Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH2:17])[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2].N([O-])=O.[Na+].[N-]=[N+]=[N-].[Na+].O>Cl>[C:1]([N:4]1[C:9]2=[CH:10][C:11]3[C:12](=[N+:14]([O-:16])[O:15][N:17]=3)[CH:13]=[C:8]2[O:7][C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)Oc2cc([N+](=O)[O-])c(N)cc21
Agent: Cl
Agent: O=N[O-]
Agent: [N-]=[N+]=[N-]
Solvent: O
Product: CC(=O)N1CC(C)(C)Oc2cc3c(cc21)no[n+]3[O-]
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a suspension of 530 mg 4-acetyl 6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazine in 3 ml 5N HCl, was added dropwise 3 ml aqueous solution containing 156 mg sodium nitrite under ice cooling, the mixture was stirred for one hour under ice cooling, 1 ml aqueous solution containing 73 mg sodium nitrite was further added dropwise, and the resulting mixture was stirred for ten minutes. To the reaction mixture thus obtained, was added dropwise 3 ml aqueous solution containing 137 mg sodium azide under ice cooling, and the mixture was stirred for 90 minutes. After addition of 10 ml water, the precipitate which separated out was collected by filtration, and its solution in 5 ml toluene was heated under reflux for eight hours. The reaction mixture was diluted with ethyl acetate, the diluted solution was dried over anhydrous magnesium sulfate, and the solvents were distilled off from the dried solution. The residue was subjected to column chromatography on silica gel, the crystals obtained by elution with a 50:1 mixture of chloroform and ethyl acetate were recrystallized from 14 ml ethanol, giving 267 mg of 8-acetyl-7,8-dihydro-6,6-dimethyl-6H-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazine 3-oxide.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([Cl:66])=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[Cl:66])[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Cl)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2Cl)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 39% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z: 373.28 [M-NH2]+. 1H NMR (MeOD) δ: 8.14 (d, J=9.0 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.71 (dd, J=9.0, 2.0 Hz, 1H), 7.39 (d, J=9.0 Hz, 1H), 4.26-4.37 (m, 1H), 3.73 (d, J=11.0 Hz, 1H), 3.69 (d, J=11.0 Hz, 1H), 2.18-2.26 (m, 2H), 1.85-1.93 (m, 2H), 1.46-1.58 (m, 5H), 1.05-1.26 (m, 3H), 0.85-0.94 (m, 9H)
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+]>O1CCCC1.CO>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([OH:23])=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(-n2cccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(-n2cccn2)cc1
Temperature: 80 °C
Yield: 88.5 %

Procedure:
To a solution of 116 (0.40 g; 1.1 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added aqueous sodium hydroxide (20 mL; 2N) and then heated at 80° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether (20 mL). The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as an off-white solid (0.34 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:25])[CH2:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:26][C@@H:27]1[CH2:32][NH:31][CH2:30][C@H:29]([CH3:33])[N:28]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:25])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][N:31]4[CH2:32][C@H:27]([CH3:26])[N:28]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C@H:29]([CH3:33])[CH2:30]4)=[CH:23][CH:24]=3)[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(CC(=O)N2CCC(Nc3ccc(F)cc3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc(CC(=O)N3CCC(Nc4ccc(F)cc4)CC3)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
A mixture of D4 (149 mg, 0.438 mmol) and 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-1-piperazinecarboxylate (94 mg, 0.438 mmol) in 1,2-DCE (3 ml) was stirred for 5 mins at room temperature. Sodium tri(acetoxy)borohydride (139 mg, 0.66 mmol) was added and the mixture was stirred for 3 h then saturated aq. NaHCO3 solution was added. The mixture was stirred for 15 mins then extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product which was purified by chromatography. Elution with 20-90% EtOAc/pentane gave 1,1-dimethylethyl (2R,6S)-4-{[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-2-oxoethyl)phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate (143 mg). δH (CDCl3, 400 MHz) 1.06 (1H, m), 1.27 (6H, d), 1.30 (1H, m), 1.46 (9H, s), 1.93 (1H, m), 2.05 (1H, m), 2.12 (2H, dd), 2.59 (2H, d), 2.88 (1H, m), 3.13 (1H, m), 3.29 (1H, m), 3.38 (1H, m), 3.45 (2H, s), 3.74 (2H, s), 3.86 (1H, m), 4.07 (2H, m), 4.50 (1H, m), 6.50 (2H, m), 6.87 (2H, t), 7.20 (2H, m), 7.31 (2H, d). MS (ES): MH+ 539
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[OH-].[Na+].Br[CH:14]([CH3:16])[CH3:15]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:14]([CH3:16])[CH3:15])[C:9]#[N:10]
Reactant: N#CCc1ccccc1F
Reactant: CC(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)C(C#N)c1ccccc1F
Temperature: 25 °C
Yield: 71.2 %

Procedure:
A mixture of 2-fluorophenylacetonitrile (10.0 g, 74.1 mmoles), 50% aqueous sodium hydroxide (5.2 g), sodium hydroxide (741 mg), tetra-n-butylammonium chloride (3.3 g), and 2-bromopropane (10.0 g, 81.5 mmoles) was stirred rapidly while heating from room temperature to 60°-65°. The temperature was increased to 90°-95 and so maintained for 1.0 hour. After cooling, the mixture was partitioned between diethyl ether and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and the solvent evaporated. Chromatography of the residue over silica gel using 30% methylene chloride-hexane as eluent gave a compound (9.35 g) as a water-white oil which was characterized by NMR, as follows: 1H NMR(CDCl3) d 7.51-7.00 (m, 4H), 3.99 (d, 1H), 2.22 (m, 1H), 1.06 (d, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(OCC)C)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41](OC)[O:42]C)[N:36]=2)=[O:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]=[O:42])[N:36]=2)=[O:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)c2cccc(C(OC)OC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(C(=O)c2cccc(C=O)n2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
186 mg (0.289 mmole) of the compound obtained in step 2 of Example 1 was dissolved in 3 ml of tetrahydrofuran and to the resulting solution was added 2 ml of aqueous 4N HCl solution. The resultant was stirred for 15 hours at room temperature, neutralized with aqueous 4N NaOH solution, concentrated under reduced pressure and purified with silica gel column chromatography to obtain 108 mg of the title compound (yield 71%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li+].CCC[CH2-].[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][C:16]1([C:19]([OH:21])=[O:20])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1
Reactant: O=C(O)C1CCOCC1
Reactant: CC(C)NC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
Diisopropylamine (6.37 mL, 44.7 mmol) in THF (50 mL) was cooled to 0° C. under argon. N-Butyllithium (16.7 mL, 2.5 M in hexane, 41.7 mmol) was added dropwise over 10 min. The reaction mixture was left to stir for 15 min at 0° C. A solution of tetrahydro-2H-pyran-4-carboxylic acid (D8) (1.94 g, 14.9 mmol) in THF (10 mL) was added and a white precipitate was formed. The resulting mixture was then heated at 50° C. for 3 h. The reaction mixture was cooled to 0° C. and methyl iodide (2.80 mL, 44.7 mmol) was added dropwise. The reaction was then allowed to warm to rt and left to stir overnight. 10% aqueous citric acid solution (40 mL) was then added and the THF was removed by rotary evaporation. The residual aqueous mixture was extracted with Et2O (2×). The organics were combined, dried (Na2SO4) and concentrated by rotary evaporation to give the title compound (D9) (1.26 g, 53%) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Cl>CCO>[CH2:3]([C:7]1[N:8]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=2)[C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
265 mg (7 mmol) of sodium borohydride are added to 3.2 g (7 mmol) of the compound from Example I in 30 ml of EtOH and the mixture is stirred at 25° C. for 1 h. After addition of dilute HCl (pH 6), the mixture is extracted three times with CH2Cl2, the organic phase is dried over Na2SO4 and concentrated, and the residue is chromatographed on silica gel 60 using petroleum ether/ethyl acetate (1:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[N:3]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([C:22]4[C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:28][CH2:29]3)[N:3]=[C:4]([CH:16]([CH3:18])[CH3:17])[N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CC(C)c1nc(Cl)cc(-c2ccc(F)c(Cl)c2)n1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1

Procedure:
Dissolve 4-chloro-6-(3-chloro-4-fluorophenyl)-2-isopropyl-pyrimidine (56 mg, 0.2 mmoles) and 1-(3-(trifluoromethyl)-pyridin-2-yl)piperazine (46 mg, 0.2 mmoles) in DMA (1.5 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (55 mg, 0.4 mmoles) to this mixture and heat at 120° C. for 18 hours. Cool, dilute with water (5 mL), extract with EtOAc (3×2 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product and purify by flash column chromatography using 7% EtOAc/hexane to afford the title product as colorless viscous oil. NMR (CDCl3) δ 1.33 (6H, d, J=1.8), 3.05 (1H, m), 3.40 (4H, m), 3.87 (4H, m), 6.68 (1H, s), 7.03 (1H, m), 7.19 (1H, t), 7.89 (2H, m), 8.07 (1H, d, J=2.3), 8.45 (1H, m). Mass spec m/z=480.22.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:10]3[NH:20][C:4]=2[CH:3]=1.[CH3:21]Br>>[CH3:21][N:20]1[C:10]2=[N:11][C:12]3[C:17]([C:18](=[O:19])[N:9]2[C:5]2[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[CH:3][C:4]1=2)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CBr
Reactant: O=c1c2ccccc2nc2[nH]c3cc(Cl)c(Cl)cc3n12
Product: Cn1c2cc(Cl)c(Cl)cc2n2c(=O)c3ccccc3nc12

Procedure:
6-Methyl-8,9-dichlorobenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 8,9-dichlorobenzimidazo[2,1-b]quinazolin-12(6H)one and methyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])=[O:4].C1OC1C.CN(C)C(=O)C.[N:21]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[N:24][N:23]=[N:22]1>C(OCC)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:27](=[O:28])[CH2:26][N:21]1[CH:25]=[N:24][N:23]=[N:22]1)=[O:4]
Reactant: O=C(Cl)Cn1cnnn1
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Agent: CC1CO1
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)Cn1cnnn1
Temperature: -30 °C
Yield: 79.3 %

Procedure:
To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 4 ml of propylene oxide and 3 ml of N,N-dimethylacetamide, which is stirred previously under ice-cooling, is added dropwise 400 mg of 1H-tetrazol-1-yl acetyl chloride, followed by stirring for 30 minutes. To the mixture is added 50 ml of ethyl ether, followed by stirring under cooling at -30° C., and then the upper layer is removed by decantation. The lower layer is subjected to the same procedure as above twice, followed by addition of 10 ml of acetone. The resultant solution is developed and purified by column-chromatography on silica-gel (40 g, 3×10 cm) using a mixture of acetone:methylene chloride (1:1) as eluent, followed by drying to give 403 mg (84%) of cis-3-(1H-tetrazol-1-ylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[NH:7][C:6]=2[CH:5]=[CH:4][N:3]=1.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[N:7][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1C1Nc2ccnc(Cl)c2C(=O)N1CCc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1-c1nc2ccnc(Cl)c2c(=O)n1CCc1ccccc1
Temperature: 20 °C
Yield: 40 %

Procedure:
5-Chloro-2-(2-methoxy-phenyl)-3-phenethyl-2,3-dihydro-1H-pyrido[4,3-d]pyrimidin-4-one (1.0 g, 2.54 mmol) was placed in a flask, acetone (10 mL) was added and the mixture stirred vigorously at 20° C. A 5% aqueous solution of potassium permanganate (KMnO4) was added (50.8 mmol, 2 equiv.). The reaction progress was monitored by HPLC. The reaction was stirred for 12 hours. Another 2 equiv. of KMnO4 was added and reaction stirred at ambient temperature for 4 hours until reaction was complete according to HPLC. The reaction was then quenched with 10% aqueous NaHSO3, filtered by gravity filtration and partitioned between ethyl acetate and water. The aqueous layer was extracted 3× with ethyl acetate, the combined organic layers washed 1× with water, 1× brine and then dried over anhydrous Na2SO4. Filtration and evaporation of the solvent gave 398 mg of tan solid. The original filter cake was suspended in dichloromethane and sonicated for 5 minutes, then repeated two more times. The suspensions were filtered through a nylon filter, combined and evaporated to dryness to give additional 282 mg of product for combined total crude yield of 680 mg (68%) of a tan solid. The product was used further without purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[CH:8][CH:7]=1
Reactant: C=C(C)C(=O)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: C=C(C)C(=O)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
A slurry of 29.4 g. (0.220 mole) of anhydrous aluminum chloride in 38.4 g. (0.40 mole) of fluorobenzene under nitrogen is cooled to 15°C. Methacrylyl chloride (21.9 g., 0.200 mole) is then added dropwise over 30 minutes while holding the temperature at 15° to 20°C. The mixture is warmed to 30°C over 10 minutes, stirred at 30°C for 10 minutes and quenched in ice. The product is extracted into hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 4'-fluoro-2-methylacrylophenone.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:43])[C:11](=[O:42])[CH2:12][N:13]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][C:38]=1[CH3:39])[N:35]([CH3:40])[N:34]=[C:33]2I)[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].[CH3:44]B1OB(C)OB(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:43])[C:11](=[O:42])[CH2:12][N:13]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][C:38]=1[CH3:39])[N:35]([CH3:40])[N:34]=[C:33]2[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2c(I)nn(C)c2cc1C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2c(C)nn(C)c2cc1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 82.1 %

Procedure:
The compound (734 mg, 1.04 mmol) of step A, trimethylboroxin (0.19 ml, 1.36 mmol), bis(tricyclohexylphosphine)palladium(II) dichloride (139 mg, 0.188 mmol), and 1.27 mol/l aqueous potassium phosphate solution (2.50 ml, 3.18 mmol) were added to 1,4-dioxane (8 ml), and the mixture was heated under reflux for 10 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (505 mg, yield 82%) as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[C:7](=[O:8])[C:2]([NH:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])=[N:3][C:4]3[CH:19]=[CH:18][CH:17]=[N:16][C:5]2=3)=[CH:10][CH:11]=1
Reactant: O=c1c(Cl)nc2cccnc2n1-c1ccc(Cl)cc1
Reactant: CCN(CC)CCN
Solvent: CCO
Product: CCN(CC)CCNc1nc2cccnc2n(-c2ccc(Cl)cc2)c1=O

Procedure:
Preparation as in Example 39 but using 2-chloro-4-(4-chlorophenyl)-3,4-dihydro-3-oxopyrido[2,3-b]pyrazine and N,N-diethylethylene diamine in refluxing ethanol gave the title compound mp 149°-150° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:15][CH:16]([CH3:18])[CH3:17])=[C:4]([C:8]2[O:9]CC(C)(C)N=2)[O:5][C:6]=1[Br:7].Cl.C[OH:21].[Li+].[OH-]>O1CCCC1>[Br:1][C:2]1[C:3]([S:15][CH:16]([CH3:18])[CH3:17])=[C:4]([C:8]([OH:9])=[O:21])[O:5][C:6]=1[Br:7]
Reactant: CC(C)Sc1c(C2=NC(C)(C)CO2)oc(Br)c1Br
Reactant: CO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Sc1c(C(=O)O)oc(Br)c1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of 3.01 g (7.58 mmol) of 2-(4,5-dibromo-3-isopropylthio-2-furanyl)-4,4-dimethyloxazoline and aqueous 4N HCl is warmed at reflux under N2 atmosphere for 0.5 hr. The reaction is cooled to 0° C. and treated with methanol (60 mL), tetrahydrofuran (30 mL), and 4.25 g (177.0 mmol) of anhydrous LiOH. The reaction is stirred at 0° C. for 2 hr and 25° C. for 16 hr, then concentrated in vacuo. The resulting residue is dissolved in H2O and extracted with diethyl ether (2X). The aqueous solution is acidified with aqueous 10% HCl and extracted with ethyl acetate (4X). The combined extracts are washed with aqueous saturated NaCl, dried (Na2SO4), and concentrated in vacuo to afford 1.63 g (2.61 g theo.; 62%) of the carboxylic acid as a beige solid. Recrystallization from diethyl ether/hexane affords an analytical sample; mp 130°-131° C.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.S(Cl)(Cl)=O.[CH3:19]O>>[N:1]1[C:2]([CH2:10][CH2:11][C:12]([O:14][CH3:19])=[O:13])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(O)CCc1cn2ccccc2n1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cn2ccccc2n1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
To a solution of 3-imidazo[1,2-a]pyridin-2-ylpropanoic acid (472 mg) in methanol (24.8 mL) was added thionyl chloride (0.215 mL), and the mixture was stirred at 60° C. for 3.5 hr. To the reaction mixture was added, under ice-cooling, saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (402 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.CN[C@@H]1CCCC[C@H]1NC>O.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1cccc2[nH]ncc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 1H-indazole-4-carboxylic acid methyl ester (5.0 g, 28 mmol), copper(I) iodide (5.7 g, 3.0 mmol), potassium carbonate (4.15 g, 30.0 mmol) and 4-fluoroiodobenzene (3.47 g, 30.0 mmol) was charged in a sealed tube at room temperature. The tube was evacuated, back-filled with argon and dimethylformamide (20 mL) was added followed by rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.93 g, 6.5 mmol). The solution was stirred at 120° C. for 3 hours. The solution was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (80 mL). The organic layer was separated, washed with brine (30 mL), and dried over sodium sulfate. The crude product was filtered, concentrated and purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester.