Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[N:26]=[C:25]([NH2:36])[N:24]=1)[CH2:19][NH:18][CH2:17][CH2:16]2.C(N(CC)CC)C>C(#N)C>[NH2:36][C:25]1[N:24]=[C:23]([C:22]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:10])[CH2:19]3)=[CH:14][C:13]=2[F:12])[CH:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[N:26]=1
Reactant: CN1CCN(c2cc(-c3cc4c(cc3F)CCNC4)nc(N)n2)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCN(c2cc(-c3cc4c(cc3F)CCN(C(=O)Nc3ccc(Cl)cc3)C4)nc(N)n2)CC1
Reaction time: 0.5 h

Procedure:
1-Chloro-4-isocyanatobenzene (4.1 mg, 0.026 mmol) was added to a mixture of 4-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (15 uL, 0.11 mmol) in acetonitrile (0.3 mL). After 30 min., the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=496.1/498.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:25][CH2:26][CH2:27][Cl:28])[C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CCCCl)c3ccccc32)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of Compound 9 (1.7 g, 5.3 mM), as prepared in Example 9, bromopropylchloride (5.3 ml, 5.3 mM) and cesium carbonate (3.5 g, 10.6 mM) in acetone (60 ml) was stirred at reflux for 24 hours then cooled to RT. The acetone was removed under reduced pressure, the residue diluted with water (60 ml) and the aqueous mixture was extracted with ethyl acetate (2×60 ml). The combined ethyl acetate layers were dried over MgSO4 and evaporated in vacuo to give the product (2.1 g, 100%) as an oil that solidified on standing. m/z (MH+) 393.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)[O:15][C:16]=2[CH3:17])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(Br)cc3)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Yield: 69.7 %

Procedure:
Method D. Reaction of benzoate 28 (320 mg, 0.71 mmol) and 2 M NaOH (10 mL) in dioxane (10 mL) gave acid 29 (216 mg, 70%) as a white solid: mp (DCM)>310° C.; 1H NMR δ 13.15 (br s, 1 H, CO2H), 7.93 (br d, J=8.3Hz, 2H, H-2, H-6), 7.84 (ddd, J=8.6, 2.3, 1.7Hz, 2 H, H-2′, H-6′), 7.68-7.73 (m, 4 H, H-3, H-5, H-3′, H-5′), 4.70 (s, 2 H, CH2SO2), 2.19 (s, 3 H, CH3); MS m/z 437.0 (MH+, 100%), 439.0 (MH+, 100%). Anal. calcd for C18H14BrNO5S.½CH2Cl2: C, 47.08; H, 3.12; N, 2.89. Found: C, 47.09; H, 2.80; N, 2.99%.
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:29][C:30]1[C:31]([CH:40]=O)=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>C1COCC1.C(OC(C)C)(C)C>[Br:2]/[CH:3]=[CH:40]\[C:31]1[C:30]([CH3:29])=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2ccccc2nc1C=O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: Cc1cc2ccccc2nc1/C=C\Br
Temperature: -75 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a suspension of (bromomethyl)triphenylphosphonium bromide (3.06 g, 7.01 mmol) in 30 mL of THF, potassium tert-butoxide (0.78 g, 7.01 mmol) was added portionwise at −75° C. under argon. After completion of the addition, the mixture was stirred for 1 h a −75° C. Then, a solution of 3-methylquinoline-2-carbaldehyde (1 g, 5.84 mmol) in 20 mL of THF was added. The reaction mixture was stirred for 5 h at −75° C. and then allowed to warm up to room temperature overnight. For work-up, the reaction mixture was diluted with diisopropyl ether (1:1) and the precipitate formed was sucked off. The filtrate was concentrated and triturated in diisopropyl ether. The precipitate was sucked off. The filtrate was purified by column chromatography (normal phase, eluent: cyclohexane/EA) to give 492.5 mg (34%) of the title compound as yellow solid. LC-MS: m/e 248.0 (M+H)+; Rt 1.561 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][P:18](=[O:27])([O:23][CH:24]([CH3:26])[CH3:25])[O:19][CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH:24]([O:23][P:18]([CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:27])[O:19][CH:20]([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(COc1ccc(C=O)cc1)OC(C)C
Reaction time: 17 h
Yield: 26.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (152 mg, 1.25 mmol) in DMF (20 mL) was added potassium carbonate (223 mg, 1.62 mmol), followed by diisopropyl bromomethylphosphonate (484 mg, 1.87 mmol). The mixture was heating in DMF at 90° C. under stirring for 17 hours. After evaporation of DMF under reduced pressure, 100 mL of water were added and the mixture was extracted with ethyl acetate (3*200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate (5:5)) to give 98.2 mg of an oil (26% yield). 1H NMR (250 MHz, CDCl3): δ 1.33 (t, J=6.0 Hz, 12H), 4.25 (d, J=10.2 Hz, 2H), 4.82 (q, J=6.0 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 9.87 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 25.4 (dd, J=12.7; 3.4 Hz), 64.0 (d, J=171.0 Hz) 73.3 (d, J=6.2 Hz), 116.3, 132.2, 133.3, 164.8 (d, J=13.4 Hz), 192.0. 31P NMR (202 MHz, CDCl3): δ 16.0
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:42](OCC)=[O:43])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[N:33]=3)=[CH:25][CH:24]=2)=[CH:20][CH:21]=1)=O)C>C(O)C>[O:43]=[C:42]1[NH:5][C:3](=[O:4])[NH:2][C:9](=[O:8])[C:11]21[N:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[O:30][CH:31]=[C:32]([C:34]5[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=5)[N:33]=4)=[CH:25][CH:24]=3)=[N:18][CH:17]=1)[CH2:13][CH2:14][CH2:15]2
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(-c3nc(-c4ccc(C#N)cc4)co3)cc2)nc1
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: N#Cc1ccc(-c2coc(-c3ccc(Oc4ccc(N5CCCC56C(=O)NC(=O)NC6=O)cn4)cc3)n2)cc1
Temperature: 80 °C
Yield: 27.8 %

Procedure:
To a flame dried flask was added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution was stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) was added and the solution was stirred at room temperature for 5 minutes. 1-(6-{4-[4-(4-Cyano-phenyl)-oxazol-2-yl]-phenoxy}-pyridin-3-yl)-pyrrolidine-2,2-dicarboxylic acid diethyl ester (300 mg, 0.54 mmol) was added as a solid and the solution was heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction was then quenched by the addition of 10 mL water and 1N hydrochloric acid was added to adjust the pH to 5. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce 290 mg of crude product. This material was chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40 s column) to provide 78 mg of a product which required further purification. Reverse-phase HPLC on a portion of this material provided 15 mg of the title compound as a white solid. MS m/z: ESI+ 521.1 (M+H)+; ESI− 519.3 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([O:20][CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=2[O:20][CH3:21])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1cc(F)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Temperature: 90 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
A batch with 2,4-dichloro-5-fluoropyrimidine (200 mg; 1.20 mmol; Aldrich Chemical Company Inc.), (4-fluoro-2-methoxyphenyl)boronic acid (224 mg; 1.31 mmol; Aldrich Chemical Company Inc.) and tetrakis(triphenylphosphin)palladium(0) (138 mg; 0.12 mmol) in 1,2-dimethoxyethane (3.6 mL) and 2 M solution of potassium carbonate (1.8 mL) was degassed using argon. The batch was stirred under argon for 16 hours at 90° C. After cooling the batch was diluted with ethyl acetate and washed with brine. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate 1:1) to give the desired product (106 mg; 0.41 mmol).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:14]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=O)=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[N:11]=[C:26]([C:25]4[CH:29]=[CH:30][C:22]([C:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[O:21])=[CH:23][CH:24]=4)[O:13][N:12]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: N=C(NO)C1CCN(C2CC2)CC1
Product: O=C(c1ccccc1)c1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-cyclopropyl-N-hydroxypiperidine-4-carboxamidine and 4-benzoylbenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][CH:6]([OH:14])[CH2:7][NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11].[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][CH:6]([OH:14])[CH2:7][NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][NH:11][C:23]1[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1ccccc1OCC(O)CNC(C)(C)CN
Solvent: c1ccccc1
Product: Cc1ccccc1OCC(O)CNC(C)(C)CNc1ccc(Cl)nn1
Temperature: 110 °C
Yield: 67.8 %

Procedure:
To 1.58 g of 1-(2-methylphenoxy)-3-(1,1-dimethyl-2-aminoethylamino)-2-propanol heated at 110° C. in an oil bath with stirring was added 934 mg of 3,6-dichloropyridazine little by little. After heating at 110° C. for 1 hour, the reaction mixture was dissolved in benzene, and extracted with 1N hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 1.55 g of 1-(2-methylphenoxy)-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinylamino)ethylamino]-2-propanol as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14]>C(O)C.O>[C:13]([NH:17][C:18]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4])=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N=C=S
Reactant: COc1ccc([C@@H](N)CO)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc([C@H](CO)NC(=S)NC(C)(C)C)cc1

Procedure:
The process is performed under the conditions of Example 1, starting with 5.78 g of (2R)-2-amino-2-(4-methoxyphenyl)-1-ethanol and 6.48 cm3 of tert-butyl isothiocyanate in 73 cm3 of ethanol for 17 h 30 minutes at a temperature in the region of 20° C. The reaction mass is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and the solid residue obtained is then ground in 45 cm3 of water, filtered and washed with twice 20 cm3 of water and twice 25 cm3 of diethyl ether. The crystals are dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 45° C. 4.9 g of N-(tert-butyl)-N′-[(1R)-1-(4-methoxyphenyl)2-hydroxyethyl]-thiourea are obtained in the form of a white solid. (Rf=0.60 in ethyl acetate, on a Merck 60F254R silica plate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a cooled solution of 4-methoxy-2-nitroaniline (25 g; 0.15 mol) in pyridine (370 ml), ethyl chloroformate (17.8 ml; 0.18 mol) was added dropwise. The mixture was refluxed for 10 hours, then cooled and poured into ice-water. The precipitated solid was collected and purified by flash chromatography (silica gel, eluent: hexane/diethyl ether 85:15) to yield the title compound as a yellow solid. 7.3 g; m.p. 56-57° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH:9]1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]1[N:18]2[CH:19]([CH3:30])[C:20](=[O:29])[NH:21][N:22]=1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][CH:28]=2)[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:30])[C:20](=[O:29])[NH:21][N:22]=2)[CH:9]1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(=O)CN1C(=O)OC(C)(C)C
Reactant: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1C(Nc2ccc3c(c2)N2C(=NNC(=O)C2C)CO3)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
To a mixture of 2-methyl-3-oxo-azetidine-1-carboxylic acid tert-butyl ester (crude, 1.17 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was added 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #2, Step E, 0.050 g, 0.215 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h then NaBH3CN (0.068 g, 1.076 mmol) was added. The mixture was stirred at ambient temperature overnight then concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 24) to give 2-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.016 g, 18%). LC/MS (Table 1, Method 5) Rt=1.087 min; MS m/z: 424 [M+23]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CN1CCCC1=O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[N:11]=[C:4]2[CH:3]=[C:2]([O:24][C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=1
Reactant: Cc1ccc(O)cc1
Reactant: Nc1cc(Br)cc2nc(-c3ccco3)nn12
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2cc(N)n3nc(-c4ccco4)nc3c2)cc1

Procedure:
A mixture of 1 eq. 7-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. p-methyl-phenol and a catalytic amount of CSCO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 306 M+H+ (100%).
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13]C)[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].B(Br)(Br)Br>ClCCl>[C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COc1cccc(C2(C#N)CCC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CC1(c2cccc(O)c2)CCC1
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a stirred solution of 1-cyano-1-(3-methoxyphenyl)cyclobutane (1.93 g, 10 mmol) in dry dichloromethane (50 ml) was added a 1.0M solution of boron tribromide in dichloromethane (22 ml, 22 mmol) at 0° C. and the mixture stirred for 30 min at the same temperature, then overnight at room temperature. The reaction mixture was quenched by the addition of water (100 ml) and extracted with dichloromethane (50 ml×2). The organic phase was washed with brine (50 ml), dried (MgSO4) and concentrated in vacuo to afford 1.70 g (100%) of the titled compound as a clear brown oil.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1.Cl>C(O)C.O.[Fe]>[F:13][CH:2]([F:1])[O:3][C:4]1[N:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)F)nc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(OC(F)F)nc1
Yield: 103.9 %

Procedure:
2-Difluoromethoxy-5-nitro-pyridine obtained in Step A (1.6 g) was treated with iron (5 g) and concentrated hydrochloric acid (0.23 ml) in ethanol (15 ml) and water (2.5 ml) at 80° C. for 20 minutes. Filtration over Celite® and evaporation of the solvent afforded 6-difluoromethoxy-pyridin-3-yl-amine (1.4 g) as an orange solid. 1H NMR (400 MHz, CDCl3) 3.51 (br s, 2H), 6.89 (d, 1H), 7.23 (d, 1H), 7.44 (dd, 1H), 7.80 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=2[CH2:20][NH:21][C:22](=[O:32])[CH2:23][P:24](=[O:31])([O:28]CC)[O:25]CC)[CH:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9].C[Si](Br)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=2[CH2:20][NH:21][C:22](=[O:32])[CH2:23][P:24](=[O:25])([OH:28])[OH:31])[CH:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9]
Reactant: CCOP(=O)(CC(=O)NCc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CNC(=O)CP(=O)(O)O)cc1Cl
Reaction time: 45 h

Procedure:
Compound 175 (0.04 g, 0.075 mmol) was dissolved in dry CH2Cl2 (0.5 mL) under an argon atmosphere. Trimethylsilyl bromide (0.1 mL, 0.75 mmol) was added and the solution was kept at room temperature for 45 h. The solution was concentrated in vacuo and then co-concentrated with MeOH three times. This afforded the title compound as an orange oil.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2.[OH-].[Na+].[BrH:18]>O>[Br:18][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2
Reactant: Br
Reactant: Nc1cccc2cnccc12
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1cccc2cnccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Add a solution of sodium nitrite (9.6 g, 139 mmol) in water (50 mL) cautiously to 5-aminoisoquinoline (20 g, 139 mmol) in hydrobromic acid (48%, 100 mL) at 0° C. Transfer this mixture to a vessel containing CuBr (25 g, 174 mmol) in hydrobromic acid (48%, 200 mL) at 75° C. After complete addition, stir the mixture at 75° C. for one hour, cool to room temperature and stir overnight. Place the mixture in an ice bath, add ice to the reaction mixture, and then add sodium hydroxide aqueous solution (20%, 250 mL). Filter the slurry and extract the filtrate with diethyl ether. Combine the solid and the extract sonicate for one hour in chloroform. Filter the suspension through a plug of Celite™, and concentrate the filtrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with chloroform.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:13])[S-:12].C([NH+](CC)CC)C.C([O:24][CH2:25][C:26]([CH2:28]Cl)=O)(=O)C.Cl>C(O)C>[OH:24][CH2:25][C:26]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:12])[S:13][CH:28]=1
Reactant: CC(=O)OCC(=O)CCl
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: CCO
Product: OCc1csc(=S)n1-c1ccc(F)c(F)c1F
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (81.2 g) prepared in the same manner as in Reference Example 1 was added to ethanol (800 ml) and thereto 1-acetoxy-3-chloroacetone (37.7 g) was added dropwise at 5° to 7° C. with stirring over a period of 20 minutes. After stirring the mixture for 50 minutes, 10% solution of hydrogen chloride in ethanol (240 ml) was added and the mixture was refluxed for 3 hours. After the solvent was distilled off under the reduced pressure, cooled water was added to the residue and resultant was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from a mixed solvent of hexane - ethyl acetate to give the title compound (59 g) as pale yellow crystals. The compound had physical properties identical to those of 4-hydroxymethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione prepared in the above Reference Example 18.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])[NH2:6].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C=O>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])[NH:6][C:22](=[O:24])[CH3:23]
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCNC(=N)N)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 148.5 %

Procedure:
To a solution of 2.0 gm (8.9 mMol) arginine methyl ester hydrochloride and 1.5 gm (14.8 mMol) triethylamine in dimethylformamide (150 ml) was added 776 mg (7.4 mMol) acetic anhydride dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour and then the volatiles removed under reduced pressure. The residue was purified using silica gel chromatography, eluting with ethyl acetate containing 0-50% methanol, to give N-acetyl arginine methyl ester as a crystalline solid (2.53 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[NH:19][C:20]1[NH:21][CH2:22][CH2:23][N:24]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:23][CH2:22][N:21]=[C:20]2[NH:19][C:13]2[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[O:8])=[CH:4][N:3]=1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(c1ccc(O)nc1)N1CCN=C1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3.25 g (22.9 millimoles) of 6-hydroxy-nicotinic acid are dissolved in 600 ml of absolute tetrahydrofuran and 60 ml of absolute hexamethylphosphorotriamide, 3.8 g (22.9 millimoles) of N,N'-carbonyl-diimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 5.3 g (11.0 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute tetrahydrofuran is then added dropwise and the mixture is left to stand overnight. The solvents are then stirred off under reduced pressure on a rotary evaporator, the residue is treated with 50 ml of 0.5% strength sodium bicarbonate solution and the mixture is decanted. 3.2 g of semi-crystalline, crude (6-hydroxynicotinoyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained, which on recrystallization from isopropanol give a pure product of melting point 256°-258° C.