Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:38]([C:35]5[CH:34]=[CH:33][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[O:27][C:28]([CH3:31])=[N:29][N:30]=7)=[CH:25][C:20]=6[CH3:19])=[CH:37][CH:36]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) and 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11) using a procedure similar to that of Example 1 (23%). This was converted to the oxalate salt which precipitated from acetone/ether as a white solid (mp 232-235° C.), and hydrochloride salt (mp>250° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:6]([CH3:8])=O)[CH3:2].[CH3:18][N:19]1[C:23]([NH2:24])=[CH:22][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:20]1.[ClH:31].CO>C(O)C>[ClH:31].[CH2:1]([O:3][C:4]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:22]2[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:20][N:19]([CH3:18])[C:23]=2[NH:24][C:6]=1[CH3:8])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccccc1C)C(C)=O
Reactant: Cn1nc(-c2ccccc2)cc1N
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C1=C(C)Nc2c(c(-c3ccccc3)nn2C)C1c1ccccc1C
Temperature: 25 °C

Procedure:
Ethyl-2-(2-methylbenzyliden)acetoacetate (0.050 mol) is added to 1-methyl-3-phenyl-5-pyrazolamine (0.050 mol) in ethanol (50 ml) and refluxed for 90 minutes. The mixture is then cooled to room temperature, further ethyl-2-(2-methylbenzyliden)acetoacetate (0.050 mol) is added thereto, and the mixture refluxed for further 90 minutes. The reaction mixture is then cooled, the solvent is evaporated, and the residue is taken up in ethyl ether, collected by filtration, and dried. The product is dissolved in methanol and a mixture of hydrochloric acid and methanol (45 mmol of HCl) is added thereto. The product of the title precipitates by adding ethyl ether. M.p. 187° C. (dec.).
Reaction SMILES: [CH3:1]I.[H-].[Na+].C(OP([CH2:13][C:14]#[N:15])(=O)OCC)C.O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>CN(C=O)C>[C:14]([C:13](=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[CH3:1])#[N:15]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of MeI (1.42 g, 10 mmol) in DMF was added NaH (0.40 g, 10 mmol, 60% in mineral oil), followed by diethyl(cyanomethyl)phosphonate (2.35 g, 10 mmol). The mixture was stirred at ambient temperature. After 30 minutes another batch of NaH (0.40 g, 10 mmol, 60% in mineral oil) was added, followed by tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol). The resulting mixture was stirred for 30 minutes before the reaction was quenched with water and the mixture was concentrated in vacuo. The crude residue was purified by MPLC on silica gel to afford the title compound. LRMS (ESI) calc'd for C13H21N2O2 [M+H]+ 237. Found 237.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19][OH:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[H-].[Na+].[CH3:23]I>C1COCC1.[Cl-].[Na+].O>[CH2:1]([C:3]1([CH2:18][CH2:19][O:20][CH3:23])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CI
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCOC)OCC3
Yield: 62.5 %

Procedure:
To a solution of compound 1 (348 mg, 1.27 mmol) in dry THF (5 mL) under argon, 60% NaH in mineral oil (64 mg, 1.59 mmol, 1.25 eq) was added in a portion-wise manner. After stirring for thirty minutes, MeI (99 μL, 1.59 mmol, 1.25 eq) was added dropwise, and the reaction was stirred for 2 days at room temperature. The resulting mixture was diluted with brine and extracted three times with Et2O. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 20:80:EtOAc:Hexane to give a yellow-white solid (228 mg, 62%): mp 125–126° C. 1HNMR (CDCl3, δ TMS): 0.86 (t, 3H), 1.37 (t, 3H), 1.94 (m, 2H), 2.15 (m, 2H), 2.78 (t, 2H), 2.85 (q, 2H) 3.37 (s, 3H), 3.52 (m, 2H), 4.00 (m, 2H), 6.99–7.38 (m, 3H, Ar—H), 8.43 (br, 1H, NH). MS−: m/z 286 ([M−H]−). Anal. (C18H25NO2): C, H, N.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[P:17]([O:23][CH3:24])[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.C(Cl)Cl>[CH3:24][O:23][P:17]([C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:8]=1)[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COP(Cl)N1CCCC1
Reactant: O=[N+]([O-])c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COP(c1nc([N+](=O)[O-])n[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a stirred solution of 3-nitro-1,2,4-triazole (2.70 g, 23.71 mmol) and triethylamine (11.0 mL, 8.0 g, 79.0 mmol) in THF (40 mL) and CH2Cl2 (20 mL) was added dropwise chloro(methoxy)pyrrolidinophosphine (3.31 g, 19.76 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a pale yellow oil (3.97 g, 82%). 31P NMR (CDCl3) δ 132.9.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30](O)=[O:31])[CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:66][S:67]([N:70]1[CH2:75][CH2:74][CH:73]([CH:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH2:72][CH2:71]1)(=[O:69])=[O:68]>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)[C:30]([N:79]3[CH2:78][CH2:77][CH:76]([CH:73]4[CH2:72][CH2:71][N:70]([S:67]([CH3:66])(=[O:69])=[O:68])[CH2:75][CH2:74]4)[CH2:81][CH2:80]3)=[O:31])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc[nH]c12
Reactant: CS(=O)(=O)N1CCC(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(S(C)(=O)=O)CC3)CC2)cc2nc[nH]c12

Procedure:
A solution of 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 80 mg (0.25 mmol) TBTU, 40 μL (0.29 mmol) triethylamine and 80 mg (0.33 mmol) 1-methanesulphonyl-[4,4′]bipiperidinyl in 1.5 mL DMF was stirred overnight at RT. The reaction mixture was purified by HPLC without working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:11]([O:19]C(=O)C1C=CC=CC=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([O-:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:11]([O-:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: CCCC[Sn](=O)CCCC
Product: CCCC[Sn+2]CCCC
Product: O=C([O-])c1ccccc1

Procedure:
A 49.74 g. (0.2 mole) portion of dibutyltin oxide and 22.62 g. (0.1 mole) of benzoic anhydride were intimately mixed in a Waring® Blender for 1 minute. A reaction initiated almost immediately, as demonstrated by infra-red spectroscopy. After standing at ambient temperature for about three weeks, the reaction appeared to be complete. Infra-red spectroscopic analysis of the product demonstrated that virtually all the original anhydride had been consumed, as demonstrated by the disappearance of absorption maxima at 5.6μ and 5.8μ. New absorption maxima at 6.3μ and 6.5μ are indicative of the presence of ##STR5## moieties. B. Dibutyltin Stearate
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:34].[C:35]1([S:41]([Cl:44])(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl.O>[ClH:44].[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:34]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cn1c(=O)ccc2cc(OCCCCCNCCc3cccnc3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cl
Product: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.35 ml) was added to a dichloromethane solution (5 ml) of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one (219 mg) and ice-cooled. Benzenesulfonyl chloride (0.096 ml) was added to the resulting mixture, and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.16 ml) was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (68 mg) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-[3-(4-aminophenyl)phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (95 mg) and triethylamine (0.05 ml) in dichloromethane (3 ml) was added benzoyl chloride (0.03 ml). The mixture was stirred at room temperature for 20 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-[3-(4-benzoylaminophenyl)phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (73 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccccn1
Temperature: 25 °C
Yield: 102.7 %

Procedure:
To a solution of 2-aminopyridine (94.12 g, 1 mole) and Et3N (167.3 mL, 1.2 mole) in CH2Cl2 (1 L) was added pivaloyl chloride (135.5 mL, 1.1 mole) dropwise at 0° C. The mixture was allowed to warm to RT as the bath warmed. After 18 hr the mixture was filtered. The filtrate was washed sequentially with H2O (1.5 L) and saturated NaHCO3 (2×1.5 L), then was dried (MgSO4)and concentrated under reduced pressure to give the title compound (183 g, 103%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.28 (m, 2H), 8.00 (br s, 1 H), 7.70 (m, 1 H), 7.03 (m, 1 H), 1.31 (s, 9 H); MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH2:31]([CH2:33][NH2:34])[OH:32].O.CN1[C:41](=[O:42])CCC1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:34][CH:33]([CH2:41][OH:42])[CH2:31][OH:32])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: NCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 88 %

Procedure:
The product of Example 121 (400 mg, 0.95 mmol) and ethanolamine (0.29 mL, 4.73 mmol) in NMP (2 mL) was stirred at 23° for 1 h. The mixture was diluted with EtOAc, washed with H2O, the organic phase was separated, EtOAc was removed in vacuo and the residue was purified by Flash chromatography on silica gel, eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by evaporation of solvent to afford a gummy residue. Trituration with H2O, gave the title compound compound 4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-ortho-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (340 mg, 88%). LC-MS: 405.4 (MH+, m/z), Rt=1.85 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](SC)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[C:32]1([CH2:38][CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[NH2:41][CH2:42][CH2:43][NH:44][CH3:45]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH2:42][CH2:43][NH:44][CH3:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCc1ccccc1
Reactant: CNCCN
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Product: CNCCNc1nc(-c2cc(C(=O)NCCc3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound is prepared from 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid by following the procedures in Example 19 using 2-phenylethanamine for the amide formation and (2-aminoethyl)methylamine for the displacement reaction: LC-MS m/z 569 (M+H)+, 1.69 min (ret time).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][N:11]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:11]=1
Reactant: C1=COCCC1
Reactant: Brc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccccc1C=Cc1nn(C2CCCCO2)c2ccccc12
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A solution of (E)-3-[2-(2-bromophenyl)vinyl]-1H-indazole (0.35 g, 1.2 mmol) obtained in Step 1 of Example 133, 3,4-dihydro-2H-pyrane (0.21 mL, 2.3 mmol) and p-toluenesulfonic acid monohydrate (22 mg, 0.12 mmol) in THF was stirred at 80° C. for 8 hours. After cooling to room temperature, the reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was reslurried with diisopropylether to obtain 3-[2-(2-bromophenyl)vinyl]-1-(tetrahydropyran-2-yl)-1H-indazole (0.39 g, 86%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.N1CCCC1>C(O)C>[CH3:10][N:11]1[CH2:12][CH:13]=[C:14]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[N:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:15][CH2:16]1
Reactant: c1cc2[nH]ccc2cn1
Reactant: CN1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CN1CC=C(c2c[nH]c3ccncc23)CC1

Procedure:
from 5-azaindole (2.0 g, 16.9 mmol); N-methyl-4-piperidone (1.92 g, 16.9 mmol) and pyrrolidine (12.04 g, 169 mmol) in ethanol (20 mL).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.CO.[NH:13](CCO)[CH2:14][CH2:15][OH:16]>C(O)(C)C>[OH:16][CH2:15][CH2:14][N:13]1[CH2:10][CH2:9][O:8][C:1](=[O:7])[C:2]1=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: OCCNCCO
Solvent: CO
Solvent: CC(C)O
Product: O=C1OCCN(CCO)C1=O
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
A 4(2-hydroxyethyl)morpholine-2,3-dione was prepared at low temperatures by the following procedure. Into a five-necked 22 liter round bottomed flask equipped with a reflux condenser, nitrogen bubbler, addition funnel, thermocouple well, and mechanical stirrer was charged 3000 g (20.53 mol) of diethyl oxalate and 2000 ml of isopropyl alcohol. The solution was cooled to 0 to 5° C. using a cold bath of ice and methanol. A solution of 2160 g (20.53 mol) of diethanolamine dissolved in 2000 ml of isopropyl alcohol was added through the addition funnel during a period of 5 to 6 hours. The reaction is exothermic. After addition was complete, the mixture was allowed to stand at room temperature overnight. The product is collected by filtration. After air drying, 2923 g (89.5% yield) of white crystals were obtained with identical spectral properties to the compound prepared in Example 1.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[CH:8]=2)[C:3]1=[O:21].[C:22]([NH2:25])(=[S:24])[CH3:23]>CC(C)=O>[BrH:1].[CH3:23][C:22]1[S:24][CH:2]2[CH2:10][C:9]3[CH:8]=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=4)[CH:6]=[CH:5][C:4]=3[C:3]2([OH:21])[N:25]=1
Reactant: CC(N)=S
Reactant: O=C1c2ccc(-c3cccc(C(F)(F)F)c3)cc2CC1Br
Solvent: CC(C)=O
Product: Br
Product: CC1=NC2(O)c3ccc(-c4cccc(C(F)(F)F)c4)cc3CC2S1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
213 mg of 2-bromo-5-(3-trifluoromethylphenyl)indan-1-one and 48.8 mg of thioacetamide are dissolved in 10 ml of dry acetone and the solution is stirred at 0° C. for 8 h. The precipitate is filtered off with suction, washed with acetone and dried in a high vacuum. 2-Methyl-6-(3-trifluoromethylphenyl)-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol hydrobromide of melting point 245-250° C. (dec.) is obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)N3CCOCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)cc(NC(=O)N3CCOCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[C:23]([CH3:29])=[N:24][C:25](Cl)=[CH:26][CH:27]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:30][S:31]C.[Na]>C(OCC)(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[C:23]([CH3:29])=[N:24][C:25]([S:31][CH3:30])=[CH:26][CH:27]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)ccc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2
Reactant: CSC
Agent: [Na]
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)c(C)n1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[5-(6-chloro-2-methyl-pyridin-3-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (160 mg) and sodium methyl sulfide (84 mg) in N,N-dimtehylformamide (1.6 mL) is stirred for 4 h at 80° C. Three more portions of sodium methyl sulfide (28 mg each) are added over the course of two days while stirring the reaction mixture at 80° C. until completion of the reaction. The reaction mixture is diluted with ethyl acetate, washed with water and brine, and concentrated in vacuo. The crude product is used without further purification for the next reaction step. LC (method 6): tR=1.31 min; Mass spectrum (ESI+): m/z=427 [M+H]+.
Reaction SMILES: [C:1]1([C:15](OC)=[O:16])[CH:6]=[C:5]([C:7](OC)=[O:8])[CH:4]=[C:3]([C:11](OC)=[O:12])[CH:2]=1.CO>C1COCC1>[OH:8][CH2:7][C:5]1[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=[C:1]([CH2:15][OH:16])[CH:6]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(=O)OC)c1
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(CO)cc(CO)c1
Temperature: 70 °C
Yield: 100 %

Procedure:
To a stirring solution of trimethyl 1,3,5-benzenetricarboxylate (10.45 g, 41.4 mmol) in 70 ml of anhydrous THF is added at room temperature a 10M solution of borane-methyl sulfide complex (25 ml, 248 mmol) and the solution is heated to reflux for 3 h. The mixture is then added slowly to 50 ml of MeOH and the resulting mixture is heated at 70° C. for 10 min to remove the methyl sulfide. Evaporation of solvent, washing twice with 50 ml of MeOH and evaporation of MeOH gives 1,3,5-tris(hydroxymethyl)benzene (6.96 g, 100%). 1H NMR (D2O): δ 4.52 (6H, s), 7.15 (3H, s).