Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([Cl:10])=[N:4][CH:3]=1.O.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[C:7]([CH:8]=[N:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]([Cl:10])=[N:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(Cl)ncc1Br
Solvent: O
Product: CC(C)(C)N=Cc1cc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 107.1 %

Procedure:
To a mixture of 5-bromo-2-chloroisonicotinaldehyde (1.047 g, 4.749 mmol) and Water (2.0 mL, 110 mmol) was added tert-butylamine (2.0 mL, 19 mmol). The reaction mixture was stirred at room temperature for 20 hours, and then excess tert-butylamine was removed by rotary evaporation. The resulting residue was partitioned between ethyl acetate and water, and the organic layer dried with brine and MgSO4, filtered, and evaporated in vacuo to yield 1.401 g (87%) of N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine. 1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 8.43 (s, 1H), 7.78 (s, 1H), 1.28 (s, 9H).
Reaction SMILES: Br[CH:2]([CH2:12][Br:13])[CH2:3][O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[N:9][CH:10]=1.C([O-])(O)=O.[Na+]>C(O)C>[Br:13][CH2:12][CH:2]1[O:11][C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=c1[nH]cncc1OCC(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: BrCC1COc2cncnc2O1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A mixture of intermediate (50) (0.0091 mol) and NaHCO3 (0.0113 mol) in ethanol (100 ml) was stirred and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated. The residue was taken up in water and ethyl acetate. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: hexane/ethyl acetate 66/33;50/50). The desired fractions were collected and the solvent was evaporated, yielding 1.1 g of 7-(bromomethyl)-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (intermediate 51).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[N-:9]=[N+:10]=[N-:11].[Na+].O>CN(C)C=O>[N:9]([CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8])=[N+:10]=[N-:11]
Reactant: O=C1NCCCC1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCCNC1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of 2.0 g of 3-bromopiperidin-2-one in 30 ml of N,N-dimethylformamide was added 5.9 g of sodium azide, followed by stirring at 60° C. overnight. After cooling down to room temperature, water was added to the reaction mixture and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 890 mg of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([CH3:11])[N:5]=[C:4]([SH:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.Br[CH2:26][CH2:27][CH2:28]Br>O>[OH:10][CH2:9][CH2:8][C:7]1[C:2](=[O:1])[N:3]2[C:4]([S:12][CH2:26][CH2:27][CH2:28]2)=[N:5][C:6]=1[CH3:11]
Reactant: Cc1nc(S)nc(O)c1CCO
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc2n(c(=O)c1CCO)CCCS2
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 30 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 25 parts of potassium carbonate, 270 parts of N,N-dimethylacetamide and 75 parts of water was stirred at room temperature and 36 parts of 1,3-dibromopropane were added at once: temperature rose to 50° C. The whole was stirred overnight at room temperature. The reaction mixture was evaporated and water was added to the residue. The solid product was washed with water and dried in vacuo at 100° C., yielding 21 parts (58%) of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one; mp. 155° C. (intermediate 1).
Reaction SMILES: C([O:8][C:9]1=[CH:10][N:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[S:12]/[C:13]/1=[N:14]\[C:15](=[O:25])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])C1C=CC=CC=1.OS(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:26]([N:11]1[CH:10]=[C:9]([OH:8])/[C:13](=[N:14]/[C:15](=[O:25])[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])/[S:12]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1O
Yield: 101.2 %

Procedure:
A solution of Example 155 (500 mg, 1.16 mmol) in anhydrous CH2Cl2 (20 mL) was treated at 0° C. with triflic acid (1741 mg, 11.6 mmol) for 1 h. A saturated solution of sodium bicarbonate was added and the organic layer was separated, dried with anhydrous MgSO4 and concentrated under reduced pressure to afford 400 mg of crude material, which was used directly without purification in the next reactions. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.71 (m, 9H), 3.77-3.87 (m, 3H), 7.18 (d, J=9.1 Hz, 1H), 7.54 (dd, J=8.9, 2.2 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 8.65 (s, 1H); MS (DCI/NH3) m/z 341 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([CH3:28])[CH:21]=1)(=[O:19])=[O:18])[CH3:2].[Br:29]Br>>[Br:29][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([CH3:28])[CH:21]=3)(=[O:19])=[O:18])[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=1
Reactant: BrBr
Reactant: CCC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Product: CCC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)c(C)c1

Procedure:
The title compound was prepared from 6-ethyl-5-[(4-methoxy-3-methylphenyl)sulfonyl]-5,6-dihydrophenanthridine and excess bromine according to the procedure and in the same manner as described in Example 19, step a and yielded, after crystallization from a mixture of ethyl acetate-hexane, 2-bromo-6-ethyl-5-[(4-methoxy-3-methylphenyl)sulfonyl]-5,6-dihydrophenanthridine as a colorless, crystalline, solid, which was characterized by LCMS (ES+, FA, CV=5) and 1H NMR;
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].[F:21][C:22]1[N:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[F:21][C:22]1[N:27]=[CH:26][C:25]([O:1][CH:2]([CH3:20])[CH2:3][N:4]2[C:12]3[C:7](=[C:8]([C:15]([F:18])([F:16])[F:17])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=3)[CH:6]=[C:5]2[CH3:19])=[CH:24][CH:23]=1
Reactant: Oc1ccc(F)nc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)Oc1ccc(F)nc1

Procedure:
Synthesized as described in Example 139C using 1-(2-hydroxypropyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 335) and 6-fluoro-3-pyridinol: 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 6.94 (m, 1H), 6.71 (m, 1H), 6.56 (s, 1H), 4.57 (m, 1H), 4.40 (m, 1H), 4.30 (m, 1H), 2.54 (s, 3H), 1.43 (d, J=6.1 Hz, 3H); MS (ES) m/z 400 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH:21]=O.[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:21][C:20]2[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=[C:18]([C:17]([F:16])([F:30])[F:31])[CH:19]=2)[CH2:10][C@H:9]1[CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[C@@H]1C[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To a solution of (2R,4S)-4-amino-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.7 mmol) in methanol (2 mL) is added to 3,5-bis-trifluoromethyl-benzaldehyde (340 mg, 1.4 mmol), and the reaction mixture is stirred at room temperature. After stirring for overnight, sodium borohydride (53 mg, 1.4 mmol) is added. After stirring for additional 1 hour, The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude (2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[CH:38]=[CH:39][C:40]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:41]([N:43]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=1)(=[O:36])[CH3:35].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:48]([N:43]([C:41]1[CH:42]=[C:37]([C:34](=[O:36])[CH2:35][Br:1])[CH:38]=[CH:39][C:40]=1[O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[S:44]([CH3:47])(=[O:46])=[O:45])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(C)(=O)=O)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N(Cc1ccccc1)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Phenyltrimethylammonium tribromide (1.19 g, 3.16 mmol) was added to a solution of N-(5-acetyl-2-benzyloxyphenyl)-N-benzylmethanesulfonamide (32) (1.23 g, 3.01 mmol) in anhydrous THF (15 mL) in three portions. The reaction mixture was stirred at rt for 16 h. An aqueous sodium bicarbonate solution (5%, 15 mL) was then added. The mixture was extracted with dichloromethane and combined organics were concentrated by rotary evaporation. The resulting residue was purified by Biotage silica gel column chromatography eluting with dichloromethane to give bromo ketone 33 as a solid (1.25 g, 85% yield): 1H NMR (500 MHz, CDCl3) δ 2.85 (s, 3H), 4.21 (s, 2H), 4.75 (br, 2H), 5.19 (s, 2H), 7.08 (d, 1H), 7.22 (m, 5H), 7.43 (m, 5H), 7.65 (d, 1H), 7.92 (dd, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1.[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:13]1([CH2:16][NH:17][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: NCC1CC1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(NCC2CC2)nc1
Yield: 95.5 %

Procedure:
Ethyl 2-chloropyrimidine-5-carboxylate (500 mg, 2.68 mmol), cyclopropylmethylamine (0.28 mL, 3.22 mmol) and DIPEA (0.58 mL, 3.35 mmol) were dissolved in DMF (4 mL) and the reaction mixture was heated using a microwave reactor at 100° C. for 20 min. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (50 mL) and sat aq NaHCO3 (40 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound (566 mg, 95.5%) as a yellow solid. LCMS (ES+): 222.1 [MH]+. HPLC: Rt 5.79 min, 92.9% purity.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([CH3:11])([N+:8]([O-:10])=[O:9])[CH2:5][O:4]C1.[ClH:12]>C(O)C.O>[ClH:12].[CH3:11][C:6]([N+:8]([O-:10])=[O:9])([CH2:7][NH:2][CH3:1])[CH2:5][OH:4]
Reactant: CN1COCC(C)([N+](=O)[O-])C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNCC(C)(CO)[N+](=O)[O-]

Procedure:
A solution of 3,5-dimethyl-5-nitro-1,3-oxazinane (11.5 g, 71.8 mmol) in 280 ml ethanol, 50 ml water, and 12 ml of concentrated hydrochloric acid was equipped with a dean stark trap and heated at reflux temperature. To the refluxing reaction was slowly added a solution of 280 ml ethanol and 50 ml water. The rate of addition of the solution was matched to the rate of distillation and removal of an equal volume of solvent over the course of ca. 2 hours. After 4 hours at reflux temperature, the remaining solvent was distilled off and the crude residue was lyophilized from water to give 14.1 g of white solid, which was used directly in the next step without further purification. 1H NMR (400 MHz, D2O) δ 1.53 (s, 3H), 2.74 (s, 3H), 3.62-3.66 (d, J=14.6 Hz, 1H), 3.68-3.72 (d, J=14.6 Hz, 1H), 3.84-3.87 (d, J=12.5 Hz, 1H), 4.10-4.13 (d, J=12.5 Hz, 1H). 13C NMR (100 MHz, D2O) δ 18.9, 34.4, 52.8, 66.2, 88.9. LRMS (ESI/APCI):149 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([OH:34])(=[O:33])[CH3:32].[O:35]1[C:39]([CH:40]=O)=[CH:38][C:37]2[CH:42]=[CH:43][CH:44]=[CH:45][C:36]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC(Cl)C.C(=O)(O)[O-].[Na+]>>[C:31]([OH:34])(=[O:33])[CH3:32].[O:35]1[C:39]([CH2:40][NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[N:14][C:15]=4[NH2:17])[N:10]([C@H:18]4[CH2:23][CH2:22][C@@H:21]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH2:20][CH2:19]4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:38][C:37]2[CH:42]=[CH:43][CH:44]=[CH:45][C:36]1=2
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(N)c4)c4c(N)ncnc43)CC2)CC1
Reactant: O=Cc1cc2ccccc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(NCc5cc6ccccc6o5)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 11.8 %

Procedure:
A mixture of cis-3-(3-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.107 g, 0.263 mmol, 1 equiv), glacial acetic acid (0.06 mL, 1.0 mmol, 3.8 equiv), benzo[B]furan-2-carboxaldehyde (0.1 g, 0.3 mmol, 1 equiv), sodium triacetoxyborohydride (0.212 g, 1.0 mmol, 3.8 equiv), and dichloroethane (2 mL) was stirred at ambient temperature for 4.5 h. Aqueous sodium bicarbonate was added, the organic layer was separated, and the aqueous layer was extracted with two portions of CH2Cl2 (10 mL each). The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford a yellow oil which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give cis-3-{3-[(benzo[b]furan-2-ylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine monoacetate salt as a white solid (0.017 g, 0.031 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 8.22 (1H, s), 7.51-7.58 (2H, m), 7.22-7.28 (3H, m), 6.98 (1H, s), 6.79-6.84 (2H, m), 6.59-6.62 (1H, m), 4.76-4.81 (1H, m), 4.50 (2H, d, J=5.6 Hz), 2.19-2.24 (14H, m), 2.05-2.07 (2H, m), 1.91 (3H, s), 1.60-1.75 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.99 min. MS: MH+ 537.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[N:21]1([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:26][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[C:28]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: Nc1ccc(CN2CCCC2)c(C(F)(F)F)c1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1ccc(CN2CCCC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-pyrrolidin-1-ylmethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 494.2 [M+H]+; tR=3.23 min (System 1); Rf=0.15 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.Cl>>[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CC(=O)OC
Reactant: FC(F)(F)c1cccc(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(C(=O)OC)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
Dioxane (100 mL) was purged with nitrogen gas for 10 minutes. Phenanthrolene (1.0 g) and copper (I) iodide (1.0 g) were added to the dioxane, the suspension was allowed to stir under a nitrogen atmosphere for 5 minutes, and then cesium carbonate (18.72 g, 57.45 mmol), dimethyl malonate (5.46 g, 50.6 mmol), and 1-iodo-3-(trifluoromethyl)benzene (12.5 g, 46.0 mmol) were added. The reaction mixture was heated to reflux for 18 hours and then cooled to room temperature. Aqueous 1N HCl was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and filtered. Celite® diatomaceous filter aid (5 g) was added to the filtrate, and the resulting suspension was concentrated under reduced pressure at 50° C. to yield a solid consisting of the crude product adsorbed onto Celite®. This solid was purified by silica gel chromatography eluting with a gradient of 100% hexanes to 25% ethyl acetate in hexanes to yield 7.36 g (58.0%) of the title product. 1H NMR (CDCl3) δ 7.59-7.65 (m, 3H), 7.49 (t, 1H), 4.70 (s, 1H), 3.76 (s, 6H).
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][N:10]2[CH2:16][CH2:15][NH:14][NH:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C(N(CC)C(C)C)(C)C>CN(C)C=O>[N+:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:14]1[CH2:15][CH2:16][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][CH2:12][NH:13]1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1ccc(CN2CCNNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CCN1

Procedure:
A mixture of hexahydro-5-(phenylmethyl)-1H-1,2,5-triazepine dihydrochloride (35.0 g), 1-fluoro-2-nitrobenzene (21 ml), N,N-diisopropylethylamine (81 ml) in N,N-dimethylformamide (400 ml) was stirred and heated at 75°-80° (under reflux) under nitrogen for 5 hours. The solution was evaporated to a syrup under oil pump vacuum and the residue was mixed with chloroform and dilute sodium hydroxide. The aqueous phase was extracted several times with chloroform. The combined extracts were dried (MgSO4) and evaporated to a syrup wich was subjected to an oil pump vacuum. The syrup in toluene was applied to a column (94×8.7 cm) of dry column grade neutral alumina prepacked in toluene. Elution with toluene removed a faster moving yellow impurity. Fractions were monitored by t.l.c. on Alox-25 uv254 plates (Brinkmann) with chloroform as developer. As soon as the major component started to issue the eluting solvent was changed to toluene-chloroform (4:1), toluene-chloroform (1:1) and finally chloroform. Appropriate fractions were evaporated to a syrup which was crystallized from ether-heptane; wt. 35.7 g (86%), mp=90°-92°. Recrystallization from chloroform-ether-heptane gave pure titled product, mp=90°-92°.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:19])[C:17]#[N:18])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20]I>>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C#N)c1ccc2oc(-c3ccccc3)nc2c1
Reactant: CI
Product: CC(C)(C#N)c1ccc2oc(-c3ccccc3)nc2c1

Procedure:
By treatment of 2-(2-phenyl-5-benzoxazolyl)propionitrile with methyl iodide in the manner described in Example 12, there was obtained 2-(2-phenyl-5-benzoxazolyl)isobutyronitrile which, on treatment with concentrated hydrochloric acid as described in Example 1(f), yielded 2-(2-phenyl-5-benzoxazolylisobutyric acid, m.p. 92° -95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])/[C:28](=[N:30]/O)/[NH2:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]1[O:6][N:29]=[C:28]([C:27]2[CH:32]=[CH:33][C:34]([O:35][CH:36]([CH3:37])[CH3:38])=[C:25]([Cl:24])[CH:26]=2)[N:30]=1)[C:11]#[N:12]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: N#Cc1ccc(C(=O)O)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C#N)cc3Cl)n2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.4 %

Procedure:
To a 250 mL RBF equipped with a stir bar was charged with 2-chloro-4-cyanobenzoic acid (3.0 g, 16.52 mmol), anhydrous DCM (80 mL), and DMF (0.064 mL, 0.826 mmol). Oxalyl chloride (8.26 mL, 16.52 mmol) (2M solution in DCM) was then added slowly and the mixture was stirred under nitrogen at ambient temperature. Upon addition of the oxalyl chloride, gas evolution began and the suspended solid began to dissolve. After about 2-3 hours, the reaction became translucent. The mixture was concentrated in vacuo. The resulting crude material was dissolved in pyridine (50 mL). To this was added (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (1.258 g, 5.50 mmol). The mixture was heated to about 100° C. under an atmosphere of nitrogen for about 16 hrs. The resulting mixture was cooled to ambient temperature. Pyridine was removed under reduced pressure and the resulting material was triturated in DCM and MeOH mixture (about 1:1). The resulting precipitate was left standing for a few minutes at ambient temperature then was collected via filtration, washed with a mixture of 1:1 DCM/MeOH, and then with straight MeOH and dried in a vacuum oven for about 48 hrs to yield 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (1.529 g, 4.09 mmol) as a beige solid. 1H NMR (400 MHz, DMSO) δ ppm 8.39 (d, J=1.53 Hz, 1H), 8.35 (d, J=8.15 Hz, 1H), 8.09 (dd, J=8.14, 1.53 Hz, 1H), 8.05 (d, J=2.11 Hz, 1H), 8.00 (dd, J=8.63, 2.12 Hz, 1H), 7.39 (d, J=8.82 Hz, 1H), 4.82 (sept, J=6.04 Hz, 1H), 1.35 (d, J=6.01 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH2:10][N:9]2[N:5]([C:6](=[O:19])[CH:7]([NH:11]C(OC(C)(C)C)=O)[CH2:8]2)[C:4]=1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])#[N:2].[ClH:26]>C(O)(=O)C>[ClH:26].[C:1]([C:3]1[CH2:10][N:9]2[N:5]([C:6](=[O:19])[CH:7]([NH2:11])[CH2:8]2)[C:4]=1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])#[N:2]
Reactant: C=CCOC(=O)C1=C(C#N)CN2CC(NC(=O)OC(C)(C)C)C(=O)N12
Agent: Cl
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(C#N)CN2CC(N)C(=O)N12
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, allyl 3-cyano-7-(R,S)-(t-butoxycarbonylamino)-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2carboxylate (1.54 g, 4.43 mmol) was combined with 3N hydrochloric acid in glacial acetic acid (45 ml) and the mixture was stirred at room temperature until it was a solution (5 minutes), when it was evaporated in vacuo to dryness. The residue was redissolved in methylene chloride and the solution was taken to dryness in vacuo two times to yield allyl 3-cyano-7-(R,S)-amino-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate hydrochloride.