Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=O.C(N(CC)CC)C.CN1CCOCC1.[Cl:29][C:30]1[CH:40]=[CH:39][C:33]2[NH:34][C:35]([CH2:37][NH2:38])=[N:36][C:32]=2[CH:31]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([NH:38][CH2:37][C:35]1[NH:34][C:33]2[CH:39]=[CH:40][C:30]([Cl:29])=[CH:31][C:32]=2[N:36]=1)=[O:7]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Reactant: NCc1nc2cc(Cl)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.61 g (7.50 mmol) of 3-chloro-4-methoxycarbonylbenzoic acid is dissolved in 40 mL of N,N-dimethylformamide and combined with 1.30 g (8.00 mmol) of N,N′-carbonyldiimidazole and stirred for 15 minutes at ambient temperature under a nitrogen atmosphere. Then 1.0 mL (7.5 mmol) of triethylamine, 1.5 mL (15 mmol) of N-methylmorpholine, and 1.69 g (7.75 mmol) of C-(5-chloro-1H-benzimidazol-2-yl)methylamine are added successively and stirred for a further 16 hours at ambient temperature under a nitrogen atmosphere. Then the reaction mixture is poured into 1 L of ice water, the precipitate is separated off by filtering, washed with a little demineralized water, and dried at 40° C. Finally the product is recrystallized from petroleum ether/ethyl acetate (2:1). Yield: 2.40 g (85%); Rf value: 0.58 (silica gel; dichloromethane/ethanol=9:1); C17H13Cl2N3O3 (378.22); mass spectrum: (M−H)−=376/78/80 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]2=[CH:12][C:11]=1[C:19]([OH:21])=O.CC1(C)[O:27][C@H:26]([CH2:28]NO)[CH2:25][O:24]1.C1C=CC2[N:40]([OH:41])N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:27][C@H:26]([CH2:25][OH:24])[CH2:28][O:41][NH:40][C:19]([C:11]1[CH:12]=[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@@H](CNO)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC[C@H](O)CO)c1cc2ccncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (90 mg, 0.23 mmol), O—(((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (35 mg, 0.23 mmol), HOBt (35 mg, 0.26 mmol), EDCI hydrochloride (50 mg, 0.26 mmol) and DIPEA (40 μL, 0.23 mmol) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was dissolved in hydrochloric acid in dioxane (2 mL, 4M) and stirred at RT for 10 minutes. The reaction mixture was concentrated in vacuo and the resultant residue subjected to reverse phase HPLC (gradient 20-80% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The product was dissolved in ethyl acetate (5 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow solid (22 mg, 20%). NMR (d6-DMSO, 400 MHz) 11.39 (1H, s), 8.68 (1H, s), 7.99 (1H, s), 7.49 (1H, dd, J=10.9, 1.8 Hz), 7.41 (2H, s), 7.14-7.17 (1H, m), 6.74 (1H, s), 5.92 (1H, t, J=8.9 Hz), 4.80-4.81 (1H, m), 4.53 (1H, s), 3.80 (1H, dd, J=9.6, 3.6 Hz), 3.56-3.66 (2H, m). LCMS (Method A): RT=7.57 min, M+H+=487.
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C=O.[C:17]([O-])(=[O:19])C.[Na+].[OH-].[Na+]>C(O)(=O)C.ClCCl>[OH:19][CH2:17][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1nc2ccccn2c1CO
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To a solution of ethyl imidazo[1,2-a]pyridine-2-carboxylate (5.0 g) in acetic acid (30 ml) were added 37% m formaldehyde (14 ml) and sodium acetate (8.0 g) at room temperature, and the reaction mixture was heated under reflux for 15 hr. The reaction mixture was cooled to room temperature and dissolved in dichloromethane. The mixture was adjusted to pH 8 with 10% aqueous sodium hydroxide solution at 0° C. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with dichloromethane-methanol (15:1) was concentrated under reduced pressure to give the object product (2.1 g).
Reaction SMILES: [CH2:1]([C:3]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=1)([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCN(CC)CC>C(Cl)Cl>[CH3:26][C:23]([CH3:25])([CH3:24])[C:22](=[O:27])[CH2:21][O:20][C:19]1[CH:28]=[CH:29][C:16]([C:3]([C:6]2[O:7][C:8]3[CH:14]=[CH:13][C:12]([O:15][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:11][C:9]=3[CH:10]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][C:18]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(O)ccc2o1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OS(C)(=O)=O)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(5-hydroxy-benzofuran-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (236 mg, 0.579 mmol) in CH2Cl2 (10 mL) was treated with methanesulfonic chloride (99 mg, 0.868 mmol) and Et3N (0.40 mL). The mixture was stirred at 0° C. for 30 min, and the reaction is quenched with MeOH (1.0 mL). The mixture is purified with EtOAc/Hexanes (25%) to obtain the title compound (260 mg, 92%). MS (ES) m/e: 504.2 (M+18).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29]C(=O)OC(C)(C)C)=[CH:28][C:22]=2[S:21](=[O:38])(=[O:37])[N:20]=1.Cl.O1CCOCC1>ClCCl>[NH2:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[N:20][S:21](=[O:38])(=[O:37])[C:22]=2[CH:28]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 93.5 %

Procedure:
To a solution of the product of Example 39-5 (407 g, 0.754 mol) in dichloromethane (550 mL) was added 4 M HCl in dioxane (760 mL, 3.04 mol) and the solution was mixed at RT for 3.5 h. The reaction was quenched by addition of ethyl acetate (1.5 L) and pH 7 phosphate buffer (1.7 L) and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (400 mL) and the combined organic layers were concentrated and chased with ethanol to a final volume of approximately 2500 mL. The product precipitated and was isolated by filtration and dried to give the title compound (309.7 g, 93.4%).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5](B3OC(C)(C)C(C)(C)O3)=[CH:6][CH:7]=[CH:8]2)=[N:3]1.Cl[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.CN(C=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:27][C:26]1[C:21]([C:5]2[C:4]3[C:9](=[CH:10][N:2]([CH3:1])[N:3]=3)[CH:8]=[CH:7][CH:6]=2)=[N:22][CH:23]=[C:24]([Cl:28])[CH:25]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: Cn1cc2cccc(B3OC(C)(C)C(C)(C)O3)c2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc2cccc(-c3ncc(Cl)cc3Cl)c2n1
Temperature: 65 °C

Procedure:
A mixture of 2-methyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (0.040 g, 0.15 mmol), 2,3,5-trichloropyridine (0.274 g, 1.50 mmol), (Ph3P)4Pd(0) (0.019 g, 0.017 mmol), 2 mL of DMF, and 2 mL of a 2 M K3PO4 solution was stirred at 65° C. for. 16 h then allowed to cool. Water (10 mL) was added, and the mixture was extracted with three 5 mL portions of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown solid. Column chromatography (0→50% EtOAc/hexanes) afforded of 7-(3,5-dichloro-pyridin-2-yl)-2-methyl-2H-indazole (7:R=Me; R′=H; Ar=3,5-dichloro-pyridin-2-yl; 0.042 g; 93%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[N:46][C:47]([Cl:50])=[CH:48][CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:44]([Cl:43])=[CH:49][CH:48]=[C:47]([Cl:50])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1nc(Cl)ccc1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nc(Cl)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,6-dichloro-2-(chloromethyl)pyridine and isolated as light-yellow gum. MS (m/e): 442.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:27][NH:28][CH3:29].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:14])[N:28]([CH3:29])[CH3:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
To 300 mg (1.49 mmol) azetidine-1,3-dicarboxylic acid mono-tert-butyl ester and 241.6 mg (1.79 mmol) 1-hydroxybenzotriazole hydrate in 20 mL DMF at 0° C., was added 364.5 mg (4.47 mmol) dimethylamine hydrochloride, and the reaction was stirred for 30 minutes. 342.8 mg (1.79 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, followed by 1.5 mL (8.94 mmol) DIPEA were added, and the reaction was stirred at room temperature for 3 hours. After evaporation of the solvent, the crude was diluted with 100 mL DCM. The organic phase was washed with a 2 M solution of HCl (2×50 mL), a saturated solution of NaHCO3 (2×50 mL), brine (2×50 mL), and dried over Na2SO4. After filtration, the solvent was evaporated to give the desired product which was used for the next step without further purification.
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:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27]CC4C=CC=CC=4)=[C:22]([Cl:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.[H][H].C(Cl)Cl.CO>C1COCC1>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([Cl:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1OCc1ccccc1
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1O
Reaction time: 12 h

Procedure:
200 mg 5% Rh on aluminium oxide were added to a solution of 800 mg (1.35 m mol) (R)-2-(4-benzyloxy-3-chloro-5-methyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 20 mL THF and the suspension was hydrogenated for 12 h at 40° C. and 3000 hPa hydrogen pressure. To complete the reaction the mixture was combined with 5 mL DCM/MeOH (1:1) and hydrogenated for a further 20 h at 40° C. and 3000 hPa. The catalyst was filtered off, the filtrate was evaporated down, the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.CCCCCC.C([Li])CCC.[C:21](#[N:23])[CH3:22].[CH3:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]2=[O:36])=[CH:28][CH:27]=1>C1COCC1.O>[C:21]([CH2:22][C:33]1([OH:36])[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:35]=2)[CH2:30][CH2:31][C:32]1([CH3:37])[CH3:38])#[N:23]
Reactant: COc1ccc2c(c1)C(=O)C(C)(C)CC2
Reactant: CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)(CC#N)C(C)(C)CC2
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a solution of 1,1,1,3,3,3-hexamethyldisilazane (4.74 g, 29.4 mmol) in THF (30 ml) was gradually added dropwise, at −78° C., a butyllithium hexane solution (1.56 M hexane solution, 18.8 ml, 29.4 mmol). The mixture was stirred for 10 minutes, to which was then added acetonitrile (1.41 ml, 26.9 mmol). The reaction mixture was stirred for further 20 minutes, to which was then added dropwise a solution of 7-methoxy-2,2-dimethyl-1-tetralone (5.0 g, 24.5 mmol) in THF (10 ml), followed by stirring for 2 hours. The reaction mixture was poured into water, and the organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (ethyl acetate:hexane=2:8) to give the above-titled compound (5.3 g, yield 88%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=2)[O:2]1.C(N(CC)CC)C.C[O-].[Na+]>CO>[N+:10]([C:6]1[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]([OH:2])=[C:8]([O:9][CH3:1])[CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Temperature: 0 °C

Procedure:
0.1 mol (21.2 g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added to a solution of 0.12 mol (16.8 ml) of triethylamine, 0.4 mol of sodium methylate (72 g of a 30% strength solution in methanol) and 60 ml of methanol. The mixture is heated for 10 minutes at the refluxing temperature of the methanol. After the mixture has been cooled to 0° C., the phenate of the expected product is drained. The phenate is dissolved in 300 ml of water at 60° C. The solution is filtered on paper in order to remove a resin. On cooling and neutralization of the filtrate with acetic acid, the expected product precipitates. After being dried, the 4,5-dinitro-2-methoxyphenol thereby obtained is recrystallized from isopropanol. It melts at 172° C. (literature: 177° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Br:13])[CH:7]=1)[CH3:2].I[CH2:16][CH3:17]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:16][CH3:17])=[C:8]([Br:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Reactant: CCI
Product: CCOC(=O)Cc1ccc(OCC)c(Br)c1

Procedure:
Prepared according to the procedure described in Example 123, Step 1, using the following starting materials: (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester and iodoethane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]2[C:15]=1[CH2:16][CH2:17][C@H:18]2[O:24][C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.[K].[OH:40]OS([O-])=O.[K+]>CO.O>[CH3:13][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][S:11]([CH3:12])=[O:40])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:14]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]2[C:15]=1[CH2:16][CH2:17][C@H:18]2[O:24][C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1
Reactant: O=S([O-])OO
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCSC)cc5C)ccc(F)c43)ccc21
Agent: [K+]
Agent: [K]
Solvent: CO
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCS(C)=O)cc5C)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(2-(methylthio)ethoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (230 mg) in methanol (4 mL) and water (2 mL) is added potassium peroxomonoslufate (Oxone®) (490 mg). The mixture is stirred for 1 hour at room temperature and then partitioned between dichloromethane and water. The organic phase is dried (MgSO4) and concentrated to give the crude product, which is directly in the next step. Yield: 220 mg; LC (method 4): tR=1.79 min; Mass spectrum (ESI+): m/z=553 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[CH3:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[C:18]=[S:19])=[CH:14][CH:13]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:17]([CH2:16][C:15]2[CH:20]=[CH:21][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:18]([S:19][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)=[N:9][N:8]=1
Reactant: NNC(=O)c1ccco1
Reactant: COc1ccc(CN=C=S)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: COc1ccc(Cn2c(SCc3ccc(C(F)(F)F)cc3)nnc2-c2ccco2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-furancarboxylic acid hydrazide, 4-methoxybenzyl isothiocyanate and 4-trifluoromethylbenzyl bromide as the starting materials. (M+H)+−446.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@@H:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@H:21]1[CH2:33][CH3:34])(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[CH2:33]([C@H:21]1[C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[CH2:25][CH2:24][NH:23][CH2:22]1)[CH3:34]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (3R,4R)-tert-butyl 4-((3-carbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate (288 mg, 0.618 mmol) in dichloromethane (5.0 ml) cooled to 0° C. was added trifluoroacetic acid (288 μl, 3.74 mmol). The reaction was allowed to warm to room temperature and stirring was continued for 1 hr. After removal of the solvent in vacuo, the residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate, water, and brine; dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (227 mg, 0.618 mmol, 99% yield) as a white solid. LCMS (Method K) m/z 368.4 ([M+H]+).
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:15][C:16](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:7]([N:15]=[C:16]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCNC(=N)N
Reactant: O=S(=O)(O)O
Agent: [Na]
Product: CCCCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in Example 18A, and using 2.3 g. of sodium, 22 g. of n-octylguanidine sulfate, and 15.5 g. of n-octyl isocyanate, there was obtained 26 g. of 1-n-octylamidino-3-n-octylurea having the structural formula ##STR69## as a white crystalline solid which melted at 60°-62° C. The solubility of this base in water at 25° C. was less than 0.25 percent. In 95 percent ethyl alcohol it was soluble to the extent of 5 percent; a precipitate formed when the 5 percent ethanolic solution was diluted with four volumes of water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[I:10]N1C(=O)CCC1=O.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+]>C(Cl)Cl>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([I:10])=[C:4]([CH:3]=1)[NH2:5]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=C1CCC(=O)N1I
Agent: F[B-](F)(F)F
Agent: [IH2+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(I)c(N)cc1Br
Yield: 83.6 %

Procedure:
A solution of 3-bromo-4-methylaniline (5.00 g, 26.9 mmol), N-iodosuccinimide (4.53 g, 20.2 mmol) and bis(pyridine)iodonium tetrafluoroborate (2.70 g, 7.26 mmol) in DCM (100 mL) was stirred at room temperature overnight. The mixture was diluted with DCM, washed sequentially with saturated aqueous NaHSO3 and water, and dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2% and 3%), to provide 5-bromo-2-iodo-4-methylaniline as a yellow solid (5.27 g, 63% yield). Mass spectrum m/z 312, 314 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J=0.6 Hz, 1H), 6.94 (s, 1H), 4.17-3.91 (br.s, 2H), and 2.25 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH2:29][CH3:30]>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:28][CH2:29][CH3:30])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2
Reactant: CCCBr
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(OC)ccc(-c2ccc3c(c2)COC3=O)c1OC
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and propyl bromide (103 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 32.8%).