Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[N:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C=O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:21]3[N:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a stirred solution of 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (1.4 g, 5.71 mmol) in dimethylformamide (10 mL) at room temperature was added sodium hydride slowly (0.5 g, 60%, 12.4 mmol). After effervescence subsided, tert-butyl 4-(6-chloropyridine-3-sulfonamido)piperidine-1-carboxylate (1.03 g, 4.75 mmol) was added slowly. The mixture was stirred at room temperature overnight and then poured into ice-water. The residue was purified by flash chromatography (silica gel, 2% methanol in methylene chloride) to afford the title compound as a yellow solid (2.75 g, 99%). 1H-NMR (CDCl3, 300 MHz): δ 8.64 (s, 1H), 7.97 (dd, 1H), 7.47 (d, 2H), 6.98 (d, 2H), 6.79 (d, 1H), 5.37 (m, 1H), 4.91 (d, 1H), 3.93 (m, 2H), 3.63 (m, 2H), 3.29 (m, 2H), 2.861 (m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.43 (s, 9H), 1.41 (m, 2H); LCMS: MS (m/z): 585 (MH+)
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:11])[CH2:8][CH2:9][OH:10].[CH:12]([CH:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13].C(OCC)(=O)C>O1CCCC1>[CH:12]([CH:14]([O:10][CH2:9][CH2:8][CH2:7][OH:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13]
Reactant: C=CC(Cl)c1ccccc1
Reactant: OCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(OCCCO)c1ccccc1
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
Potassium tert-butoxide (23.07 g, 0.206 mol) was added to a stirred solution of 1,3-propanediol (44.92 g, 0.591 mol) in dry tetrahydrofuran (400 ml) under an atmosphere of nitrogen. The reaction mixture was stirred for 15 min then a solution of vinylbenzylchloride (mixture of meta and para isomers) (30.00 g, 0.197 mol) in dry tetrahydrofuran (100 ml) was added dropwise over 30 min. The reaction was heated at reflux overnight then the tetrahydrofuran was removed in vacuo and the residue taken-up in water (400 ml) and diethyl ether (400 ml). The organic phase was washed with water, dried (magnesium sulfate) and concentrated in vacuo to give a liquid. The liquid was purified by column chromatography over silica gel (eluent 3:1:petrol ether/ethyl acetate, then ethyl acetate) to give the title compound (30.59 g, 0.159 mol, 81%) as a straw colored liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([O:28][C:29](=[O:36])[NH:30][C:31]1([CH2:34]I)[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:34][C:31]3([NH:30][C:29](=[O:36])[O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:32][CH2:33]3)[C:6]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)NC1(CI)CC1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(Cn2c3ccccc3c3cc(C(N)=O)c(N)nc32)CC1
Temperature: 100 °C
Yield: 13 %

Procedure:
To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 318 mg, 1.41 mmol) in N,N-dimethylformamide (17 mL) was added powdered cesium carbonate (2.29 g, 7.03 mmol), tert-butyl[1-(iodomethyl)cyclopropyl]carbamate (2.26 g, 7.61 mmol, prepared from the corresponding alcohol (J. Med. Chem. 1988, 31, 1694-7) following the procedure detailed in the preparation of xxvii below) was added. The mixture was heated at 100° C. under nitrogen for 2 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed thrice with water and twice with brine. The extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (95/5 methylene chloride/methanol to 93/7 methylene chloride/methanol gradient) to afford the titled product (63, 75 mg, 13%). NH4OAc Standard conditions. DAD Retention time=7.29 min. M+H=396. 1H NMR (300 MHz, DMSO-d6): δ 8.72 (s, 1H), 7.79 (d, J=7.3 Hz, 1H), 7.54-7.41 (m, 2H), 7.26 (dd, J=7.3 Hz, 1H), 7.20-7.11 (m, 2H), 4.34 (s, 2H), 1.35 (s, 9H), 1.18-1.05 (m, 2H), 0.65-0.54 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].O=[C:19]1[CH2:24][CH2:23][S:22][CH2:21][CH:20]1[C:25](OCC)=[O:26].Cl>C(O)C>[OH:10][C:9]1[C:8]2[C:19]3[CH2:24][CH2:23][S:22][CH2:21][C:20]=3[C:25](=[O:26])[O:12][C:7]=2[CH:6]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:11]=1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CCOC(=O)C1CSCCC1=O
Agent: Cl
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CSCC3
Reaction time: 120 h

Procedure:
A solution of 6.4 g (0.027 mole) of 5-(3-methyl-2-octyl)resorcinol of Example 1 and 5.0 g. (0.0266 mole) of ethyl 4-oxo-2,3,5,6-tetrahydro-4H-thiopyran-3-carboxylate (Bennett and Scorah, J. Chem. Soc., 194 (1922)) in 35 ml. of absolute ethanol was cooled in an ice bath while it was saturated with hydrogen chloride. The resulting deep red solution was tightly stoppered and allowed to stand at room temperature for 120 hours. After one day yellow crystalline material had collected on the bottom of the flask. The reaction mixture was warmed gently on the steam bath for 15 minutes, cooled and poured onto a water-ice mixture. The gum-like material that precipitated was extracted with several portions of chloroform. The chloroform solution was washed with aqueous potassium bicarbonate and with water and dried over sodium sulfate. Evaporation of the solvent left 7.5 g. of a light-colored solid. This material was triturated several times with boiling petroleum ether to remove unreacted keto ester. The residue was recrystallized from an ethyl acetate-petroleum ether mixture to give 6.5 g. (68%) of the compound of formula XXXII, m.p. 153°-155°C. ##SPC30##
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[C:21]([CH2:24][NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:23])[NH2:22]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:30]2[CH:31]=[C:26]([NH:25][CH2:24][C:21]([NH2:22])=[O:23])[CH:27]=[CH:28][CH:29]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: NC(=O)CNc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: COc1cc[nH]c1C=C1C(=O)Nc2ccc(F)c(-c3cccc(NCC(N)=O)c3)c21

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol), 2M aqueous Na2CO3 solution (0.13 mL) (Starting Material 13), (Ph3P)2PdCl2 (22 mg, 0.027 mmol) and 3-(carbamoylmethyl-amino)-phenylboronic acid (55 mg, 0.26 mmol) in 1,2-dimethoxyethane (5 mL) was heated at 103° C. for 3 days. The reaction mixture was filtered and concentrated. The crude material was purified by C18 reverse phase chromatography to give 2-[3-[5-Fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-2,3-dihydro-1H-indol-4-yl]-phenylamino]-acetamide. (Yield 1 5mg, 28%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]=[C:11]=[O:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N+:13](=[C:15]1[N:19]=[CH:18][N:17]=[C:16]1[C:20]([NH2:22])=[O:21])=[N-:14].CCOCC>CCOC(C)=O.CS(C)=O>[CH2:6]([O:5][P:4]([CH2:9][N:10]1[C:11](=[O:12])[N:19]2[CH:18]=[N:17][C:16]([C:20](=[O:21])[NH2:22])=[C:15]2[N:13]=[N:14]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: CCOP(=O)(CN=C=O)OCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOP(=O)(Cn1nnc2c(C(N)=O)ncn2c1=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
Isocyanatomethyl-phosphonic acid diethyl ester (953 mg, 6.95 mmol) in EtOAc (10 mL) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.5 g, 3.65 mmol) in dry dimethylsulfoxide (10 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into Et2O and the resultant collected by filtration and washed with Et2O (3 reaction volumes) and dried to give the title compound as a solid (1.14 g, 50%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.91 (1H, s), 7.88 (1H, s), 7.74 (1H, s), 4.85 (2H, t, J=11.2 Hz), 4.12 (4H, m), 1.25 (6H, t, 7.2).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:10])(C)(C)C.Cl.CCOC(C)=O>CCOC(C)=O>[CH:21]1([CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][CH2:20][N:11]2[C:9](=[O:10])[CH2:8][NH2:7])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCc2ccccc2C1C1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)N1CCc2ccccc2C1C1CCCCC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
Tert-butyl[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]carbamate (1.5 g) was dissolved in EtOAc (20 mL), and 4 M HCl/EtOAc (3 mL) was added thereto under ice-cooling, followed by stirring at 50° C. for 5 hours. Then, the reaction solvent was evaporated. Saturated aqueous sodium bicarbonate was added to the reaction liquid which was then extracted with chloroform. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanamine (1.09 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][N:30]([C:34](=[O:42])[CH2:35][CH:36]5[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]5)[CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:43])[N:19]=2)[CH2:14][CH2:13]1>>[C:1]([N:39]1[CH2:38][CH2:37][CH:36]([CH2:35][C:34]([N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:24]([C:22]4[CH:23]=[C:18]([N:15]5[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]5)[N:19]=[C:20]([NH2:43])[N:21]=4)=[CH:25][CH:26]=3)[CH2:31]2)=[O:42])[CH2:41][CH2:40]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCN(C(=O)c5ccccc5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 71, Step 4 starting from benzoyl chloride (Alfa Aesar, Cat. #A14107) and 4-(4-methylpiperazin-1-yl)-6-[2-(piperidin-4-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=554.3.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[O:11]=[C:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]1)[CH2:13][C:14]([OH:16])=O.CCN=C=NCCCN(C)C.Cl.[C:47]1([C:53]2[N:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[O:11]=[C:12]([N:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22]1)[CH2:13][C:14]([NH:59][C:56]1[CH:57]=[N:58][C:53]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:54][CH:55]=1)=[O:16]
Reactant: Nc1ccc(-c2ccccc2)nc1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)nc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
HOBt (48 mg, 0.35 mmol) and DMAP (54 mg, 0.44 mmol) were added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (100 mg, 0.29 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (67 mg, 0.35 mmol) followed by 6-phenyl-pyridin-3-ylamine (50 mg, 0.29 mmol) were added. The reaction mixture was stirred at the room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 36 mg (25%) of 3-oxo-N-(6-phenyl-pyridin-3-yl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 497.16 (M+1)+, 97.8%, 1H NMR: (CDCl3): δ 10.0 (d, 1H), 8.7 (d, 1H), 8.2 (dd, 1H), 8.0 (d, 2H), 7.7 (m, 4H), 7.4 (m, 4H), 4.03 (m, 2H), 3.7 (m, 3H), 3.54 (m, 3H), 3.23 (m. 2H).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:7]=1[OH:14])=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].CN(C)C=O>>[OH:1][C:2]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:14])=[O:5]
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2O)c(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O

Procedure:
82.2 g (0.30 mol) of 2,2'-dihydroxy-4,4'-dimethoxybenzophenone were reacted with 600 g of AlCl3 (4.50 mol) and 180 g (2.47 mol) of DMF (dimethylformamide) as in Example 2, and the product was worked up as described.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)[O:23][N:22]=1
Reactant: COC(=O)c1cc(O)cs1
Reactant: Cc1cc(CCCCCCCI)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCCCCCCCc2cc(C)no2)cs1
Reaction time: 8 h

Procedure:
6.42 g (40.60 mmol) of methyl 4-hydroxy-2-thiophenecarboxylate (XIa) and 11.88 g (38.67 mmol) of 5-(7-iodoheptyl)-3-methyl-isoxazole (IX) are heated under reflux with 5.34 g (40.60 mmol) of potassium carbonate (K2CO3) in 130 ml of anhydrous acetone for 8 hours. After the mixture has been left to stand overnight, it is concentrated, the residue is partitioned between 2N NaOH and ether and the aqueous phase is extracted several times with a total of 150 ml of ether. The organic phase is dried over sodium sulfate/active charcoal and evaporated.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH:6][NH2:7])=[NH:5].C(O)C.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[ClH:11].[NH2:2][NH:3][C:4]([NH:6][N:7]=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)=[NH:5]
Reactant: N=C(NN)NN
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N=C(NN)NN=Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
The preparation of the subject compound may also be accomplished as follows: 25 g. of 1,3-diaminoguanidine hydrochloride is dissolved in 1800 ml. of boiling ethanol. To this boiling solution, 28 g. of 4-chlorobenzaldehyde in 300 ml. of ethanol is added over a period of 8 hours. The reaction mixture is then cooled at 0° C. overnight, clarified, and the filtrate concentrated to 500 ml. volume and cooled at 0° C. 29 g. of precipitate is obtained. This is slurried in 300 ml.of water, the pH adjusted to 8-8.5 with sodium hydroxide solution, the slurry heated to boiling and filtered. Cooling the filtrate gives 18 g. ofessentially pure product melting at 243°-244° C., as in the previous preparation.
Reaction SMILES: C(OC[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:20])[N:11]=[CH:10]1)(=O)C(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][N:41]([CH3:47])[C:42](=[O:46])[C@H:43]([CH3:45])O>C(Cl)Cl>[CH3:40][N:41]([CH3:47])[C:42](=[O:46])[C@H:43]([O:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:18](=[O:19])[NH:9][CH:10]=[N:11]2)[CH3:45]
Reactant: CC(C)(C)C(=O)OCn1cnc2cccc(O)c2c1=O
Reactant: C[C@H](O)C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
DTAD (13.34 g, 58 mmol) was added portion-wise to an ice-cooled solution of (5-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (8 g, 29 mmol), triphenylphosphine (15.2 g, 58 mmol) and (S)—N,N-dimethyl lactamide (5.1 g, 43.5 mmol; obtained as described in Larcheveque M., Synthesis 1986, 1, 60) in DCM (300 ml). The mixture was stirred at room temperature for one hour. After evaporation of the solvents under vacuum, the residue was diluted with 6N methanolic ammonia (100 ml). The mixture was stirred at room temperature for 18 hours. After evaporation of the solvents, the residue was triturated in ether. The resulting solid was filtered and purified further by chromatography on silica gel (eluant: 3 to 5% methanol in DCM) to give (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide as a white solid (5.4 g, 71%); NMR Spectrum (CDCl3) 1.77 (d, 3H), 2.94 (s, 3H), 3.19 (s, 3H), 5.10 (q, 1H), 6.92 (d, 1H), 7.35 (d, 1H), 7.63 (t, 1H), 8.00 (s, 1H); Mass spectrum MH+ 262.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:47][C@H:48]1[CH2:54][CH2:53][C:50]2([CH2:52][CH2:51]2)[O:49]1)(=O)=O>CC(N(C)C)=O>[CH2:51]1[C:50]2([CH2:53][CH2:54][C@H:48]([CH2:47][O:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([O:12][C:13]5[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]6[C:23](=[O:35])[N:24]([C:29]7[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=7)[N:25]([CH3:28])[C:26]=6[CH3:27])=[O:21])=[N:17][CH:18]=5)=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)[O:49]2)[CH2:52]1
Reactant: CS(=O)(=O)OC[C@H]1CCC2(CC2)O1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@H]5CCC6(CC6)O5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C

Procedure:
The title compound was prepared according to the procedure described in Example 2 by using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (280 mg, 0.69 mmol), cesium carbonate (1.17 g, 3.45 mmol, Aladdin), and ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate (204 mg, 0.99 mmol) in DMA (5 mL). The title compound was purified by a silica gel column chromatography (1:8 (v/v) n-hexane/EtOAc) as a colorless solid (110 mg, 27.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][NH:23]3)=[CH:19][CH:18]=2)=[O:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([O:41][CH3:42])=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:36]=1>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6](=[O:26])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][N:23]3[S:37]([C:35]3[CH:36]=[C:31]([Cl:30])[CH:32]=[CH:33][C:34]=3[O:41][CH3:42])(=[O:38])=[O:39])=[CH:19][CH:18]=2)=[O:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Cc1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1S(=O)(=O)n1ccc2ccc(C(=O)Nc3ccc(CC(=O)OC(C)(C)C)cc3)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester (0.20 g, 0.57 mmol) in toluene (2.90 mL) was treated with tetrabutylammonium hydrogensulfate (0.02 g, 0.05 mmol) and a 50% solution of NaOH in water (0.57 mL, 7.12 mmol). After stirring at room temperature for 5 min, 5-chloro-2-methoxybenzenesulfonyl chloride (0.21 g, 0.85 mmol) was added. The mixture was stirred for 2 hours, then poured over ice. The resulting slurry was extracted with ethyl acetate and the combined organic phases washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield (4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-phenyl)-acetic acid tert-butyl ester as a light yellow oil, 0.26 g (81%), MS (ISP): m/e=555.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.C([O-])(O)=O.[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Cl:9][C:4]1[N:3]=[C:2]([NH:1][C:15](=[O:17])[CH3:16])[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
4-Amino-2,6-dichloropyrimidine (500 mg, 3.05 mmol) was refluxed in acetic anhydride (10 ml) for 3 h. Upon cooling to room temperature, the reaction mixture was cooled in an ice bath and basified to pH 8 with 10% aqueous NaHCO3. The phases were separated, and the aqueous portion was extracted twice with EtOAc. The combined organic portions were dried over Na2SO4, filtered, and concentrated to give an off-white solid (503.7 mg, 2.44 mmol, 80% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([CH:7]([C:11]([OH:13])=O)[C:8]([OH:10])=O)[CH3:6])[CH3:2].[NH2:15][C:16]([NH2:18])=[O:17].C([O-])(O)=O.[Na+]>CC(OC(C)=O)=O>[O:17]=[C:16]1[NH:18][C:8](=[O:10])[CH:7]([C@@H:5]([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:11](=[O:13])[NH:15]1
Reactant: CCOC(=O)[C@H](C)C(C(=O)O)C(=O)O
Reactant: NC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)[C@H](C)C1C(=O)NC(=O)NC1=O
Temperature: 25 °C

Procedure:
The (R)-2-(1-ethoxy-1-oxopropan-2-yl)malonic acid (3.5 g, 0.017 mol) and the urea (1.03 g, 0.017 mol) was dissolved into Ac2O (20 ml) and then added to the reaction vessel of the microwave reactor and were allowed to react under microwave irradiation at 60° C. for half an hour. After cooled to rt, added NaHCO3 aqueous and extracted with EtOAc. The organic phase was dried and concentrated to afford (R)-ethyl 2-(2,4,6-trioxohexahydropyrimidin-5-yl)propanoate, which was purified by silica gel chromatography (2.0 g, 52%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH2:15][CH2:16][C:17](O)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:17](=[O:18])[CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCCCCCBr
Reactant: O=C(O)CCc1ccccc1
Product: O=C(CCc1ccccc1)OCCCCCCBr
Yield: 85 %

Procedure:
From 6-bromo-1-hexanol and 3-phenylpropionic acid. Yield: 85% (oil).