Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:7]2[C:14]3[CH2:15][CH2:16][CH2:17][C:13]=3[S:12][C:8]2=[N:9][C:10]=1[CH3:11].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]OC[CH2:37]1.ICCC>CN(C=O)C>[CH3:11][C:10]1[N:9]=[C:8]2[S:12][C:13]3[CH2:17][CH2:16][CH2:15][C:14]=3[C:7]2=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[C:5]=1[CH:4]([CH2:37][CH2:36][CH3:40])[C:3]([O:2][CH3:1])=[O:25]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 58.6 %

Procedure:
This compound was prepared according to the procedure C from methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.189 g; 0.538 mmol), LHMDS 1N in THF (0.594 mL; 0.594 mmol), 1-iodopropane (0.080 mL; 0.823 mmol) in DMF (8 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.124 g (59%) of the title compound as a yellow solid.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:22][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[C:17]([CH3:20])=[CH:16][C:15]([CH3:21])=[N:14]3)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:21][C:15]1[CH:16]=[C:17]([CH3:20])[N:18]2[C:13]([N:14]=1)=[C:12]1[CH2:22][NH:9][CH2:10][C:11]1=[N:19]2
Reactant: Cc1cc(C)n2nc3c(c2n1)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C)n2nc3c(c2n1)CNC3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 4M solution of HCl in 1,4-dioxane (3.34 mL; 91.5 mmol; 29.9 eq.) was added to a solution of 5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (900 mg; 3.06 mmol; 1 eq.) in 1,4-dioxane (8 mL) and the resulting mixture was stirred at room temperature for 16 hours then concentrated in vacuo to afford the title compound (740 mg, quantitative) as a yellow solid which was used without further purification. UPLC/MS: (MS+) 189.2 ([M+H]±).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([NH2:24])[CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:25]([CH:30]1[CH2:35][C:34](=[O:36])NC1=O)(OCC)=[O:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:19][CH2:20][CH:21]([N:24]1[C:25](=[O:26])[CH2:30][CH2:35][C:34]1=[O:36])[CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)C1CC(=O)NC1=O
Reactant: CCCCCCCCCCCCCCCCCCOCC(N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(CO)N1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 21 %

Procedure:
A mixture of 3.43 g (10 mmoles) of 3-octadecyloxy-2-aminopropanol synthesized according to the method of J. Hajdu et al. [J. Org. Chem., 48, 1197-1202 (1983)] and 1.73 g (10 mmoles) of carboethoxysuccinimide in 50 ml of dichloromethane was stirred, and 1.01 g of triethylamine was added to the mixture under ice-cooling. The resulting mixture was stirred at room temperature for 30 hours and concentrated to dryness. The residue was purified by silica gel chromatography to give 894 mg of the desired 2-succinimidopropane derivative.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](/[N:24]=[N:25]/[C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=O)=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[O:15])=[CH:4][C:3]=1[CH:36]([CH3:38])[CH3:37].[CH2:39]([NH2:42])[CH2:40][NH2:41]>CO.O.C(Cl)(Cl)Cl>[NH2:41][CH2:40][CH2:39][NH:42][C:30](=[O:32])[C:29]1[CH:28]=[CH:27][C:26](/[N:25]=[N:24]/[C:21]2[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:5]3[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([OH:1])=[C:3]([CH:36]([CH3:38])[CH3:37])[CH:4]=3)=[CH:19][CH:20]=2)=[CH:35][CH:34]=1
Reactant: NCCN
Reactant: COC(=O)c1ccc(/N=N/c2ccc(CNC(=O)CCCc3cc(C(C)C)c(O)c(C(C)C)c3)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)c1cc(CCCC(=O)NCc2ccc(/N=N/c3ccc(C(=O)NCCN)cc3)cc2)cc(C(C)C)c1O

Procedure:
The solution of the compound 9 (258 mg, 0.50 mmol) and ethylenediamine (600 mg, 10 mmol) in methanol (10 mL), water (5 mL) and chloroform (2.5 mL) was refluxed for 24 h. The solvents were then evaporated, the residue was dissolved in 1N potassium hydroxide (15 mL), and the mixture extracted with methylene chloride (4×15 mL). The combined organic phases were washed with water and brine, dried over magnesium sulfate, concentrated under vacuum, and the residue chromatographed on silica gel using chloroform and chloroform-methanol (5%) step-gradient as an eluent to produce pure MCP088 (201 mg, 74%) as orange crystals. 1H NMR (360 MHz, CD3OD): δ 8.04-7.91 (m, 6H), 7.50 (d, J=8.4 Hz, 2H), 6.83 (s, 2H), 4.47 (s, 2H), 3.49 (t, J=6.4 Hz, 2H), 3.26 (septet, J=6.8 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 2.30 (t, J=7.4 Hz, 2H), 1.92 (q, J=7.4 Hz, 2H), 1.19 (d, J=6.8 Hz, 12H). 13C NMR (90.55 MHz, CD3OD): δ 175.13, 168.66, 154.57, 152.02, 148.72, 143.39, 136.55, 135.84, 133.40, 128.42, 128.38, 128.20, 129.90, 123.21, 122.99, 122.65, 120.98, 120.02, 42.66, 42.48, 40.89, 35.54, 35.08, 28.21, 26.83, 22.48. HRMS (m/z): [M+H]+ calcd. for C32H41N5O3 544.3282. found 544.3308.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[F:19][C:20]([F:34])([F:35])[C:21]1[CH:22]=[C:23]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:17]=2)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: FC(F)(F)c1cc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc(C(F)(F)F)c1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401 (c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (Aldrich Chemical Company) (64 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 441 (M+1). Mp: 130.0-131.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=O.[OH-].[Na+].[CH2:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC)[CH:9]1[O:11][CH2:10]1.Cl.[CH2:28](O)[CH3:29]>>[OH:5][CH2:3][CH2:2][NH:1][CH2:28][CH2:29][C:9]([CH3:10])([OH:11])[CH2:8][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: NCC(=O)O
Reactant: CCO
Reactant: CCCCCCCCCCCCCCOCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCOCC(C)(O)CCNCCO
Temperature: 80 °C
Yield: 30.7 %

Procedure:
A 300-ml two-necked flask equipped with a stirrer was charged with 7.51 g (0.1 mol) of glycine, 8.3 g (0.1 mol) of 48% NaOH and 200 ml of ethanol. While stirring the mixture at 80° C., an ethanol solution of 2.70 g (10 mmol) of tetradecyl glycidyl ether was added, and the resultant mixture was stirred for 3 hours. After ethanol was distilled off under reduced pressure, methanol and hydrochloric acid was added to the mixture to acidify it. The mixture was subjected to extraction with chloroform. The resultant extract was concentrated under reduced pressure, and the residue was then purified by column chromatography on silica gel, thereby obtaining 1.17 g (yield: 30.7%) of the title compound [(IIa-10) hydrochloride].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25]([N:27]3[CH2:31][CH2:30][S:29][CH2:28]3)=[O:26])[CH:15]=2)[CH:5]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCS(=O)C3)=[O:52])C=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25]([N:27]3[CH2:31][CH2:30][S:29](=[O:52])[CH2:28]3)=[O:26])[CH:15]=2)[CH:5]=[C:6]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])[CH:7]=1
Reactant: O=C(c1cc(-c2cc(F)cc(OCC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Agent: O=C(OO)c1cccc(Cl)c1
Product: O=C(c1cc(-c2cc(F)cc(OCC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCS(=O)C1

Procedure:
44 mg (0.10 mmol) of the compound of Example 72 is reacted analogously to the synthesis of the compound of Example 6 with 24 mg (0.10 mmol, 70%) of meta-chloroperbenzoic acid overnight at room temperature. The crude product is filtered over a Millipore spray filter and separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient). 35 mg (77% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([S:15]([C:18]2[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:21]1[S:22][C:18]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1)(=[O:24])=[O:25]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)c2ccccc2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(S(=O)(=O)c3ccccc3)s2)c1Br
Yield: 59 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-benzenesulfonylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-benzenesulfonylthiophene-2-sulphonyl chloride in 59% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 139°-142° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH2:33][CH:34]([OH:36])[CH3:35])[CH2:28][CH2:27]2)[C:19](=[O:37])[C:18]=1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:46]([C:51]#[N:52])=[CH:47][CH:48]=[CH:49][CH:50]=2)=[CH:41][CH:40]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH2:33][CH:34]([OH:36])[CH3:35])[CH2:28][CH2:27]2)[C:19](=[O:37])[C:18]=1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[NH:3][C:4](=[O:7])[O:5][N:52]=2)=[CH:43][CH:44]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.43 g), sodium hydrogen carbonate (0.66 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C. for 30 min, 4′-({7-butyl-4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.27 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.10 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.090 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.22 g, 70%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>C(OCC)(=O)C.[OH-].[Na+]>[Cl:12][C:10]1[CH:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[C:11]=1[C:2]([O:21][C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)=[CH:3][CH:4]=[N:5]2
Reactant: Clc1cc(Cl)c2c(Cl)ccnc2c1
Reactant: Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2ccnc3cc(Cl)cc(Cl)c23)cc1
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 76.4 %

Procedure:
A mixture of 29.11 g of 4,5,7-trichloroquinoline and 16.84 g of 4-fluorophenol was heated to 160° C. After approximately 40 minutes, the molten solution solidified. The solid was dissolved in ethyl acetate and 2N NaOH. The organic layer was washed with base to remove excess phenol, then dried. Solvent was removed by reducing pressure, and the residue was purified by recrystallizing in heptane to produce 29.49 g of the title product. M.P. 105°-106° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6](F)[N:5]=1.[CH2:12]([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[NH2:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([O:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:5]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: CCCCCCCO
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCOc1cc(F)nc(N)n1
Reaction time: 2.5 h

Procedure:
A solution of 1.14 g (0.038 mol) of 80% sodium hydride (suspension in linseed oil) in 30 ml of n-heptanol was added to a stirred mixture of 5 g (0.038 mol) of 2-amino-4,6-difluoropyrimidine in 70 ml of n-heptanol at 20° to 25° C. within 5 minutes. After 2.5 hours working up was carried out as in Example 6. 6.3 g (73% of theory) of the title compound of melting point 30°-32° C. were obtained in this way.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26]>C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:9][O:10][C:11]1[C:16]([CH2:17][Br:1])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26]
Reactant: COc1ccccc1Oc1cccc(C)c1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1ccccc1Oc1cccc(CBr)c1OC
Yield: 101.6 %

Procedure:
N-Bromosuccinimide (6.56 g) and 2,2'-azobisisobutyronitrile (100 mg) were added to a solution of 2-methoxyphenyl 2-methoxy-3-methylphenyl ether (9.0 g) in benzene (100 ml), and the mixture was refluxed under heating for 2 hrs. The reaction mixture was evaporated, and water was added to the residue. The mixture was extracted with diethyl ether, and the extract was washed with water, dried over magnesium sulfate and then evaporated to give oily residue of 2-methoxyphenyl 2-methoxy-3-bromomethylphenyl ether (12.10 g).
Reaction SMILES: [C:1]1([C:7]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([CH3:20])[C:11]3=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]1([C:7]2[C:8]3[CH2:9][C:10]([CH3:20])=[CH:11][C:12]=3[CH:13]=[C:14]3[C:18]=2[CH2:17][CH2:16][CH2:15]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1Cc2c(cc3c(c2-c2ccccc2)CCC3)C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC1=Cc2cc3c(c(-c4ccccc4)c2C1)CCC3
Temperature: 50 °C
Reaction time: 3 h

Procedure:
9.6 g (24.4 mmol) of 4-phenyl-2-methyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (2a) and 2.10 g (55 mmol) of sodium borohydride in 40 ml of toluene were placed in a reaction vessel. The solution was heated to 50° C. and 7 ml of methanol was added slowly and the reaction mixture was stirred at 50° C. for 3 hours. After cooling to room temperature 12 ml of water and 40 ml of 1 N sulfuric acid were added and the mixture was stirred for 30 minutes. After phase separation the water phase was extracted with toluene. Organic phase was evaporated and the residue was taken up in 100 ml of toluene and mixed with 100 mg of p-toluenesulfonic acid. Water was distilled off from this reaction mixture by refluxing for 2 hours on a water separator until reaction was complete. The reaction mixture was washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was dried in an oil pump vacuum. This gave 11.5 g of brawn oil. The crude product was purified by column chromatography (200 g of silica gel, 1 l of heptane: diethylether=9:1).
Reaction SMILES: Cl[C:2]1[C:3]([CH:15]([CH3:17])[CH3:16])=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:18][CH2:19][CH3:20].[Na+].O>C(O)C>[CH2:19]([O:18][C:2]1[C:3]([CH:15]([CH3:17])[CH3:16])=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:20]
Reactant: CC(C)c1c(Cl)nn2c(N)nnc2c1C(C)C
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nn2c(N)nnc2c(C(C)C)c1C(C)C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
6-Chloro-7,8-diisopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.015, 0.1 g) was dissolved in ethanol (15 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (110 mg) and stirred at RT for 1 h, then at 55° C. for 1 h. Subsequently, the mixture was left to stand overnight, then stirred again at 55° C. for 7.5 h and then the solvent was drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 100 mg of the title compound were obtained. LC-MS rt: 0.90 min [M+H]+: 264.2 (met. b)
Reaction SMILES: [C:1]([O:10]C)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([N:14]([CH2:19][CH3:20])[CH2:15][CH2:16]CCl)[CH3:13].[C:21](=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:19]([N:14]([CH2:12][CH3:13])[CH:15]([CH3:16])[CH2:21][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)CCCCl
Reactant: COC(=O)c1ccccc1O
Agent: [K+]
Solvent: CCC(C)=O
Product: CCN(CC)C(C)COc1ccccc1C(=O)O

Procedure:
A mixture of 15.2 g. (0.10 mol.) of methyl salicylate, 16.45 g. (0.11 mol.) of 3-diethylaminopropyl chloride and 27.7 g (0.20 mol.) of potassium carbonate in 250 ml. of 2-butanone is refluxed for 22 hours to give 2-(2-diethylaminopropoxy)benzoic acid which is converted to the corresponding hydrochloride salt by heating with 100 ml. of concentrated hydrochloric acid for three hours, m.p. 137°-140°.
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[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:19]([C:18]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:21])=[CH2:23]
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (2.14 g, 5.39 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (668 mg, 6.50 mmol) in DMF (50 mL) was added EDCI (1.14 g, 5.93 mmol), HOBt (0.80 g, 5.93 mmol) and DIPEA (1 mL, 5.93 mmol). The reaction mixture was stirred at room temperature for 2 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (30 mL), washed with aqueous saturated sodium hydrogen carbonate solution (300 mL) and the aqueous fraction extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a pale yellow solid (1.85 g, 71%). LCMS (Method B): RT=3.52 min, [M−H]−=481.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[Br:19][C:20]1[C:21]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:22]([CH2:34]Br)[N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:24]=1[Br:25].CO>CN(C=O)C.ClCCl>[Br:19][C:20]1[C:21]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:22]([CH2:34][N:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[N:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:24]=1[Br:25]
Reactant: CCOC(=O)c1c(Br)c(Br)n(Cc2ccc(F)cc2)c1CBr
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)c(Br)n(Cc2ccc(F)cc2)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a stirring solution of methyl N-[(4-methylphenyl)sulfonyl]glycinate (51.75 g, 0.213 mol, prepared by the method of: Ginzel, K. D.; Brungs, P.; Steckhan, E. Tetrahedron 1989, 45, 1691-1701) in anhydrous DMF (0.5 L) was added NaH (60% in oil, 8.59 g, 0.215 mol) in one portion. The mixture was allowed to stir for 30 minutes (warms and returns to room temperature) at which time a solution ethyl 4,5-dibromo-2-(bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylate (105.92 g, 0.213 mol) in anhydrous DMF (0.5 L) was added over 1 hour. The mixture was allowed to stir at room temperature for 16 hours, then the DMF was removed in vacuo (approx 2 Torr, 40° C. water bath) and the oily residue was dissolved in dichloromethane (0.75 L), the solution was washed with saturated aq. NH4Cl (0.5 L), brine (0.5 L), and dried (Na2SO4). Filtration and concentration in vacuo provided the crude alkylated material as a viscous reddish oil. The crude material was heated in the presence of MeOH (0.75 L) until the MeOH was boiling, then dichloromethane was added slowly until solution was achieved. The red solution was cooled to room temperature (see off-white crystals) and the crystallization was completed by cooling in a refrigerator (4° C.) for 16 hours. The ivory solid was isolated by filtration, the solid was rinsed with diethyl ether:hexanes (0.5 L, 10:90 v/v) and the solid was dried in a vacuum oven (approx. 20 Torr, 50° C.) overnight to furnish ethyl 4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-methoxy-2-oxoethyl)[(4-methylphenyl) sulfonyl]amino}methyl)-1H-pyrrole-3-carboxylate (108.2 g, 77%) as a free flowing, fine, ivory solid. TLC (Merck, hexanes:EtOAc 75:25, UV-+, cerium molybdate-+-purple): Rf=0.38 LCMS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT—4.436 min, m/e=680.8 (55), 681.8 (18), 682.9 (base), 683.9 (30), 684.8 (62), 686.8 (10)—M+Na