Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[S:9][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:6]=1)[CH3:4].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[F:30][C:18]([F:17])([F:29])[C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:2][C@@H:3]([C:5]2[S:9][C:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:7][CH:6]=2)[CH3:4])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)s1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the vial containing (R)-tert-butyl 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride from Step 1 was added N,N-dimethylaminopyridine (3.91 mg, 0.0320 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (0.059 g, 0.24 mmol), N,N-dimethylformamide (2 mL), and triethylamine (0.178 mL, 1.28 mmol). The mixture was stirred at rt for 16 h and then evaporated. To the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give crude (R)-tert-butyl 5-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)thiophene-2-carboxylate as a brown solid. LC-MS: (FA) ES− 434.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[N:11]=[C:12]([NH:15][C:16]([CH:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]2C(OC(C)(C)C)=O)=[O:17])[S:13][CH:14]=1>ClCCl.FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[N:11]=[C:12]([NH:15][C:16]([CH:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19]2)=[O:17])[S:13][CH:14]=1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)C3Cc4ccccc4N3C(=O)OC(C)(C)C)n2)c(C)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(-c2csc(NC(=O)C3Cc4ccccc4N3)n2)c(C)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
35 g of N-[4-(2,4,6-trimethylphenyl)-2-thiazolyl]-1-tert-butoxycarbonyl-indoline-2-carboxamide are dissolved in 200 of dry dichloromethane and 40 ml of trifluoroacetic acid are added dropwise. The reaction mixture is kept at ambient temperature for 2 hours and then evaporated to dryness. The residue obtained is taken up in 150 ml of ethyl acetate. The organic solution is washed with 1N aqueous sodium hydroxide solution and then with water saturated with NaCl and dried over anhydrous magnesium sulphate. After removal of the ethyl acetate, the final product is obtained, from which the salt is prepared by the action of gaseous HCl in isopropanol. The hydrochloride melts at 212° C. Yield 88%. Salt: 1H NMR: 80 MHz(DMSOd6) δ(ppm): 2.1(s,6H); 2.4(s,3H); 3.2-3.8(m,2H); 5.0(m,1H); 6.0(s,1H 6.0(s,1H); 6.9-7.6(m,7H); 12.1(s,1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([CH:9]=[S:10])=[C:6]([NH2:8])[CH3:7])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1>C(O)C.CCOCC>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH3:7])=[N:8][S:10][CH:9]=1)=[O:11])[CH3:2]
Reactant: CCOC(=O)C(C=S)=C(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1csnc1C
Temperature: 25 °C

Procedure:
To a solution of 3-amino-2-thioformyl-but-2-enoic acid ethyl ester (method 52) (25.6 g, 147 mmol) in ethanol (300 mL), was added m-chloroperbenzoic acid (33.3 g, 77%, 149 mmol) in ethanol (200 mL) dropwise with stirring at room temperature. After the completion of the addition the reaction mixture was heated at 75° C. for 2 h after which the MS showed the complete disappearance of the starting material. The reaction mixture was diluted with ether (500 mL) and the ethereal solution was washed with 0.1 M NaOH solution (3×500 mL) and once with water (400 mL) dried (Na2SO4) and concentrated to get the pure product as light brown oil. Yield 23.5 g (93%). 1NMR (300 MHz) δ: 1.40 (t, 3H), 2.73 (s, 3H), 5.07 (t, 1H), 4.36 (q, 2H), 9.24 (s, 1H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:9][CH:8]=1)(C)C.[OH-].[Na+]>ClCCl.CO>[C:6]([C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(CN2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.75 g (2.91 mmol) of 1-(4-trimethylsilanylethynylbenzyl)pyrrolidine in 10 mL of dichloromethane and 10 mL of methanol is combined with 2.4 mL of a 1M sodium hydroxide solution and stirred for 3 hours at ambient temperature. The reaction mixture is evaporated down and the residue is extracted with water and ethyl acetate. The organic phase is stirred with activated charcoal, filtered, and then dried over sodium sulfate. Yield: 0.4 g (74.1% of theory); C13H15N (M=185.27); calc.: molecular ion peak (M+H)+: 186; found: molecular ion peak (M+H)+: 186.
Reaction SMILES: Br[CH:2]=[CH:3]Br.[Li]CCCC.[CH3:10][O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3>C1COCC1.C(Cl)Cl>[C:2]([C@@:23]1([OH:31])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:13]2([CH3:14])[C@H:15]3[CH2:16][CH2:17][C@@H:12]2[O:11][CH3:10])[CH2:22]1)#[CH:3]
Reactant: BrC=CBr
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 4.3 %

Procedure:
A solution of 1,2-dibromoethylene (1.7 mL, 21 mmol) in dry THF (25 mL) was treated with n-BuLi (16.8 mL, 2.5 M in THF, 42 mmol) at −65° C. After stirring the mixture at −70° C. for 0.25 hr, a solution of 17β-methoxy-5α-androstan-3-one (2.128 g, 7 mmol) in THF (22 mL) was added and the mixture was stirred at −78° C. for 30 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (100 mg) as a colorless solid; mp 138-145° C.; TLC Rf (hexane:acetone 7:3)=0.45; and then 3α-ethynyl-3β-hydroxy-17β-methoxy-5β-androstane (1.6 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:10]=1[CH3:11])=[O:4].C([Sn](CCCC)(CCCC)[C:24]#[C:25][CH2:26][O:27][CH3:28])CCC>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:24]#[C:25][CH2:26][O:27][CH3:28])=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: CCCC[Sn](C#CCOC)(CCCC)CCCC
Reactant: COC(=O)c1c(C)cc(N2CCOCC2)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COCC#Cc1nc(N2CCOCC2)cc(C)c1C(=O)OC
Temperature: 100 °C
Yield: 63.1 %

Procedure:
To a solution of 700 mg (2.6 mmol) 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester and 1.39 g (3.9 mmol) tributyl(3-methoxyprop-1-ynyl)stannane in dioxane (10 ml) was added 273 mg (0.39 mmol) PdCl2(PPh3)2. Then the reaction solution was heated at 100° C. for 16 h. After cooling to RT the mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (5% KF-silica, hexane/EtOAc 19:1) provided 500 mg (1.64 mmol, 63%) 2-(3-methoxyprop-1-ynyl)-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:7]1(C1C=CC(C)=CC=1)C1C=CC(C)=CC=1)([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C(OCC)C>[CH:1]([NH:4][CH2:5][C:6]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCN1c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C(CNC(C)C)C1(c1ccc(C)cc1)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(-c2nc3c(CNC(C)C)cn(CCCCCCC(=O)O)c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 7-(7-((isopropylamino)methyl)-2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Example 4.1) (53 mg, 0.101 mmol) in EtOH (1 ml) was treated with 2M NaOH (0.151 ml, 0.302 mmol) and stirred at RT for 16 hours. The solvent was removed under reduced pressure and the crude product was dissolved in water and the pH was adjusted to pH 1 using 2M HCl. The mixture was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure to afford an orange solid. The solid was suspended in diethyl ether, sonicated and then filtered, rinsing the filter-cake with diethyl ether (×3). The resultant solid was dried under atmosphere to afford the titled compound as an orange solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[CH3:12][S:13]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC1CCCCC1
Product: CS(=O)(=O)OCCCCC1CCCCC1

Procedure:
4-Cyclohexyl-1-butyl methanesulfonate was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (734 mg, 95%) from 4-cyclohexyl-1-butanol (515 mg, 3.20 mmol) and methanesulfonyl chloride (540 mg, 4.80 mmol). 1H NMR (CDCl3, 300 MHz) δ0.83-0.90 (m, 2H), 1.13-1.25 (m, 5H), 1.34-1.44 (m, 2H), 1.60-1.76 (m, 8H), 2.99 (s, 3H), 4.21 (t, 2H, J=6.5 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH2:37]([NH2:41])[CH:38]([CH3:40])[CH3:39]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:30])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:41][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)CN
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CNCc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]-diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with isobutylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (160 mg, 65%).
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:36]/[O:37][CH3:38])/[C:17]([NH:19][CH:20]2[C:34](=[O:35])[N:22]3[C:23]([C:31]([OH:33])=[O:32])=[C:24](/[CH:27]=[CH:28]\[CH2:29][CH3:30])[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:36]/[O:37][CH3:38])/[C:17]([NH:19][CH:20]2[C:34](=[O:35])[N:22]3[C:23]([C:31]([O:33][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:32])=[C:24](/[CH:27]=[CH:28]\[CH2:29][CH3:30])[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC/C=C\C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h

Procedure:
Pivaloyloxymethyl iodide (162 mg, 0.67 mmole) was added at 0° C. to a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (197 mg, 0.45 mmole) and K2CO3 (93 mg, 0.67 mmole) in DMF (4 ml). The mixture was stirred at 0°-5° C. for 1 hour and diluted with ethyl acetate (30 ml). The dilute was washed with water and a saturated NaCl solution, dried over anhydrous MgSO4 and evaporated in vacuo. The residue was chromatographed on a silica gel column (5 g) with 1% methanol in CHCl3. The desired fractions were combined and concentrated in vacuo. The residue was dissolved in dioxane and lyophilized to afford 242 mg (97%) of the dioxane solvate of the title compound. Silica gel TLC: Rf 0.25 (1:1 CHCl3 -ethyl acetate). Estimated purity 85% (by HPLC). Mp. 90°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1.[H-].[Na+].CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:1])[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1
Reactant: CCc1cc(NC(CC)CCCCCCO)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [Cl-]
Agent: [H-]
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cc(NC(CC)CCCCCCOC)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
In 20 ml of anhydrous tetrahydrofuran was dissolved 0.56 g of dl-5-chloro-6-ethyl-4-(1-ethyl-7-hydroxyheptyl)aminopyrimidine, and 0.15 g of sodium hydride was added thereto. After stirring at room temperature for 30 minutes, 0.43 g of methyl iodide was added to the mixture, and the mixture was refluxed for 5 hours under stirring. After allowing to stand for cooling, an aqueous ammonium chloride solution was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=10:1) to give 0.19 g of the title compound as pale yellow oily liquid. nD23.0 1.5094.
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[C:19]1[NH:27][C:26]2[C:21](=[N:22][C:23](Cl)=[N:24][CH:25]=2)[N:20]=1>C(O)C1C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[C:19]1[NH:27][C:26]2[C:21](=[N:22][C:23]([O:1][CH2:19][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=3)=[N:24][CH:25]=2)[N:20]=1
Reactant: [OH-]
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc2nc(Cl)ncc2[nH]1
Agent: [K+]
Solvent: OCc1ccccc1
Product: COc1cc(OCc2ccccc2)ccc1-c1nc2nc(OCc3ccccc3)ncc2[nH]1
Temperature: 150 °C

Procedure:
An amount of 4.5 gm of powdered potassium hydroxide is dissolved in 70 ml of benzyl alcohol, and then 7.2 gm of 8-(2-methoxy-4-benzyloxy-phenyl)-2-chloro-purine are added. The mixture is heated to 150° C. for three hours, cooled, and filtered, the filtrate is mixed with ether, and the precipitate obtained is purified by chromatography on silica gel [eluant: methylene chloride/ethanol (100:2.5)].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])=[N:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:56][O:57][C:58]([NH:60][CH:61]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=1)[C:62](O)=[O:63])=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Li+].[OH-]>C(Cl)Cl.CO>[CH3:53][O:52][C:50](=[O:51])[NH:49][CH:45]([C:44]([N:40]1[CH2:41][CH2:42][CH2:43][CH:39]1[C:36]1[NH:35][C:34]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:62](=[O:63])[CH:61]([NH:60][C:58]([O:57][CH3:56])=[O:59])[C:65]6[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=6)=[N:17][CH:16]=5)=[CH:19][CH:20]=4)[CH:25]=3)[CH:30]=2)=[CH:38][N:37]=1)=[O:54])[CH:46]([CH3:47])[CH3:48]
Reactant: COC(=O)NC(C(=O)O)c1ccccn1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
To a solution of 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.0.14 mmol) in CH2Cl2 (1.3 mL) and MeOH (0.1 mL) was added HCl (in dioxanes, 4 M, 0.35 mL, 1.4 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness. The resulting solid was dissolved in DMF (1.5 mL). Methoxycarbonylamino-pyridin-2-yl-acetic acid (assumed 0.23 g, 1.1 mmol), HATU (0.06 g, 0.15 mmol) and DIPEA (0.12 mL, 0.69 mmol) were added. The solution was stirred at room temperature for 2 h. Additional HATU (0.13 g, 0.30 mmol) was added and the solution was stirred for 2 h. LiOH (2.5 M, 0.1 mL) was added and the reaction was concentrated. The crude oil was purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-pyridin-2-yl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.02 g, 22%). LCMS-ESI+: calc'd for C46H49N9O6: 823.38 (M+); Found: 824.88 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[N:16]#[C:17][NH2:18]>C(O)C.O>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[NH2:16][C:17]([NH2:4])=[NH:18]
Reactant: N#CN
Agent: Cc1ccc([N+](=O)[O-])cc1N
Solvent: O
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)N
Temperature: 0 °C

Procedure:
2-Methyl-5-nitroaniline (100 g, 0.657 mol) was dissolved in ethanol (250 ml), and 65% aqueous nitric acid solution (48 ml, 0.65 mol) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4 g) dissolved in water (41.4 g) was added thereto. The brown mixture was reacted under reflux for 24 hours. The reaction mixture was cooled to 0° C., filtered, and washed with ethanol:diethyl ether (1:1, v/v) to give 2-methyl-5-nitrophenyl-guanidine nitrate (2) (98 g). Rf=0.1 (Methylene chloride:Methanol:25% Aqueous ammonia=150:10:1). MS: 195.2 (M+H); 1H-NMR (DMSO-d6)=1.43 (s, 3H), 6.59 (s, 3H), 6.72-6.76 (d, 1H), 7.21-7.27 (m, 1H), 8.63-8.64 (br, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=O)=[CH:7][CH:6]=1.[CH3:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].Cl>O1CCCC1>[CH3:16][N:4]([CH3:3])[C:5]1[CH:6]=[CH:7][C:8]([C:9](=[O:11])[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:15]=1
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)c1ccc(N(C)C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=O)CC(=O)C(C)(C)C)cc1
Reaction time: 3 h
Yield: 70 %

Procedure:
Into a 100 ml three-necked flask equipped with a stirrer, a dropping funnel, a reflux condenser, and a nitogen-inlet tube, were charged 2.08 gm (31 mmol) of 60% sodium hydride and 5.0 gm (26 mmol) of ethyl 4-dimethylaminobenzoate. The mixture was dispersed in 40 ml of tetrahydrofuran and heated under refluxing. To the mixture was dropwise added 3.0 gm (30 mmol) of pinacolone and the mixture was heated with stirring for 3 hours. After cooling, 50 ml of 1N hydrochloric acid was added to the reaction mixture, and the organic layer was extracted twice with chloroform. The extract was thoroughly washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain an yellow oil. The oily substance was submitted to the Kugelrohr distillation 150° C., 1 mmHg, and crystallized from hexane to give 4.5 gm (yield: 70%) of yellow solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 67 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.25 mmol), 3-(trifluoromethyl)benzoic acid (57 mg, 0.25 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 318, the title compound (83 mg, 63%) was obtained as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[N:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1nc(-c2ccccc2)nc1N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)nn2C)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 22.8 %

Procedure:
To a solution of 1-methyl-3-phenyl-1,2,4-triazol-5-amine (320 mg, 2 mmol) in 10 mL of dry pyridine was added 427 mg of 4-methylbenzenesulfonyl chloride (224 mmol). The solution was stirred at room temperature under Argon. After 23 h, the pyridine was removed in vacuo and flashed off with toluene, and the residue was partitioned between 1M NaOH and EtOAc. The alkaline phase was made acidic and the flocculent solid was collected by filtration and taken up in acetone. The aqueous phase was extracted with EtOAc, washed with H2O and dried over Na2SO4. The acetone and the EtOAc phases were combined and evaporated in vacuo to give 0.15 g of a white solid which was taken up in hot HOAc (7 mL), diluted with water (4 mL), and seeded to give 80 mg of needles with mp 300-302° C.