Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
A mixture of ethyl 3-[3-benzyloxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (379 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 5 hours, diluted with 1 N hydrochloric acid (2 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-benzyloxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (299 mg, yield: 83%). This was recrystallized from ethanol-hexane. Melting point: 104–105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[OH:35][CH2:34][C:33]([NH:32][S:29]([C:25]1[CH:24]=[C:23]([NH:22][C:19]([C:18]2[CH:17]=[N:16][N:11]3[C:12]([CH2:14][CH3:15])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:20])[CH:28]=[CH:27][CH:26]=1)(=[O:31])=[O:30])([CH3:37])[CH3:36]
Reactant: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(=O)(=O)NC(C)(C)CO)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-ethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.26) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 528.0 [(M+H)+]; mp 239-240° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH:27]([OH:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(C(C)C)C(C)C)C.[CH3:64][O:65][CH2:66]Cl>ClCCl>[C:40]([NH:39][C@H:38]([C:37]([NH:36][CH:28]([CH:27]([O:54][CH2:64][O:65][CH3:66])[CH:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:53])[CH:50]([CH3:52])[CH3:51])([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 10 %

Procedure:
A solution of 22 mg of the resultant compound of Example 70 in 1 ml of dichloromethane was treated with 0.07 ml of ethyldiisopropylamine and 0.03 ml of chloromethyl methyl ether. The resulting solution was heated at reflux for 1 h. The cooled solution was concentrated in vacuo to give 26 mg of a crude solid which was recrystallized from ethyl acetate/chloroform to provide 15 mg of the desired compound (Rf 0.6, 10% methanol in chloroform) as a white solid, m.p. 197°-198° C. Mass spectrum: (M+H)+ =781.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH:12]=[C:13]([C:39]2[CH:38]=[C:37]([C:36]([F:51])([F:50])[F:35])[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(F)cc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 91 %

Procedure:
The title compound was prepared in 91% yield from 2-(3′-fluoro-5-trifluoromethanesulfonyloxy-5′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Intermediate B) and 3,5-bis-trifluoromethylphenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[C:18]([CH:19]=O)=[CH:17][N:16]=[C:15]([CH3:21])[N:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:10]([NH2:11])=[N:12][C:13]2[N:14]=[C:15]([CH3:21])[N:16]=[CH:17][C:18]=2[CH:19]=1
Reactant: Cc1cccc(Cl)c1CC#N
Reactant: Cc1ncc(C=O)c(N)n1
Product: Cc1ncc2cc(-c3c(C)cccc3Cl)c(N)nc2n1

Procedure:
Following the procedure of Example 1, 2-chloro-6-methylphenylacetonitrile is condensed with 4-amino-2-methylpyrimidine-5-carboxaldehyde to give 6-(2-chloro-6-methylphenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-amine, mp 267°-271° C., after recrystallization from isopropanol.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][OH:47])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][O:47][S:58]([CH3:57])(=[O:60])=[O:59])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 108d (105 mg, 0.16 mmol) in DCM (2 mL) was added DIPEA (43 μL, 0.25 mmol) followed by methanesulfonyl chloride (15 μL, 0.20 mmol). The reaction mixture was stirred for 2 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.09 min, m/z 717 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.O[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.Cl.C(O)(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: OCc1ccncc1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc2c(Cl)cnnc2cc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
The starting material, 4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride, was obtained by adding 4-chloro-7-hydroxy-6-methoxycinnoline (200 mg, 0.95 mmol), followed by 4-hydroxymethylpyridine (108 mg, 1 mmol) and 1,1′-(azodicarbonyl)dipiperidine (647 mg, 2.5 mmol), in portions, to a solution of tri(n-butyl)phosphine (640 μl, 2.5 mmol) in methylene chloride (6 ml). After stirring for 1 hour at ambient temperature, a solution of 7M hydrogen chloride in isopropanol (300 μl, 2.1 mmol) was added. The resulting solid was filtered off, washed with methylene chloride and ether to give 4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride as a solid (196 mg, 55%).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>C(#N)C>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([O:11][CH2:12][C@@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)=[CH:28][CH:27]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1N[C@H](COc2ccc(Br)cc2)CO1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A solution of Example 1C (4.154 kg), potassium carbonate (2.522 kg), and 4-bromophenol (3.183 kg) in acetonitrile (30.3 kg) was stirred at 70° C. for 23.5 hours, cooled to 55° C., treated with 2% (w/w) K2CO3 (41.52 kg) over 20 minutes, cooled to room temperature, and separated into an aqueous fraction and an organic fraction. The organic fraction was concentrated to approximately one third of its original volume, treated with the aqueous fraction to provide a precipitate, concentrated to remove the remainder of the acetonitrile, treated with the 2% (w/w) K2CO3 solution (41.52 kg), stirred at room temperature for 18 hours, and filtered. The filter cake was rinsed with 2% K2CO3 (16.62 L) air-dried, slurried in ethyl acetate (9.44 kg), and heated at 55° C. This solution was treated with hexanes (23.615 kg) and cooled to room temperature to provide a solid. The solid was filtered, rinsed with a solution of ethyl acetate (2.24 kg) and hexanes (7.3 kg), air dried, and vacuum dried (100 mnu/Hg) at 50° C. with a nitrogen bleed to provide 3.307 kg (79.6%, >99.5% ee) of the desired compound. 1H NMR (300 MHz, DMSO-d6) δ7.91 (br s, 1H), 7.47 (dd, J=17 Hz, 2H), 6.93 (dd, J=17 Hz, 2H), 4.44 (m, 1H), 4.15 (m, 2H), 3.95 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]([O:13][CH2:14][C:15](Cl)=[O:16])(=[O:12])[CH3:11].O>C(Cl)(Cl)Cl>[C:10]([O:13][CH2:14][C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[F:9])=[O:16])(=[O:12])[CH3:11]
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)OCC(=O)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (9.5 g, 50.0 mmol) in 150 ml dry CHCl3 was added drop wise acetoxyacetyl chloride (7.5 g, 55.0 mmol) under nitrogen. The mixture was stirred at room temperature for 0.5 h, then water was added and the solution was extracted several times with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 2-(4-bromo-2-fluorophenylamino)-2-oxoethyl acetate (15.2 g) as colorless solid in quantitative yield.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9][CH:8]=[CH:7]1.[C:21](=O)([O-])[O-:22].[K+].[K+]>CN(C)C=O>[CH:21]([C:10]1[N:6]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][CH:9]=1)=[O:22]
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-n2cccc2C=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Phosphoryl chloride (5.5 ml) was dropwise added to N,N-dimethylformamide (4.6 ml) under ice-cooling and the mixture was stirred for 15 minutes at 40°-50° C. To the mixture was added a solution of methyl 3-(pyrrol-1-yl)benzoate (6.0 g) in N,N-dimethylformamide (30 ml) at ambient temperature and the whole was stirred for 3 hours at 110°-120° C. An ice-cooling mixture was poured into ice-water and the mixture was adjusted to pH 9 with potassium carbonate. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-(2-formylpyrrol-1-yl)benzoate (5.31 g).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:45])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36][CH:35]=2)[C:15]1=[O:44])=[O:12])C(=O)OC(C)(C)C.[ClH:46]>O1CCOCC1.CCOCC>[ClH:46].[CH3:21][C@@H:20]1[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36][CH:35]=2)[C:15](=[O:44])[C@H:14]1[NH:13][C:11](=[O:12])[C@@H:10]([NH:2][CH3:1])[CH3:45]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2ccnc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2ccnc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Yield: 85.7 %

Procedure:
A rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-5-(quinolin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (56 mg, 87.8 μmol) in 4 M HCl in dioxane (439 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-5-(quinolin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (43.2 mg, 75.2 μmol, 85.7% yield) as a white solid. MS m/z 538 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.[CH3:19][PH:20](=[O:26])[O:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH2:22]([O:21][P:20]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])([CH3:19])=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: NS(=O)(=O)c1ccccc1Br
Reactant: CC(C)CO[PH](C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)COP(C)(=O)c1ccccc1S(N)(=O)=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A solution of 11.8 g (0.05 mole) of 2-bromophenylsulfonamide in 14 ml (0.1 mole) of triethylamine and 30 ml of dimethylformamide is treated with 6.8 g (0.05 mole) of isobutyl methylphosphinate and 1.1 g (0.001 mole) of tetrakistriphenylphosphine-palladium complex. The yellow suspension is stirred for 15 hours at 100° C., cooled and filtered. After the filtrate has been evaporated, the residue is crystallised from toluene. This gives 4.12 g of 2-(i-butoxy-P-methylphosphinyl)-phenylsulfonamide, melting point 50°-52° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:25][N:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH2:3]1.[OH-].[Na+].Cl>C(O)C>[OH:1][CH:2]1[CH2:25][N:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)[N:9]=[C:4]2[CH2:3]1
Reactant: CCOC(=O)CCCCCCN1CC(O)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CC(O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Enantiomer 1 of ethyl 7-(7-hydroxy-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 3) (5.6 mg, 0.011 mmol) was dissolved in ethanol (0.5 ml) and 2M NaOH (0.023 ml, 0.046 mmol) was added. The solution was stirred at room temperature overnight under an atmosphere of nitrogen. To the reaction mixture was added 2M HCl until the pH was below pH5. The volatile solvent was removed by distillation. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3×10 ml). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an oil which was dried in a vacuum oven at 40° C. overnight;
Reaction SMILES: O[CH:2]([N:7]1[C@H:10]([CH2:11][C:12](=[O:14])[CH3:13])[CH2:9][C:8]1=[O:15])[C:3]([O:5][CH3:6])=[O:4].N1C(C)=CC=CC=1C.S(Cl)([Cl:26])=O>O1CCCC1>[Cl:26][CH:2]([N:7]1[C@H:10]([CH2:11][C:12](=[O:14])[CH3:13])[CH2:9][C:8]1=[O:15])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(O)N1C(=O)C[C@H]1CC(C)=O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(Cl)N1C(=O)C[C@H]1CC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-hydroxy-2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]acetate (268 mg) in tetrahydrofuran (5 ml) was cooled to -40° C. 2,6-Lutidine (0.287 ml) and thionyl chloride (0.18 ml) were added, and the mixture was stirred for one hour, during which time the temperature was allowed to warm to 0° C. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 2-chloro-2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]acetate. This product was diluted with benzene and concentrated in vacuo again. The residue was diluted with tetrahydrofuran (5 ml), and 2,6-lutidine (0.287 ml) and triphenylphosphine (650 mg) were added at 0° C. The mixture was stirred at room temperature for 15 hours, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (10 g) eluting with a mixture of ethyl acetate and acetone (10:1-10:5) to give methyl 2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-2-(triphenylphosphoranylidene)acetate (350 mg) as an oil.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=2[CH3:14])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[CH:21][C:20]=1[F:29].O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH2:18][C:19]3[C:20]([F:29])=[CH:21][C:22]([O:26][CH2:27][CH3:28])=[CH:23][C:24]=3[F:25])[N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=2[CH3:14])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1n[nH]c(C2CC2)c1C
Reactant: CCOc1cc(F)c(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(C2CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
46.9 g of ethyl 5-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate 1-15-1 (266 mmol, 1.0 eq.) in 588 mL THF were cooled to 0° C. and 11.6 g sodiumhydride (60%, 290 mmol, 1.2 eq.) were added in small portions. The resulting suspension was diluted with 250 mL THF. 66.7 g 2-(bromomethyl)-5-ethoxy-1,3-difluorobenzene (266 mmol, 1.1 eq., commercially available) were added slowly. The reaction mixture was stirred at rt for 2 hours. 300 mL water was added and the THF was evaporated in vacuum. The aqueous residue was extracted with ethylacetate three times. The combined organic layers were dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to provide 79.8 g (195 mmol, 81%) of 89% pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[N:8][CH2:9][C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([N:8]1[CH2:9][C:10](=[O:12])[O:11][CH:7]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C=NCC(=O)[O-])cc1
Agent: [Na+]
Product: COc1ccc(C2OC(=O)CN2C(=O)c2ccccc2)cc1

Procedure:
(R/S)-N-Benzoyl-2-(4'-methoxyphenyl)-1,3-oxazolidin-5-one (21) was prepared from sodium N-(para-methoxybenzylidene)-glycinate (2.15 g, 10.0 mM) and benzoyl chloride (1.16 mL, 10.0 mM) following general procedure D and obtained as a white solid after purification by flash column chromatography, using 20% ethyl acetate/petrol as eluant (2.08 g, 70%): mp 130-132° C.; IR (KBr): 1795, 1635 cm-1 ; 1H NMR (200 MHz, CDCl3): δ 6.84-7.55 (m, 10H), 4.35 (br, 2H), 3.78 (s, 3H); 13C NMR (50.3 MHz, CDCl3): 169.4, 169.3, 160.6, 133.6, 131.6, 128.6, 128.3, 127.7, 127.5, 114.3, 89.9, 55.4, 46.7; LRMS (EI): 298 (MH+). Anal. Calcd for C17H15NO4 : C, 68.68; H, 5.05; N, 4.71; found: C, 68.62; H, 5.01; N, 4.57.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:28][C:25]3[CH:26]=[N:27][C:22]([CH3:21])=[CH:23][CH:24]=3)[N:20]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(N)cn1
Reactant: COc1cccc(CNc2cccn3nc(Cl)nc23)c1
Product: COc1cccc(CNc2cccn3nc(Nc4ccc(C)nc4)nc23)c1

Procedure:
N(8)-(3-Methoxy-benzyl)-N(2)-(6-methyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) and 6-methyl-pyridin-3-ylamine (41.91 mg, 0.3875 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (8.55 mg, 7%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.48 (s, 1H), 8.74 (s, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.96 (d, J=6.7 Hz, 1H), 7.23 (t, J=15.8, 7.7 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 6.96 (s, 2H), 6.82-6.70 (m, 2H), 6.57 (m, 1H), 6.31 (d, J=7.8 Hz, 1H), 4.48 (d, J=6.0 Hz, 2H), 3.71 (s, 3H), 2.40 (s, 3H). MS=361 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(=O)(O)[O-:17].[Na+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:17])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(CBr)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)c1ccc(C=O)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To an ambient temperature solution of 2-(4-Bromomethyl-phenyl)-2-methyl-propionic acid methyl ester (275 mg, 1.01 mmol) in DMSO (8 mL) is added sodium bicarbonate (127 mg, 1.52 mmol). The reaction mixture is heated to 120° C. After 3 h, the reaction is concentrated and the residue is partitioned between EtOAc and NaHCO3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed (0% to 20% EtOAc/Hex) to yield the title compound (179 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.85 (d, 2H, J=8.4 Hz), 7.50 (d, 2H, J=8.4 Hz), 3.67 (s, 3H), 1.61 (s, 6H).