Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[CH:9][C:8](=[O:23])[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+:34]>CO.O.[Zn]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]2[NH:34][C:9]3[C:8](=[O:23])[N:7]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[C:6](=[O:32])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10]=3[N:11]=2)=[CH:15][CH:16]=1
Reactant: CCCCn1c(NCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(Cc2ccccc2F)c1=O
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
1-Butyl-3-(2-fluorobenzyl)-6-[2-(4-nitro-phenyl)-ethylamino]-1H-pyrimidine-2,4-dione (2.0 g, 4.46 mmol) was dissolved in methanol (100 mL) and treated with zinc dust (<10 μm, Aldrich; 2.91 g) followed by the addition of a solution of ammonium chloride (5.96 g, 112 mmol) in water (50 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered through a pad of celite. The filtrate was concentrated to remove methanol and the residual aqueous solution was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford 8-(4-amino-benzyl)-3-butyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione as a pale yellow solid (1.64 g, 87%). LCMS, m/z(M+H)=422.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:29][NH:28][C:26](=[O:27])[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:33])[F:32])=[CH:31][CH:30]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: NNC(=O)COc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(COc1ccc(OC(F)(F)F)cc1)NNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared from 3,4-dichlorobenzyl-4-piperidone (J. Med. Chem, 1999, 42, 3629; 100 mg), 2-[4(trifluoromethoxy)phenoxy]acetohydrazide (100 mg), sodium triacetoxyborohydride (100 mg), and 0.02 ml acetic acid, stirred together for 2 hours in dichloromethane by the method of Example 369 step ii. MS [M+H]+ (ES+) 492 1H NMR: (CDCl3) δ 1.4-1.6 (3H, m) 1.7 (2H, m), 2.0 (2H, m) 2.7-2.9 (2H, m), 3.4 (2H, m), 4.4 (3H, m), 5.3 (1H, s) 6.9 (2H, m), 7.2-7.5 (4H, m), 7.8 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].O>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[CH:10][C:11]=1[CH3:16]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccc(OCC(=O)OC(C)(C)C)cc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.1 g (8.9 mmol) of the title B compound, (4-amino-3-methylphenoxy)-acetic acid t-butyl ester and 2.44 g (17.7 mmol) of potassium carbonate in 8 mL of DMF are added 1.76 g (11.5 mmol) of methyl bromoacetate. The mixture is stirred at 60° C. for 1 h, then allowed to cool to RT. The mixture is poured into water and extracted with EtOAc. The organic phase is washed with water and brine, and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue is chromatographed using CH2Cl2 as the eluant to afford (4-t-butoxycarbonylmethoxy-2-methylphenylamino)-acetic acid methyl ester as an oil (contaminated with approx 25% of dialkylated product): 1H-NMR (CDCl3) δ 6.76-6.64 (m, 2H), 6.40 (d, J=8.46, 1H), 4.43 (s, 2H), 3.91 (s, 2H), 3.78 (s, 3H), 2.19 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:24])[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1
Reactant: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1cc(-c2c(-c3cccc(F)c3)nc(N)n(C)c2=O)ccc1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
To a solution of 2-amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) were added potassium carbonate (20 mg, 0.12 mmol) and iodomethane (20 μL, 0.30 mmol), followed by stirring at 50° C. for 16 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (4 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.[C:16]1([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:30]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:26][CH2:25]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.8 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 6.1 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 7.5 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and water is added. The layers are separated and the 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 1-{3-[4-(diphenylmethoxy)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 149.2° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN1CC[O:18][CH2:17][CH2:16]1.C(Cl)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:17](=[O:18])[CH3:16])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc(F)c2)n[nH]1
Reactant: CN1CCOCC1
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2cccc(F)c2)n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
To a solution of 3-(3-fluorophenyl)-1H-pyrazol-5-amine (6.5 g, 36 mmol) and N-methylmorpholine (9.7 mL, 88 mmol) in CH2Cl2 (150 mL) was added acetyl chloride (6 mL, 85 mmol) dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1 d. The reaction mixture was concentrated in vacuo. MeOH (50 mL) and THF (50 mL) were added to the residue, followed by the addition of NaOH solution (aq. 2.5 M, 42.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 min and HCl solution was added until pH reached ˜6. The organic solvents were evaporated in vacuo. The solid from the resulting aqueous suspension was collected by filtration, yielding the title compound as a solid (7.6 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[C:21]([O:29][CH:30]([CH3:32])[CH3:31])[CH:20]=2)=[CH:15][CH:14]=1.CN(C=O)C>O>[Br:1][C:24]1[CH:23]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:20][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)cc1OC(C)C
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2)cc1OC(C)C
Yield: 127.9 %

Procedure:
Dibromoisocyanuric acid (4.60 g) was added to a mixture of methyl 4′-fluoro-3-isopropoxybiphenyl-4-carboxylate (6.61 g) and DMF (60 mL), and the resultant mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.53 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]4[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([NH:37][CH2:38][CH2:39][OH:40])=[N:35][CH:36]=2)O1>>[OH:40][CH2:39][CH2:38][NH:37][C:34]1[N:35]=[CH:36][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]5[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:32][CH:33]=1
Reactant: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(NCCO)nc2)OC1(C)C
Product: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(NCCO)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate E, 65 mg, 0.181 mmol) and 2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamino]-ethanol (stage 21.1.1, 82 mg, 0.218 mmol) to give the title compound as an off-white foam. (HPLC: tR 2.08 min (Method A); M+H=416 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.12-8.02 (m, 2H), 7.80-7.75 (m, 2H), 7.51-7.44 (m, 1H), 6.95-6.89 (m, 1H), 6.85-6.73 (br, 1H), 6.69 (s, 1H), 6.60-6.53 (m, 1H), 3.66 (s, 3H), 3.58 (s, 3H), 3.54-3.49 (m, 2H), 3.37-3.31 (m, 2H))
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10]Cl)=[CH:3][CH:2]=1.[C:12]1([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[K+]>C(#N)C>[C:12]1([C:18]2[CH2:23][CH2:22][N:21]([CH2:10][CH2:9][CH2:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: ClCCCCc1ccncc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: C1=C(c2ccccc2)CCN(CCCCc2ccncc2)C1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A mixture of 4-(4-pyridinyl)-1-butylchloride (Example A) (0.76 g, 4.47 mmol), 1,2,3,6-tetrahydro-4-phenylpyridine (0.796 g, 5.0 mmol), and potassium bicarbonate (1.0 g, 10 mmol) in 5 mL of acetonitrile are heated to reflux for 8 hours. The reaction is cooled to room temperature and the acetonitrile removed in vacuo. The residue is partitioned between 50 mL of water and 50 mL of chloroform. The aqueous layer is extracted again with 50 mL of chloroform and the combined organic extracts are dried over sodium sulfate and the solvent removed in vacuo. The resulting residue is chromatographed on silica gel (2% to 3% methanol, 0.1% ammonia, chloroform) to obtain 1.10 g of 4-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-butyl]pyridine as a white solid; mp 89°-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([CH2:27][CH3:28])([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([CH3:26])[CH:20]=3)([CH2:27][CH3:28])[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)cc(C)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc(C)c2o1
Yield: 71.6 %

Procedure:
5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-7-methyl-benzofuran-2-carboxylic acid ethyl ester (5.55 g, 14.6 mmol) and 1-bromopinacolone (3.92 g, 21.9 mmol) and K2CO3 (6.04 g, 43.8 mmol) are reacted analogous to Example 1E to give the title compound as a pale yellow oil (5.00 g, 72%).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: CC(N=Cc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
9.96 g (0.082 mole) of (R)-(+)-1-phenylethylamine and 10.54 g (0.086 mole) of p-hydroxybenzaldehyde were dissolved in 140 ml of ethyl alcohol, and the resulting solution was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature, and the crystalline material thus formed was separated by filtration to give 13.0 g of (-)-N-(p-hydroxybenzylidene)-1-phenylethylamine. Yield: 70.4%. m.p. 176°-178° C.; α!D22 -120.7° (C 1.0, MeOH) NMR-spectral data (δ ppm, DMSO-d6) 1.50 (d) 3H; 4.50 (q) 1H; 6.7-7.8 (m) 9H; 7-7.8 (broad) 1H; 8.34 (s) 1H
Reaction SMILES: O[C:2]1[C:3]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.P(Cl)(Cl)([Cl:23])=O>O1CCOCC1>[Cl:23][C:2]1[C:3]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: Oc1nc(-c2ccccc2)nc2c1[nH]c1ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Clc1nc(-c2ccccc2)nc2c1[nH]c1ccccc12

Procedure:
A mixture of 4-Hydroxy-2-phenyl-5H-indolo[3,2-d]pyrimidine (800 mg), phosphorous oxychloride (10 mL), and dioxane (10 mL) was refluxed for 40 min. The reaction mixture was concentrated in vacuo and the residue was treated with saturated ammonium chloride and methylene chloride. After drying over magnesium sulfate the solvent was removed in vacuo and the residue was triturated with ether/hexane to afford 4-Chloro-2-phenyl-5H-indolo[3,2-d]pyrimidine (Compound 3) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([C:28]1[CH:33]=[C:32](CO)[CH:31]=[CH:30][N:29]=1)(=[O:27])[NH2:26]>C(Cl)Cl>[Br:24][CH2:20][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([C:25](=[O:27])[NH2:26])[CH:33]=1
Reactant: NC(=O)c1cc(CO)ccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: NC(=O)c1cc(CBr)ccn1

Procedure:
Triphenylphosphine (200 mg, 0.76 mmol) and carbon tetrabromide (273 mg, 0.82 mmol) were added to a solution of 2-carbamoyl-4-(hydroxymethyl)pyridine (101 mg, 0.66 mmol, Reference compound No. 13-1) in methylene chloride (3 mL), then the mixture was stirred at room temperature for 3 hours. The solvent of the reaction solution was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 4-bromomethyl-2-carbamoylpyridine. Triethylamine (134 μL, 0.96 mmol) was added dropwise to a solution of this bromo-intermediate and N-(3,5-dimethylphenyl)-2-thiopyridone-3-carboxamide (103 mg, 0.40 mmol, Reference compound No. 18-1) in N,N-dimethylformamide (1 mL) at room temperature, then the mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate (50 mL), then the ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution (100 mL) and brine (50 mL), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 40 mg of the target compound as a white solid. (Yield 16%)
Reaction SMILES: [OH-].[Na+].[O:3]1[C:8]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12]CC)=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1>CO>[O:3]1[C:8]([C:9](=[N:15][O:16][CH3:17])[C:10]([OH:12])=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C(=NOC)C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)C1=CSCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
1 N Aqueous solution (24 ml.) of sodium hydroxide was added to a solution of ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (syn isomer, 4.6 g.) in methanol (50 ml.), and stirred at room temperature for 16 hours. After the resultant solution was concentrated in vacuo, the residue was dissolved in water. The solution was washed with ethyl acetate and adjusted to pH 1.0 with 10% hydrochloric acid. The solution was extracted with ethyl acetate, and the extract was washed with water and dried over magnesium sulfate. The solution was concentrated under reduced pressure at 40° C., and the residue was washed with diisopropyl ether and then dried to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer, 3.8 g.), white crystals, mp. 129° to 131° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:16][N:17]1[C:21]([CH3:22])=[C:20]([C:23](O)=[O:24])[C:19](=[O:26])[N:18]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:23]([C:20]3[C:19](=[O:26])[N:18]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:17]([CH3:16])[C:21]=3[CH3:22])=[O:24])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2)cc1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a mixture of 4-(4-aminophenoxy)pyridin-2-amine (101 mg, 0.5 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (118 mg, 0.51 mmol) in DCM (5 mL) was added EDCI (115 mg, 0.6 mmol) and HOAT (13.6 mg, 0.1 mmol). The reaction was stirred at 45° C. for 3 hours, and then quenched with water (20 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=20/1) to give the title compound as a light grey solid (110 mg, 49.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH:33]([C:36](Cl)=[O:37])([CH3:35])[CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:36](=[O:37])[CH:33]([CH3:35])[CH3:34])[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 18 mg, 0.042 mmol) in CH2Cl2 (1 ml) was added i-PrCOCl (8.7 μl, 0.089 mmol) and DMAP (10 mg, 0.089 mmol). The reaction was stirred at room temperature for 2 h, diluted with EtOAc, washed with aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[C:11]1([S:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:7][CH:6]([CH3:8])[C:5]([C:14]1[CH:15]=[CH:16][C:11]([S:17][CH3:18])=[CH:12][CH:13]=1)=[O:9]
Reactant: CSc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(=O)C(C)C)cc1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a suspension of aluminum chloride (136 g, 1.02 mol) in chloroform (1.0 L) cooled to -10° C., was added dropwise isobutyrylchloride (115 mL, 1.10 mol). Then thioanisole (100 mL, 0.85 mol) was added dropwise. Upon completion of addition the reaction was allowed to proceed at r.t. for 1.5 h. The reaction was cooled to 10° C. and quenched by addition of water (750 mL). The organic layer was separated, washed with water (2×500 mL), saturated NaHCO3 solution (2×500 mL), brine (1×500 mL), and then dried over Na2SO4. After concentration in vacuo., the resulting crude product crystallized upon standing under high vacuum for 30 min to give the title compound as a brown solid.