Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12](=[S:14])=[S:13]>C(O)C>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[S:13])[SH:14]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: S=C=S
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=S)S
Reaction time: 8 h

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (10.2 g) in ethanol (75 ml) was added slowly, with stirring, to carbon disulphide (200 ml). The mixture was set aside overnight at room temperature and the solid formed was collected and recrystallised from aqueous isopropyl alcohol to afford N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]dithiocarbamic acid (9.8 g)., m.p. 127-129°.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(OCC)(=O)[CH2:18][C:19]([O-:21])=[O:20].[Na]>>[N+:14]([C:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH2:18][C:19]([OH:21])=[O:20])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Na]
Product: O=C(O)Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
2,4,6-Trinitrophenylacetic acid (mp 159°-160° C.) is prepared from 1-chloro-2,4,6-trinitrobenzene and ethyl malonate in the presence of metallio sodium in accordance with a procedure by M. Kimura in J. Pharm. Soc. Jpn., 73, 1216 (1953).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:13]3[C:20]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=4[CH2:18][N:17]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:16](=[O:31])[CH2:15][N:14]3[C:32]=2[CH:33]=1)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.O.[SiH](CC)(CC)CC>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]2[C:13]3=[C:12]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[C:11]4[CH:10]=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:33][C:32]=4[N:14]3[CH2:15][C:16](=[O:31])[N:17]([CH2:26][CH2:27][N:28]([CH3:29])[CH3:30])[CH2:18][C:19]=2[CH:24]=1
Reactant: CN(C)CCN1Cc2cc(Cl)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2CC1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C)CCN1Cc2cc(Cl)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl-3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 9, 1 eq) in a mixture of TFA:H2O:Et3SiH (95:3:2) (0.03 M) was stirred at RT for 1 h. Volatiles were removed in vacuo and the residue purified by RP-HPLC to afford the title compound; MS (ES+) m/z 494 (M+H)+.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][C:16]([CH3:18])=O)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:28])=O>O.C1(C)C=CC=CC=1>[NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH:15]=[C:16]([Cl:28])[CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1cc(C)nc(Nc2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Cl)=Cc1cc(C)nc(Nc2ccccc2)n1
Yield: 94.3 %

Procedure:
Into a 500 ml reaction flask equipped with a stirrer, a thermometer, a condenser and a dropping funnel, 48.3 g (0.2 mol) of 2-anilino-4-methyl-6-acetonyl-pyrimidine and 200 ml of toluene were charged and dissolved. To this solution, 61.4 g (0.4 mol) of phosphorus oxychloride was dropwise added from the dropping funnel. The mixture was reacted at a temperature of from 88° to 90° C. for further 6 hours. The reaction mixture was cooled and put into a water/toluene solution and subjected to liquid separation. The toluene layer was washed with an aqueous sodium carbonate solution and then with water. The toluene layer was concentrated to obtain 49 g of 2-anilino-4-methyl-6-(2-chloropropen-1-yl)pyrimidine having a melting point of from 63° to 66° C. The yield was 94.4%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.FC(F)(F)S(O[CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(=O)=O.Cl>C1C=CC=CC=1.C(COC)OC>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH2:24][C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=S(=O)(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: COCCOC
Product: Oc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
First, 3.0 g of 60% sodium hydride and 120 ml of dehydrated dimethoxyethane were put in an argon-replaced 300 ml flask. Then, 9.93 g of 4,4′-dihydroxybiphenyl was added while icing, and stirred at room temperature for two hours. The reaction solution was cooled again to −60° C., and 28.7 g of 2-(perfluorobutyl)ethyl trifluoromethanesulfonate was dropped into the reaction solution. After the resultant reaction solution was left to resume room temperature, it was stirred for 12 hours. After the reaction, dilute hydrochloric acid and benzene were added to the reaction solution to separate an organic layer. The organic layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:benzene/ethyl acetate=9/1), and recrystallized from toluene to obtain 6.26 g (Y: 27.1%) of 4-hydroxy-4′-[2-(perfluorobutyl)ethyloxy]biphenyl. The purity of the resultant compound was 98.4% as measured by GC.
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[OH-].[Na+]>CO.O1CCCC1>[O:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: COC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 122.2 %

Procedure:
To a solution of 275 mg of methyl 3-benzo[b]furan-2-yl-1H-5-indazolecarboxylate in 3 ml methanol and 3 ml tetrahydrofuran was added 1.5 ml of 5 N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for five days. After removing the solvent by distillation, the residue was added with 9 ml of 1 N hydrochloric acid, and the mixture was extracted with 200 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 320 mg of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:3]([Cl:8])=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[C@H:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[NH:23][CH:22]=1)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[C@H:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:2]3[C:3]([Cl:8])=[N:4][N:5]([CH3:7])[CH:6]=3)[CH:28]=2)[NH:23][CH:22]=1)[CH3:20]
Reactant: Cn1cc(Br)c(Cl)n1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cn(C)nc3Cl)cc12
Temperature: 100 °C

Procedure:
A solution of 4-bromo-3-chloro-1-methyl-1H-pyrazole (0.0136 g, 0.0697 mmol), 3-[(S)-1-(2-chloro-3-fluoro-6-methoxy-phenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.020 g, 0.046 mmol), potassium carbonate (0.0193 g, 0.139 mmol) and Pd(PPh3)4 (5.37 mg, 0.00464 mmol) in previously degassed 4:1 dioxane:water (1.0 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. This was purified by Gilson HPLC. The combined fractions were concentrated in vacuo resulting in the title compound as off-white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.3 Hz, 3H), 3.60-3.71 (m, 2H), 3.87 (s, 3H), 5.11 (q, J=7.1 Hz, 1H), 6.89 (dd, J=4.2, 9.0 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 7.34 (d, J=1.3 Hz, 2H), 7.72-7.77 (m, 2H), 7.80 (s, 2H), 8.20 (d, J=1.8 Hz, 2H). MS (ES+): m/z 419.05, 421.03 (76, 24) [MH+]. HPLC: tR=1.84 min (polar—3 min, TOF)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([Si:15]([CH3:36])([CH3:35])[O:16][CH:17]1[CH2:22][CH:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C:19]([OH:34])([C:31]([O-])=[O:32])[CH2:18]1)([CH3:14])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH:21]1[CH2:22][CH:17]([O:16][Si:15]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:35])[CH3:36])[CH2:18][C:19]([OH:34])([CH2:31][OH:32])[CH2:20]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(O[Si](C)(C)C(C)(C)C)CC(O)(C(=O)[O-])C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CC(O[Si](C)(C)C(C)(C)C)CC(O)(CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
Diisobutyl aluminum hydride (6 mL, 9 mmol, 1.5M in toluene) was added to a solution of the ester 14 (0.56 g, 1.3 mmol) in anhydrous toluene (20 mL) at -78° C. After 20 min the solution was warmed to 0° C. and stirred for 1 h. The solution was slowly quenched by adding to a stirred 0° C. solution of 2N potassium sodium tartrate. Ethyl acetate was added and the organic layer separated and the water phase extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The material was further purified by column chromatography on silica gel with ethyl acetate hexane mixtures to give the diol 15 (0.3 g, 59%) 1H NMR (CDCl3, 500 MHz) δ0.11 (s, 3H), 0.12 (s, 3H), 0.14 (s, 3H), 0.16 (s, 3H), 0.90 (s, 9H), 0.91 (s, 9H), 1.28 (dd, 1H), 1.43 (dd, 1H), 2.00 (ddd, 3H), 2.16 (dd, 1H), 3.33 (dd, 1H), 3.40 (dd, 1H), 4.34 (m, 2×1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19](N(OC)C)=[O:20]>C1COCC1>[Cl:16][C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19](=[O:20])[CH2:15][C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: CON(C)C(=O)c1ccccc1Cl
Reactant: Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To lithium diisopropyl amide (6.5 mL, 1.6 M in cyclohexane, 10.4 mmol) in THF (20.0 mL) at −78° C. was added a solution of 4-picoline (1.07 g mL, 11.5 mmol) in THF (10.0 mL) dropwise. The dry ice bath was removed. The reaction mixture was stirred at 0° C. for 30 minutes, and cooled back to −78° C. A solution of 2-chloro-N-methoxy-N-methylbenzamide (21) (2.39 g, 12 mmol) in THF (10.0 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. White solid was filtered off and dissolved in ethyl acetate. The organic phase was washed with water, brine, dried over dried magnesium sulfate and concentrated under vacuum to give 1-(2-chlorophenyl)-2-(pyridin-4-yl)ethanone (22) (1.09 g, 4.7 mmol, 47%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:32]1([C:38](Cl)=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:38](=[O:39])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(N)n3)cc2C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(NC(=O)c4ccccc4)n3)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(2-Amino-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester and Et3N (4 eq.) in dry THF, PhCOCl (2 eq.) was added and the mixture was stirred at room temperature under argon overnight. Thus NaOH(1N) was added; after 30′ the solvent was evaporated and the residue was dissolved in water and the aqueous phase was extracted with AcOEt (2×). The organic phase was then washed with aq. NH4Cl and dried over Na2SO4. After solvent evaporation the crude product was purified by flash chromatography (CH2Cl2:MeOH 97:3) to give the pure product as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:21]=[CH:20][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:22][N:2]([CH3:1])[S:3]([C:6]1[CH:21]=[CH:20][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(Cc2ccc(N)cc2)cc1
Yield: 102.2 %

Procedure:
4-(4-Dimethylaminosulfonylbenzyl)-nitrobenzene (311 mg) was dissolved in ethyl acetate and hydrogenated at 40 psi using a 10% palladium on carbon catalyst for 2 hours. The mixture was filtered, and solvents evaporated to give 4-(4-dimethylaminosulfonylbenzyl)-phenylamine as a white solid (288 mg, 99%).
Reaction SMILES: [I:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].F[C:13]1[C:21]2[CH:20]=[C:19]([C:22]#[N:23])[S:18][C:17]=2[C:16](O)=[CH:15][CH:14]=1>C1COCC1>[I:1][CH2:2][CH2:3][C@H:4]([O:5][C:16]1[C:17]2[S:18][C:19]([C:22]#[N:23])=[CH:20][C:21]=2[CH:13]=[CH:14][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1cc2c(F)ccc(O)c2s1
Reactant: O[C@H](CCI)c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cc2cccc(O[C@@H](CCI)c3ccccc3)c2s1
Reaction time: 18 h
Yield: 90.5 %

Procedure:
4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenyl phosphonium (383 mg, 0.93 mmol) was added in one portion to a stirred solution of (R)-3-iodo-1-phenyl-1-propanol (Ref: Molander, Gary A.; Shakya, Sagar R.; J. Org. Chem.; EN; 59; 12; 1994; 3445–3452.) (182 mg, 0.69 mmol) and 4-fluoro-7-hydroxy-benzo[b]thiophene-2-carbonitrile (112 mg, 0.58 mmol) in dry THF (12 mL) under an inert atmosphere on nitrogen. The resulting suspension was allowed to stir for a further 18 hrs before the solvent was removed in vacuo. The residue was purified by flash chromatography with a gradient of 0–4% diethyl ether in hexane to give the title compound as a colourless oil (0.22 g, 88%); δH (300 MHz, CDCl3) 7.83 (1H, s, 3-ArH), 7.36–7.12 (5H, m, ArH), 6.85–6.75 (1H, m, ArH), 6.65–6.57 (1H, m, ArH), 5.40–5.30 (1H, m, CHO), 3.47–3.28 (1H, m, CH2CHHI), 3.23–3.12 (1H, m, CH2CHHI), 2.60–2.42 (1H, m, CHHCH2I) and 2.34–2.19 (1H, m, CHHCH2I).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][CH:20]([CH3:28])[C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])(=[O:3])[NH2:2].[OH-].[K+]>CO.O>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][CH:20]([CH3:28])[C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])(=[O:3])[NH2:2]
Reactant: COC(=O)C(C)(C)C(C)Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)C(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Methyl 3-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-2,2-dimethylbutanoate (0.2 g, 0.526 mmol) was taken in a mixture of MeOH (30 mL) and water (3 mL). Potassium hydroxide (0.442 g, 7.89 mmol) was added and the reaction mixture was heated at reflux overnight. After completion of the reaction, MeOH was concentrated under reduced pressure and the crude mass was cooled to 0° C. and acidified to pH 5 by stirring in 1.5N HCl solution for 15 min. An off white colored solid separated out which was filtered and dried under vacuum to give the title compound (0.16 g, 83.3% yield). 1H NMR (400 MHz, DMSO-d6): δ 1.22-1.23 (d, J=7.2 Hz, 6H), 1.31-1.32 (d, J=6.4 Hz), 4.70-4.75 (m, 1H), 7.26-7.29 (t, J=6.8 Hz, J=7.2 Hz, 2H), 7.40-7.44 (t, J=7.6, J=7.6 Hz, 2H), 7.78-7.80 (d, J=7.6 Hz, 2H), 8.20-8.23 (d, J=13.2 Hz, 2H), 10.95-10.98 (d, J=9.6 Hz, 1H), 12.45 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH:17]C(=O)C(F)(F)F)[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]([CH3:25])([CH3:24])[CH2:5]1)(=[O:3])[CH3:2].CO.C(=O)(O)[O-].[Na+]>O>[C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH2:17])[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]([CH3:25])([CH3:24])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)Oc2cc([N+](=O)[O-])c(NC(=O)C(F)(F)F)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)N1CC(C)(C)Oc2cc([N+](=O)[O-])c(N)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 85.1 %

Procedure:
A mixture of 21.6 g 4-acetyl-3,4-dihydro-2,2-dimethyl-7-nitro-6-trifluoroacetylamino-2H-1,4-benzoxazine, 500 ml methanol, 50 ml water and 10.5 g sodium bicarbonate was stirred at room temperature for seven hours, the reaction mixture was poured into 1.5 l ice water, and the precipitate which separated out was collected by filtration and recrystallized from 450 ml ethanol, giving 13.5 g of 4-acetyl-6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazine.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[CH2:20][C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][C:13]2=[O:23])[CH2:3]1.Cl[C:25]1[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=1>>[O:22]=[C:21]1[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:4]2[CH2:5][CH2:6][N:7]([C:25]3[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:2]([CH3:1])[CH2:3]2)[C:13](=[O:23])[CH2:14][C:15]2([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:20]1
Reactant: N#Cc1cccnc1Cl
Reactant: CC1CN(CCCCN2C(=O)CC3(CCCC3)CC2=O)CCN1
Product: CC1CN(CCCCN2C(=O)CC3(CCCC3)CC2=O)CCN1c1ncccc1C#N

Procedure:
The product of Procedure 6 is allowed to react with 2-chloro-3-cyanopyridine as described in Procedures 2 and 5 to yield this substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[Cl:13].Cl[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[N:1]1[CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]1
Reactant: CC(C(=O)O)c1ccc(N)c(Cl)c1
Reactant: OC(CCl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(N2CCC(O)C2)c(Cl)c1

Procedure:
To the solution of 2.0 g of α-(4-amino-3-chlorophenyl)-propionic acid in 20 ml of ethanol, 1.4 g of 1,4-dichloro-2-butanol are added, followed by 4 g of potassium carbonate while stirring. The mixture is stirred for 4 hours at the steam cone and evaporated under reduced pressure. The residue is taken up in water, the solution acidified with N hydrochloric acid to a pH of 5.5 and extracted with diethyl ether. The extract is dried, filtered and evaporated, to yield the α-[3-chloro-4-(3-hydroxypyrrolidino)-phenyl]-propionic acid of the formula ##SPC9##
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]>C1C=CC=CC=1>[SH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]=[CH:8][C:7]1[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:17]
Reactant: Nc1ccccc1S
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C=Nc2ccccc2S)c(O)c(C(C)(C)C)c1
Temperature: 100 °C

Procedure:
A solution of 3,5-di-tert-butyl-2-hydroxybenzaldehyde (6.79 g, 0.03 mol) in benzene (50 mL) was added to a solution of 2-Aminothiophenol (3.63 g, 0.03 mol) in benzene (50 mL) and heated at 100° C. in closed glass vessel for 3 days. The solvent was removed in vacuum. The product was obtained as a yellow oil in a quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:34]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:34])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccc(C(C)(C)C)cc3n2)c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-butylbenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-butylbenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 6.274 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-tert-butylbenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-butylbenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-butylbenzotriazole was 6.8 g (84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[Cl:36][CH:37]([Cl:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:13])=[O:14])[CH2:38][CH:37]([Cl:47])[Cl:36])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Reactant: O=S(=O)(OCC(Cl)Cl)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1nccnc1N(CC(Cl)Cl)S(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 29 %

Procedure:
To a solution of 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester (Example 2.1) (0.5 g) in acetonitrile (5 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.71 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before dropwise addition of 2,2-dichloroethyltrifluoromethanesulfonate (0.603 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (eluent: iso-hexane/ethyl acetate 4:1) to give 3-[(2-chloro-5-trifluoromethyl-phenylmethanesulfonyl)-(2,2-dichloro-ethyl)-amino]-pyrazine-2-carboxylic acid methyl ester as a white solid (0.179 g). 1H-NMR (400 MHz, CDCl3): 8.61 (d, 1H), 8.51 (d, 1H), 7.73 (s, 1H), 7.53-7.59 (m, 2H), 5.99-6.02 (m, 1H), 4.71 (s, 2H), 4.58 (d, 2H), 4.02 (s, 3H) ppm.