Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCN.[CH:7]1([CH2:10][O:11][N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:9][CH2:8]1.C(O)(=O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])=[C:30]([C:42](=O)[CH2:43][CH3:44])[CH:29]=1>CCO>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])=[C:30]([C:42](=[N:12][O:11][CH2:10][CH:7]2[CH2:9][CH2:8]2)[CH2:43][CH3:44])[CH:29]=1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1OCC1CC1
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(=NOCC1CC1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.3 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(cyclopropylmethoxy)phthalimide (326 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of a solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (316 mg, 1.0 mmol) in EtOH (2 mL), and the mixture stirred for 65 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(1-cyclopropylmethoxyiminopropyl)phenyl]trifluoromethanesulfonamide 196 (205 mg, 53%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.88, br s, 1H, 7.66, d, J=8.8 Hz, 1H, 7.49, d, J=2.4 Hz, 1H, 7.33, dd, J=2.4 and 8.8 Hz, 1H, 4.02, d, J=7.2 Hz, 1H, 2.83, q, J=7.6 Hz, 2H, 1.22, m, 4H, 0.64, m, 2H, 0.33, m, 2H. HRMS (M+) 384.0515. N-(cyclopropylmethoxy)phthalimide was prepared by the procedure described in Example 1G.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([CH:12]([CH:18]([CH3:20])[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2=[O:21])=[CH:4][CH:3]=1.Cl.Cl[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O>[CH3:19][CH:18]([CH3:20])[CH:12]([N:9]1[CH2:10][CH2:11][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[C:8]1=[O:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: ClCc1ccncc1
Reactant: CCOC(=O)C(C(C)C)N1CCN(Cc2ccc(O)cc2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(C)C)N1CCN(Cc2ccc(OCc3ccncc3)cc2)C1=O
Temperature: 50 °C
Yield: 73.3 %

Procedure:
Ethyl 2-(3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (50 mg; 0.15 mmol) was dissolved in DMSO (1 ml). 4-Chloromethylpyridine hydrochloride (39 mg; 0.23 mmol), potassium carbonate (86 mg; 0.62 mmol) and potassium iodide (8 mg, 0.4 mmol) were successively added thereto. The mixture was heated at 50° C. for 3 h. Cooling to RT was followed by partitioning between water (10 ml) and EtOAc (10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (3×; 5 ml). The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. Purification of the residue by column chromatography (SiO2) resulted in ethyl 3-methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin-1-yl}-butyrate (45 mg; 0.11 mmol). MS: 412.50 (M+H); Rt: 1.04 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: C1C2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[N:10]SC=2C=CC=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23].FC1C=CC=CC=1C#N>>[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]#[N:10]
Reactant: Nc1ccccc1S
Reactant: C1=NSc2ccccc2-c2ccccc21
Agent: N#Cc1ccccc1F
Product: N#Cc1ccccc1Sc1ccccc1N

Procedure:
WO 92/19607 describes that a dibenzothiazepine derivative of the formula (5) can be prepared by the steps of reacting 2-aminothiophenol with 2-fluorobenzonitrile to give 2-(2-aminophenylthio)benzonitrile, hydrolyzing the resultant to give 2-(2-carboxyphenylthio)aniline, and finally cyclizing the aniline derivative.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](O)=[O:17].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CCN=C=NCCCN(C)C>>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)=[O:17])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(CO)cc1)c1ccccn1
Yield: 91.9 %

Procedure:
Using General Procedure F: Reaction of (4-Amino-phenyl)-methanol (200 mg, 1.63 mmol), picolinic acid (217 mg, 1.79 mmol), 1-hydroxybenzotriazole (242 mg, 1.79 mmol), 4-methyl morpholine (269 μL, 2.45 mmol) and EDCI (343 mg, 1.79 mmol) for 24 h at room temperature, gave the title compound (342 mg, 92%) as a red solid. 1H NMR (300 MHz, CDCl3) δ 4.70 (d, 2H, J=3.9 Hz), 7.41 (d, 2H, J=8.4 Hz), 7.50 (ddd, 1H, J=7.5, 4.8, 1.3 Hz), 7.79 (d, 2H, J=8.4 Hz), 7.92 (ddd, 1H, J=7.5, 7.5, 4.5 Hz), 8.31 (d, 1H, J=6.0 Hz), 10.06 (br s, 1H).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])C.CCN(C(C)C)C(C)C.C([O-])=O.[Na+].FC(F)(F)S(O[C:27]1[CH2:32][O:31][CH2:30][CH2:29][C:28]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34])(=O)=O.[Li+].[Cl-].Cl>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[CH2:36]([O:35][C:33]([C:28]1[CH2:29][CH2:30][O:31][CH2:32][C:27]=1[C:1]([OH:4])=[O:3])=[O:34])[CH3:37]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)COCC1
Reactant: CC(=O)OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(C(=O)O)COCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetic anhydride (5.19 g, 4.8 mL, 50.9 mmol), DIPEA (6.58 g, 8.89 mL, 50.9 mmol) and sodium formate (5.19 g, 76.3 mmol) was stirred at RT for 1 h. A solution of ethyl 5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-4-carboxylate (8.6 g, 25.4 mmol; prepared according to WO2010038167) in DMF (50 mL) was added dropwise, followed by the addition of palladium (II) acetate (286 mg, 1.27 mmol) and LiCl (3.24 g, 76.3 mmol). After stirring at RT for 1.5 h the black suspension was poured on 2M aqueous HCl solution (100 mL) and EtOAc (100 mL) and the layers were separated. The aqueous layer was extracted twice with EtOAc (100 mL). The organic layers were washed twice with H2O and once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 120 g column using an MPLC system eluting with a gradient of CH2Cl2:MeOH (100:0 to 80:20). Light brown oil (4.14 g; 81.3%). MS (ESI): m/z=199.06 [M−H]−.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:1]([C:5]1[CH:10]=[C:9]([C:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:9]2[CH:8]=[C:7]([CH3:11])[C:6]([OH:12])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)=[O:23])[CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)CCCCCCCCC(=O)c2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
18 g (110 mmol) of 2-tert-butyl-6-methylphenol are reacted with 10.7 g (50 mmol) of decanedioic acid chloride in the presence of 27.5 g (200 mmol) of aluminium chloride by the method described in Example 2 to give the corresponding 1,10-di(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)-1,10-decanedione. 19.2 g (78% of theory) of the product of melting point 165°-168° C. are obtained. The vibration band of the CO groups in the infra-red spectrum appears at 1660 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.Cl.[CH3:35][C:36]1([CH3:43])[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:42][CH:39]3[CH2:40][CH2:41][C:36]([CH3:43])([CH3:35])[CH2:37][CH2:38]3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: CC1(C)CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C)(C)CC4)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 47.2 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.0921 g, 0.244 mmol), N,N-dimethylpyridin-4-amine (0.00299 g, 0.0244 mmol), triethylamine (0.0511 ml, 0.367 mmol), and 4,4-dimethylcyclohexanamine hydrochloride (0.060 g, 0.367 mmol) in DMF (1.5 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0562 g, 0.293 mmol), and the reaction was stirred for 16 hours. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP 1 system eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 56 mg of the title compound (47.2% yield).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:32][O:33]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@H:9]([O:10]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@H:8]2[F:53])[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:32][OH:33])[C@@H:9]([OH:10])[C@@H:8]2[F:53])[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1
Reactant: F[C@H]1[C@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1c(Cl)nc2cc(Cl)c(Cl)cc21
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@@H](F)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
Compound 4 (0.10 g, 0.12 mmol) was dissolved in 10% CF3COOH in CHCl3 (10 mL) and stirred at room temperature in a stoppered flask for 60 min. The reaction mixture was evaporated to dryness in vacuo, the oily residue was purified by flash chromatography (EtOAc/hexane 5:1, 2 cm×15 cm), appropriate fractions pooled, solvent removed in vacuo and the white residue crystallized from MeOH/H2O to give 25 mg (60%) of compound 6 as white crystals.
Reaction SMILES: Br[C:2]1[CH:19]=[N:18][C:5]2[N:6]=[CH:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:9](=[O:10])[C:4]=2[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:42])=[O:43])[C:37]([C:2]4[CH:19]=[N:18][C:5]5[N:6]=[CH:7][N:8]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=6[F:17])[C:9](=[O:10])[C:4]=5[CH:3]=4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=c1c2cc(Br)cnc2ncn1-c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4ncn(-c5ccccc5F)c(=O)c4c3)cc12
Temperature: 80 °C
Yield: 9.6 %

Procedure:
To a degassed mixture of 6-bromo-3-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (100 mg, 0.313 mmol), and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.199 mmol) in N, N-dimethyl-formamide (5 mL) were added Pd(dppf)Cl2 (15 mg) and K3PO4 (135 mg, 0.637 mmol) under N2. The mixture was heated to 80° C. overnight. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated, and the residue was purified by prep-HPLC to give 2-(4-fluorophenyl)-5-(3-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (11.78 mg, yield: 10%). 1H-NMR (CDCl3, 400 MHz) δ 9.12 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.94 (t, J=6.8 Hz, 3H), 7.68 (s, 1H), 7.54˜7.59 (m, 1H), 7.47 (t, J=6.8 Hz, 1H), 7.33˜7.39 (m, 2H), 7.21 (t, J=8.4 Hz, 2H), 6.04 (d, J=4.4 Hz, 1H), 3.27 (s, 3H), 3.01 (d, J=4.8 Hz, 3H), 2.83 (s, 3H). MS (M+H)+: 616.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[NH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)=[N:10][C:6]=2[CH:5]=1)([O-])=O.[ClH:23]>CO.[Pt]>[ClH:23].[ClH:23].[ClH:23].[ClH:23].[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[NH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)=[N:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(CN3CCN(CCO)CC3)nc2c1
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: Nc1ccc2[nH]c(CN3CCN(CCO)CC3)nc2c1
Reaction time: 2 h
Yield: 83 %

Procedure:
2-[4-(5-Nitro-1H-benzimidazol-2-ylmethyl)-piperazin-1-yl]-ethanol (1.085 g, 2.587 mmol) [Goker, H.; Kus, C.; Abbasoglu, U. Arch. Pharm. (Weinheim, Ger.) 1995, 328, 425]was dissolved in Methanol (20.0 mL) and 5% Platinum on Carbon, Sulfided (0.5%) (162 mg, 0.0415 mmol) and 3.00 M of Hydrogen Chloride in Methanol (8.0 mL, 24 mmol) were added. The mixture was shaken under an atmosphere of Hydrogen (25 psi) for 2 h. The mixture was filtered through Celite with MeOH and additional 3.00 M of Hydrogen Chloride in Methanol (3 mL, 9 mmol) was added to the filtrate prior to conc. in vacuo to afford 2-[4-(5-Amino-1H-benzimidazol-2-ylmethyl)-piperazin-1-yl]-ethanol tetrahydrochloride as a foam (0.90 g, 83%). 1H-NMR (DMSO-d6): 10.41 (br s, 1H), 7.72 (d, 1H, J=8.6 Hz), 7.52 (s, 1H), 7.25 (d, 1H, J=8.6 Hz), 4.20 (s, 2H), 3.78 (t, 2H, J=4.8 Hz), 3.53 (m, 2H), 3.19 (m, 4H), 3.09 (m, 2H), 2.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH:26]2[CH2:29][O:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:26]2[CH2:29][O:28][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(OC2COC2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
4-Bromophenol (2.5 g, 14.5 mmol) and K2CO3 (5.45 g, 39.4 mmol) were added to a solution of oxetan-3-yl 4-methylbenzenesulfonate (3.00 g, 13.1 mmol) in DMF (10 mL) in a sealed tube. The reaction was heated to 100° C. and stirred at this temperature for 24 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound. MS (GCMS) m/z 228. This material was used in subsequent steps without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([Mg]Cl)(C)C.[Li+].[Cl-].[B:34](OCC)([O:38]CC)[O:35]CC.Cl>C1COCC1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([B:34]([OH:38])[OH:35])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(I)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: CCOB(OCC)OCC
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(Cl)c2cc(B(O)O)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
To solution of 3-chloro-5-iodo-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (1.45 g, 3.0 mmol, see step (a) above) in THF (9 mL) was added i-PrMgCl×LiCl (0.95 M solution in THF; 3.26 mL, 3.1 mmol) at −40° C. over 5 min. After stirring for 15 min at −40° C., B(OEt)3 (1.56 mL, 9.0 mmol) was added. The temperature of the reaction mixture was allowed to reach 0° C. over 2 h, then HCl (2.5 M solution in water; 3.6 mL, 36 mmol) was added and stirring continued for a further 1 h at 0° C. The reaction mixture was diluted with brine (70 mL) and extracted with t-BuOMe (4×70 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated. The solid thereby obtained was washed several times with light petrol and filtered affording pure sub-title compound (1.04 g, 86%)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si](Cl)(C)C.N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>ClCCl>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)ccc1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1ccccc1
Reaction time: 3 h

Procedure:
A mixture of Example 125B (2 g, 9.2 mmol) and dichloromethane (56 mL) was treated sequentially with 1M trimethylsilyl chloride (20.4 mL, 20.4 mmol) and pyridine (3.4 mL, 41.7 mmol), stirred for 3 hours, treated with benzenesulfonyl chloride (1.4 mL, 11.1 mmol), stirred for 48 hours, diluted with dichloromethane (100 mL), acidified to pH 1 with 1M HCl and stirred for 15 minutes. The organic layer was dried (Na2SO4), filtered, and concentrated. Purification by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min provided the desired product as an off-white solid. MS (ESI(−)) m/e 354, 356 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 11.36 (br s, 1H), 7.84 (m, 3H), 7.66 (m, 4H), 7.33 (dd, 1H), 3.38 (br s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20](F)=[C:19]([C:24]#[N:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[C:24]([C:19]1[CH:18]=[C:17]([S:14]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[C:6]2[CH3:26])(=[O:16])=[O:15])[CH:22]=[CH:21][C:20]=1[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)#[N:25]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(C#N)c2)c2ncccc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(N2CCOCC2)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (Example 54a) (60.7 mg, 0.157 mmol) in acetonitrile (3 ml) is added potassium carbonate (43.3 mg, 0.314 mmol) followed by morpholine (27.6 μl, 0.314 mmol). The reaction mixture is stirred at room temperature for 2 hours and then filtered and concentrated in vacuo to yield the titled compound as an orange oil which is used crude in the next step. (MH+ 455).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:26])[NH:15][C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O.O>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH:15][C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:26])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1

Procedure:
A solution of [4-(quinolin-3-ylcarbamoyl)-phenyl]-carbamic acid tert-butyl ester (7.2 g, 19.8 mmol) in dichloromethane (70 mL), trifluoroacetic acid (70 mL) and water (7 mL) was stirred at ambient temperature for approximately 18 hours. The solvent was evaporated in vacuo, and the resultant residue was triturated in water (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The product was collected by filtration, washed with water and dried in vacuo, to give a colorless solid, 4.36 g (84%). MS: m/z 264 (MH+). 1H NMR (DMSO-d6): δ 5.87 (br s, 2 H), 6.64 (d, 2 H), 7.55-7.67 (m, 2 H), 7.81 (d, 2 H), 7.94 (t, 2 H), 8.81 (d, J=2 Hz, 1 H), 9.14 (d, J=2 Hz, 1 H) and 10.22 (br s, 1 H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][CH3:9])(=[O:7])[CH:5]=[CH2:6]>CO>[CH3:1][N:2]([CH3:3])[CH2:6][CH2:5][C:4]([O:8][CH3:9])=[O:7]
Reactant: CNC
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(C)C

Procedure:
Liquid dimethylamine (500 g) is added to 1800 ml of methanol cooled to -35°. A solution of 500 g of methyl acrylate in 850 ml of methanol is then added keeping the temperature between -50° and -60°. The reaction mixture is kept at -50° to -60° for 21/2 hours and then at room temperature overnight. The solvent is removed in vacuo and the residue is distilled under reduced pressure to give methyl 3-dimethylaminopropionate b.p. 60°-70°/16 mm Hg.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]2[C:11]=1[CH2:12][CH2:13][C:14](=[O:26])[NH:15]2.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>C(OCC)(=O)C.O>[C:32]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:31]=[CH:30][C:29]([CH2:28][N:15]2[C:16]3[C:11](=[C:10]([O:9][CH3:8])[CH:19]=[CH:18][C:17]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:13][C:14]2=[O:26])=[CH:34][CH:33]=1
Reactant: COc1ccc(-c2ccccc2)c2c1CCC(=O)N2
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccccc2)c2c1CCC(=O)N2Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
Sodium hydride (60% in oil) (0.87 g) was added at 0° C. to a DMF solution (50 ml) of 5-methoxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one (5.0 g), followed by stirring for 30 minutes. 4-Bromomethylbiphenyl (5.37 g) was added, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10→1:5). The purified product was recrystallized from an ethyl acetate-n-hexane-diethyl ether mixed solvent to thereby obtain 6.8 g (yield: 82%) of 1-(biphenyl-4-ylmethyl)-5-methoxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.C[O-].[Na+]>CO>[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[N:10]=[C:8]([NH2:9])[CH:7]=[CH:6][N:9]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C(=N)N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nccc(N)n2)cc1
Reaction time: 0.25 h
Yield: 194.7 %

Procedure:
The above intermediate 2-(4-methoxyphenyl)-4-pyrimideneamine was prepared as follows: A slurry containing 81 g of 4-methoxybenzamidine hydrochloride, 24 g of sodium methoxide and 200 ml of methanol was stirred for 15 minutes, filtered and the filtrate concentrated in vacuo on a steam bath. To the residue was added β-ethoxyacrylonitrile (same as ethoxymethyleneacetonitrile) and the solution was heated at 100°-115° C. for 2 and 1/2 hours and poured into water. The solid was collected, washed with water, air-dried, and crystallized from ether-n-hexane to yield 85 g of 2-(4-methoxyphenyl)-4-pyrimidinamine, m.p. 102°-104° C.