][C:7]=1[NH2:8].[OH-].[Na+].Br[CH:13](Br)[C:14](=O)[C:15]([F:18])([F:17])[F:16]>>[F:16][C:15]([F:18])([F:17])[C:14]1[N:1]=[CH:2][C:7]([NH2:8])=[N:6][CH:13]=1
Reactant: Nc1ncnc(O)c1N
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Nc1cnc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.1 %

Procedure:
To an ice bath-cooled solution of 5,6-diaminopyrimidin-4-ol (18 g, 143 mmol) in 3M sodium hydroxide (180 mL, 540 mmol), was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (25.2 g, 93 mmol). The reaction was stirred for 3 days at ambient temperature. The solids were filtered, dissolved in 60% sulfuric acid (140 mL), and stirred at 135° C. for 8 h. The reaction was cooled, poured over ice and allowed to sit for 16 hours. The solution was neutralized to pH 8 with conc. ammonium hydroxide and extracted with ethyl acetate (5×100 mL), dried over sodium sulfate, filtered and concentrated. The solid residue was recrystallized from benzene/hexane to afford 5-(trifluoromethyl)pyrazin-2-amine (2.28 g, 14 mmol, 15% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (1 H, s), 7.99 (1 H, d, J=1.26 Hz), 5.02 (2 H, br. s.). MS (LC/MS) R.T.=1.56; [M+H]+=164.03.
Reaction SMILES: [N:1]1([C:10]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.CS(C)=O>O>[N:1]1([C:10]2[C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc43)nc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-n3ccc4ccccc43)nc2c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-(indolin-1-yl)-2-phenylquinoxaline-6-carboxylate (150 mg, 0.39 mmol, 1.00 equiv), DDQ (447 mg, 1.97 mmol, 4.00 equiv), DMSO (3 mL). The resulting solution was stirred for overnight at 30° C. in an oil bath. The resulting solution was diluted with 20 mL of H2O. The resulting solids were collected by filtration and applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 30 mg (20%) of methyl 3-(1H-indol-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]Cl>>[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][N:20]1[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:6]2[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]3)/[S:22][C:21]1=[O:23]
Reactant: CN(C)CCCCl
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Agent: Cl
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCCN(C)C)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-3-[3-(Dimethylamino)propyl]-5-[(1-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 3-dimethylamino-1-propyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].I[CH:11]([CH3:13])[CH3:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[S:9][CH:11]([CH3:13])[CH3:12])(=[O:23])=[O:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1S
Reactant: CC(C)I
Product: CC(C)Sc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure A and B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 2-iodo-propane, and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]([N:6]([C:13]1[C:18]([C:19](=[O:25])[CH2:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[CH:17][CH:16]=[C:15]([CH3:26])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.CO.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[C:18]([C:19](=[O:25])[C:20]=1[CH2:21][CH:22]1[CH2:23][CH2:24]1)=[CH:17][CH:16]=[C:15]([CH3:26])[N:14]=2)=[O:27]
Reactant: COC(=O)C(=O)N(c1ccccc1)c1nc(C)ccc1C(=O)CCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(CC2CC2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 80 °C

Procedure:
To N-[3-(3-cyclopropyl-propionyl)-6-methyl-pyridin-2-yl]-N-phenyl-oxalamic acid methyl ester (˜0.3 g) dissolved in toluene was added MeOH (5 mL) and K2CO3 (0.3 g). The mixture was heated to 80° C. for 30 min, cooled to RT, then taken up in EtOAc and washed 2× with LiCl (0.3 wt %, aq). The product was dried over MgSO4, filtered and concentrated, then purified by prep TLC (1:4 EtOAc/hexane) to provide 3-cyclopropylmethyl-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (compound 142).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1>>[C:28]([C:25]1([NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:27][CH2:26]1)#[N:29]
Reactant: N#CC1(N)CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2(C#N)CC2)cn1
Yield: 51 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 1-amino-1-cyclopropanecarbonitrile instead of 2-aminoethyl isopropylether, to the title compound (61 mg, 51%) which was obtained as a white solid. MS: m/e=375.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=4[F:26])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[N:34]1(OC(N(C)C)=[N+](C)C)[C:38]2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN>CN(C)C=O.O1CCCC1>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:25]=[CH:24][C:20]([C:21]([NH:34][CH3:38])=[O:22])=[CH:19][C:18]=4[F:26])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzoic acid (E272) (164 mg, 0.36 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (438 mg, 1.15 mmol) in dimethylformamide (2 ml) was treated with diisopropyl ethylamine (0.40 ml, 2.3 mmol) followed by a 2M methylamine solution in tetrahydrofuran (2 ml). The reaction was stirred at room temperature for 4 hours, applied to a SCX ion exchange column (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol, and the basic fractions concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound. MS (ES+) m/e 369 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:19][C:18](=[O:20])[C:17]2[C:12](=[C:13]([CH3:21])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:2].Cl[S:23]([OH:26])(=O)=[O:24].S(Cl)(Cl)(=O)=O.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:23]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)(=[O:26])=[O:24])=[CH:6][C:5]=1[C:10]1[NH:19][C:18](=[O:20])[C:17]2[C:12](=[C:13]([CH3:21])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: C1CNCCN1
Reactant: CCOc1ccccc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=S(=O)(Cl)Cl
Product: CCOc1ccc(S(=O)(=O)N2CCNCC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-(2-Ethoxyphenyl)-8-methylquinazolin-4(3H)-one (Preparation 4; 2.1 g, 0.0071 mol) was added portionwise to stirred chlorosulfonic acid (15 ml) under a nitrogen atmosphere at 0° C. After 18 hours, the mixture was cautiously added dropwise to stirred ice/water (100 g) and the resulting mixture extracted with dichloromethane-methanol (9:1, 10×100 ml). The organic extracts were combined, dried (MgS4) and evaporated under vacuum. A quantity (1.0 g) of the crude sulphonyl chloride was then added portionwise to a stirred solution of piperazine (2.1 g, 0.0244 mol) in ethanol (30 ml) at room temperature under a nitrogen atmosphere. After 18 hours the mixture was poured into stirred saturated aqueous sodium carbonate solution (100 ml) and the resulting mixture extracted with dichloromethane-methanol (9:1, 10×100 ml). The organic extracts were combined, dried (MgS4) and evaporated under vacuum to give the title compound, which crystallized from ethanol as a colorless solid (0.8 g, 71%), m.p. 163°-165 ° C. Found: C,56.76; H,5.72; N,11.77. C21H4N4O5S; 0.75 C2H5OH requires C,56.41; H,6.00; N,11.70%.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[CH:13][C:12]([Cl:25])=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[CH:32](N(CC)C(C)C)(C)C>C(#N)C>[Cl:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:14]1[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([CH:2]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH3:32])[CH2:4][CH2:5]2)=[N:10][CH:11]=[C:12]([Cl:25])[CH:13]=1)=[O:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1cc(Cl)cnc1N1CCC(CBr)CC1)c1cccc(Cl)c1
Reactant: C1CCNCC1
Solvent: CC#N
Product: CC(C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1)N1CCCCC1
Temperature: 25 °C
Yield: 6.6 %

Procedure:
A mixture of 0.030 g (0.066 mmol) of N-(4-bromomethyl-5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-3-chloro-benzamide, 0.028 g (0.033 mmol) of piperidine, and 0.10 mL (0.58 mmol) of N,N-diisopropylethylamine in acetonitrile (1 mL) is heated at 175 C in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and purified by preparative reverse phase HPLC to give 0.001 g (3%) of the title compound (43) as a colorless solid. [M+H]+=461.2.
Reaction SMILES: [F:1][C:2]1([F:14])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:4]=2[O:3]1.C([N-]C(C)C)(C)C.[Li+].[Li]CCCC.[I:28]I>O1CCCC1>[F:14][C:2]1([F:1])[C:6]([F:7])([F:8])[C:5]2[CH:9]=[CH:10][C:11]([I:28])=[C:12]([F:13])[C:4]=2[O:3]1
Reactant: Fc1cccc2c1OC(F)(F)C2(F)F
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1c(I)ccc2c1OC(F)(F)C2(F)F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
2,2,3,3,7-Pentafluoro-2,3-dihydrobenzofuran (500 mg, 2.4 mmol) was added in portions to a −70° C. solution of lithium diisopropylamide (LDA) prepared in dry tetrahydrofuran (7 mL) from disopropylamine (380 mg, 3.8 mmol) and 2.5 M n-BuLi (1.4 mL, 3.6 mmol). After 40 min at −70° C. a solution of iodine (1.0 g, 4.0 mmol) in tetrahydrofuran (5 mL) was added over 15 min. After 20 min at −70° C., the mixture was warmed to −20° C. and quenched by addition of saturated NH4Cl. The mixture was treated with 10% NaHSO3 (15 mL), stirred for 10 min and extracted twice with diethyl ether (15 mL portions). The combined extracts were dried (Na2SO4) and evaporated. The residue was purified by reverse-phase HPLC eluting with 85% acetonitrile-water to afford the title compound (200 mg, 25%): 1H NMR (400 MHz, CDCl3) δ 7.25 (dd, J=8.1, 4.8 Hz, 1H), 6.63 (dd, J=8.0, 1.1 Hz, 1H), 4.13 (s, 3H); EIMS m/z 336.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:6]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: COC(C(=O)O)c1ccccc1
Product: COC(C(=O)N(C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1)c1ccccc1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from methoxy(phenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 407.