Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=O)[NH:21][C:20]=2[CH:31]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:25]([Cl:12])[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[CH:22]=[N:21][C:20]=2[CH:31]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Temperature: 95 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
N,N-dimethylaniline (5.1 ml, 40 mmol) and phosphorus oxychloride (2.8 ml, 30 mmol) was added to a mixture of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (2.45 g, 10 mmol) in dry toluene (20 ml). The mixture was shaken at 95° C. for 2 h. The temperature was then decreased and the excess N,N-dimethylaniline and phosphorus oxychloride were removed at reduced pressure using an oil pump. The remaining oil was dissolved in dioxane (20 ml) and aqueous Na2CO3-solution (10 ml, 2 M) was added. The two-phase mixture was shaken at 80° C. for 30 min. The temperature was then decreased and ether was added to the reaction mixture. The ethereal phase was washed with saturated aqueous NaCl-solution, dried (Na2SO4) and finally concentrated at reduced pressure. The obtained oil crystallized upon standing at room temperature. Recrystallization (heptane-ether) gave 1.8 g (69%) of the title compound (160FE64). 1H NMR (CDCl3) δ 7.61 (dd, 1H, J=1.4, 7.8 Hz), 7.31 (dt, 1H, J=1.5, 8.0 Hz), 7.15 (d, 1H, J=2.5 Hz), 7.02 (m 2H), 6.66 (dd, 1H, J=1.0, 7.8 Hz), 6.58 (d, 1H, J=8.4 Hz), 4.94 (bs, 1H). 13C NMR (CDCl3) δ 157.2, 152.4, 140.3, 138.9, 134.0, 131.9, 129.7, 128.5, 128.0, 127.0, 123.5, 121.0, 119.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([S:12]([OH:15])(=[O:14])=[O:13])([CH2:8][C:9]([O-:11])=[O:10])[C:5]([O-:7])=[O:6])[CH3:2].[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]OS([O-])(=O)=O.[Na+:33]>>[CH2:1]([O:3][C:4]([S:12]([OH:15])(=[O:13])=[O:14])([CH2:8][C:9]([O-:11])=[O:10])[C:5]([O:7][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[O:6])[CH3:2].[Na+:33]
Reactant: CCOC(CC(=O)[O-])(C(=O)[O-])S(=O)(=O)O
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCOC(=O)C(CC(=O)[O-])(OCC)S(=O)(=O)O

Procedure:
coconut monoethanolamide ethoxysulphosuccinate, (e.g. EMPICOL SGG)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cc1OC
Temperature: 110 °C
Yield: 35.8 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 3,4-dimethoxyphenylboronic acid (41 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (45-45% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (27.8 mg, 36%). ESI-MS: m/z 447.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.[Cl:7][C:8]1[CH:9]=[C:10]([N:15]2[C:19](=[O:20])[CH:18]([CH3:21])[NH:17][C:16]2=[O:22])[CH:11]=[CH:12][C:13]=1[Cl:14].C(N(CC)CC)C>C(OC(=O)C)C>[Cl:5][C:2]([Cl:6])([F:1])[S:3][N:17]1[CH:18]([CH3:21])[C:19](=[O:20])[N:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]1=[O:22]
Reactant: CC1NC(=O)N(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: FC(Cl)(Cl)SCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1C(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)N1SC(F)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.4 g of fluorodichloromethanesulphenyl chloride is added dropwise at 0° C, with thorough stirring, to 25.9 g of 3-(3',4'-dichlorophenyl)-5-methyl-imidazolidine-2,4-dione in 500 ml of acetic acid ethyl ester, and after 2 hours an addition is made dropwise, likewise at 0° C. of 12.1 g of triethylamine in 100 ml of acetic acid ethyl ester. After the whole has been stirred for 3 hours at room temperature, the triethylamine hydrochloride is filtered off; the solvent is evaporated off from the filtrate and the residue is recrystallised in methanol. Compound No. 2 melts at 138° - 140° C after recrystallisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](Br)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[CH2:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](/[CH:26]=[CH:25]/[C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(/C=C/c2cc([N+](=O)[O-])cc3c(O)nc(Nc4ccc(Cl)c(Cl)c4)nc23)cc1
Temperature: 120 °C
Yield: 62.3 %

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-8-bromo-6-nitroquinazolin-4-ol (50 mg) in N,N-dimethylformamide (2 mL) was added 4-vinylbenzoic acid (35 mg), followed by palladium acetate (2.6 mg), tri-o-tolylphosphine (7.1 mg) and N,N-diisopropylethylamine (0.24 mL). The reaction mixture was heated at 120° C. for 24 h, then was cooled to room temperature and concentrated in vacuo. The residue was triturated with 50% (v/v) methanol/dichloromethane (2 mL). The resulting solid was isolated by filtration, washed sequentially with diethyl ether and water, then was dried in vacuo to give the title compound (36 mg). 1H NMR (300 MHz, DMSO-d6/CF3CO2H) δ8.75 (d, J=2.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.43 (d, J=4.5 Hz, 1H), 7.99-7.88 (m, 3H), 7.74 (d, J=8.4 Hz, 1H), 7.67-7.51 (m, 2H), 7.38 (dd, J=8.7, 2.6 Hz, 1H). HPLC Method B 8.26 min. MS (APCI−) m/z 496, 498.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:17][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[S:11]
Reactant: CC(C)(C)CN
Reactant: Fc1ccc(N=C=S)c(F)c1
Solvent: ClCCl
Product: CC(C)(C)CNC(=S)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 2,4-difluoro-phenyl isothiocyanate (1.00 g, 5.84 mmol) in dichloromethane (20 mL) at room temperature was added neopentylamine (0.90 mL, 7.6 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.28 g (85%) of 1-(2,4-difluoro-phenyl)-3-(2,2-dimethylpropyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22]([NH:25][C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29]([Br:34])=[CH:28][N:27]=1)(=[O:24])=[O:23])=O)C1C=CC=CC=1.C(OCC)C>Br.C(O)(=O)C>[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22]([NH:25][C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29]([Br:34])=[CH:28][N:27]=1)(=[O:23])=[O:24]
Reactant: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(NC(=O)OCc3ccccc3)cccc12
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N)cccc12
Reaction time: 1 h
Yield: 13.3 %

Procedure:
5-(N-Benzyloxycarbonylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.7 g) was dissolved in 33% hydrobromic acid in acetic acid (14 ml) and the resulting solution was stirred for 1 hour. Diethyl ether (60 ml) was added and after 10 minutes further stirring, the mixture was filtered. The solid was dissolved in water (5 ml), basified to pH 8 by the addition of 1N aqueous sodium hydroxide and extracted with ethyl acetate (3×25 ml). The combined organic extracts were evaporated and the residue was purified by flash chromatography on silica gel (10 g), eluting with a gradient of 20-50% ethyl acetate in hexane to give 5-amino-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.07 g); 1H NMR (d6 -DSO): 3.82 (s,3H), 6.78 (d,,H), 7.35 (t,(H), 7.50 (t,(H), 7.78 (s,1H), 7.91 (d,2H), 8.25 (d,2H), 8.40 (d,1H); mass spectrum (+ve FAB, methanol/NBA): 409 (M+H)+.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH3:22][C:23]1([CH3:42])[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:33]=1>C(#N)C>[CH3:22][C:23]1([CH3:42])[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[S:30][C:31]([F:21])=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:33]=1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)c(F)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
The Selectfluor® reagent (2.042 g, 5.76 mmol) in 250 mL of acetonitrile was added under nitrogen dropwise to a solution of 4-[2-(4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (1.566 g, 5.23 mmol), prepared in Example 6, in 250 mL of acetonitrile at room temperature. After the addition, the reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to remove the acetonitrile. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed once with water, and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 25+™ cartridge) using a linear gradient of methylene chloride in hexane as the eluent gave the title compound (566.7 mg, 34%) as a white solid, mp 177-178° C.; MS (ESI) m/z 318 [M+H]+. Anal. Calcd for C15H12FN3O2S: C, 56.77; H, 3.81; N, 13.24. Found: C, 56.53; H, 3.91; N, 13.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Product: CCC(NC(=O)Cc1ccc(Cl)cc1Cl)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:27][C:23]1[CH:22]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:12]3[N:11]=[N:10][C:9]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:14][CH:13]=3)[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(N2CCN(c3ccc(Oc4ccccc4)nn3)CC2)c1
Temperature: 150 °C
Yield: 60 %

Procedure:
A mixture of 1.9 parts of phenol, 2.9 parts of 3-chloro-6-[4-(3-methylpheyl)-1-piperazinyl]pyridazine and 2.76 parts of potassium carbonate was stirred and heated for 7 hours in an oil bath at 150° C. After cooling, water was added. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (60%) of 3-[4-(3-methylphenyl)-1-piperazinyl]-6-phenoxypyridazine: mp. 123.4° C. (compound 264).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[O:6][CH3:7])[CH2:2][CH2:3][CH3:4].OC[C:18]1[CH:31]=[CH:30][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1>ClCCCl>[CH2:8]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:12][CH2:13][CH2:14][CH3:15])[O:6][CH2:7][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:21]2[CH:30]=[CH:31][CH:18]=[CH:19][CH:20]=2)=[O:23])=[CH:25][CH:26]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC[Sn](CCCC)(CCCC)OC
Reactant: O=C(c1ccccc1)c1ccc(CO)cc1
Solvent: ClCCCl
Product: CCCC[Sn](CCCC)(CCCC)OCc1ccc(C(=O)c2ccccc2)cc1
Yield: 56.2 %

Procedure:
In a 50 ml dry three-neck-flask, 2.5 g (7.8 mmol) of tri-n-butylmethoxy tin are added to 1.5 g (7.1 mmol) of 4-(hydroxymethyl)-benzophenone in 15 ml of 1,2-dichlorethane at room temperature in the course of 0.5 h under argon. 1H-NMR-spectrum confirms the complete conversion. The solution is concentrated and the crude product, 3.6 g of a yellow oil, is distilled in a bulb-to-bulb distillation apparatus in vacuum (0.016 mbar) at 160-170° C. The resulting colorless oil (2.8 g) is distilled a second time in a bulb-to-bulb distillation apparatus (0.020 mbar). 2.0 g of the title product are obtained as a colorless oil (boiling area 294-308° C.). The structure is further confirmed by 1H-NMR and 13C-NMR-spectra.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1)([CH3:9])[CH:7]=[CH2:8])[CH3:2].B(Br)(Br)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([CH3:9])[CH:7]=[CH2:8])[CH3:2]
Reactant: C=CC(C)(CC(=O)OCC)Cc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: C=CC(C)(CC(=O)OCC)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of the product of STEP 4 (0.79 g) and dichloromethane (15 ml) was cooled to 0° C. A 1 M solution of boron tribromide in dichloromethane (6.00 ml) was added slowly. The solution was stirred at room temperature for 1 hour. Ethanol (5 ml) was added to quench the reaction. Solvent was removed. Residue was extracted with 1% of hydrochloric acid aqueous solution and ethyl acetate. The organic extract was washed with saturated sodium bicarbonate/water, and then dried over MgSO4. Solvent was removed. The crude product was purified on a silica gel column, eluting with 20% ethyl acetate/hexane to afford colorless oil (0.32 g). The 1H NMR was consistent with the proposed structure.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:38])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:34]3[CH2:37][CH2:36][CH2:35]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5](=[O:38])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH:34]3[CH2:35][CH2:36][CH2:37]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCC4COC(C)(C)O4)cc3n2C2CCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCC(O)CO)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-{3-cyano-1-cyclobutyl-6-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-1H-indol-2-yl}-phenyl)-carbamic acid isopropyl ester (70 mg, 0.135 mmole) in DCM (2 mL) is added TFA (10 uL). The resulting mixture is stirred at ambient temperature for 2 h. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(3,4-dihydroxy-butoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1429, 45 mg, (70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3C3C=C(Cl)C=CC=3OC3CCC4(OCCO4)CC3)[C:5]2=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>O1CCCC1.O>[Cl:22][C:18]1[CH:17]=[C:16]([CH:15]2[CH2:14][C:13](=[O:23])[NH:12][CH2:11][C:10]32[C:5]2[C:6](=[CH:7][CH:2]=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:42])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2OC2CCC3(CC2)OCCO3)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC(c2cccc(Cl)c2)C2(CN1)C(=O)Nc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.32 mmol) in tetrahydrofuran (15 mL) and water (1 mL) was added aqueous HCl (2 N, 1 mL). The reaction mixture was stirred at room temperature for 1 h, then neutralized to “pH” 7 by aqueous NaHCO3 solution. The mixture was then extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:1) to give racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-cyclohexyloxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.1 g, 54%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:17])[C:7]2[C:8]3[CH:9]=[N:10][NH:11][C:12]=3[CH2:13][CH2:14][C:15]=2[CH:16]=1)=[O:4].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:17])[C:7]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]1[C:8]=2[CH:9]=[N:10][NH:11]1)=[O:4]
Reactant: COC(=O)c1cc2c(n1C)-c1cn[nH]c1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COC(=O)c1cc2ccc3[nH]ncc3c2n1C
Yield: 67 %

Procedure:
A mixture of 1-methyl-1,4,5,6-tetrahydro-1,6,7-triaza-as-indacene-2-carboxylic acid methyl ester A2 (1.03 mmol) and DDQ (1 eq) in dry dioxane (15 mL) was refluxed for 1.5 h with stirring. After solvent removal the slurry was treated with water under vigorous stirring. The precipitate was filtered, washed with water and dried. Obtained the title compound (67%). ESI (+) MS: m/z 230 (MH+). 1H NMR (300 MHz): 3.89 (s, 3H), 4.34 (s, 3H), 7.17 (d, J=8.71, 1H), 7.26 (s, 1H), 7.28 (d, J=8.71, 1H), 8.38 (s, 1H), 13.32 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@H:18]4[C@@H:22]([CH2:23][CH3:24])[CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])[CH2:19]4)=[C:15]([C:35](=[O:37])[NH2:36])[CH:14]=[N:13][N:12]3[CH:38]=2)=[CH:5][CH:4]=1.[CH3:39][O:40][CH2:41][C:42](O)=[O:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:35]([C:15]1[CH:14]=[N:13][N:12]2[CH:38]=[C:9]([C:6]3[CH:7]=[N:8][C:3]([CH2:2][NH:1][C:42](=[O:43])[CH2:41][O:40][CH3:39])=[CH:4][CH:5]=3)[CH:10]=[C:11]2[C:16]=1[NH:17][C@H:18]1[C@@H:22]([CH2:23][CH3:24])[CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH2:19]1)(=[O:37])[NH2:36]
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CN)nc3)cc12
Reactant: COCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of (3S,4S)-benzyl 3-((6-(6-(aminomethyl)pyridin-3-yl)-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (29 mg, 0.056 mmol), 2-methoxyacetic acid (9.56 μl, 0.124 mmol), BOP (54.9 mg, 0.124 mmol) and diisopropylethylamine (0.039 mL, 0.226 mmol) in DMF (0.5 mL) was stirred at rt overnight. The reaction mixture was partitioned between EtOAc (20 ml) and 10% LiCl solution (20 ml). The organic layer was washed with 10% LiCl solution (2×20 ml) and brine (20 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (22 mg, 0.038 mmol, 66.5% yield) as a yellow semisolid. The material will be used as is in the next step. MS (ES+) m/z: 586.22 (M+H); LC retention time: 2.370 min (analytical HPLC Method O).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:30](=[O:31])[CH2:29][O:28][C:27]3[CH:33]=[CH:34][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[S:14][C:9]=2[N:10]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccccn3)sc2n1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccccn3)sc2n1
Yield: 57 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-2-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyactic acid in a yield of 57%, according to the procedure for the synthesis of example 50.
Reaction SMILES: I.[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23](=[NH:26])SC)[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:23]([NH:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([NH:11][C@H:2]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3]2)[CH:21]=[CH:20]3)=[NH:26])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: CSC(=N)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: I
Product: N=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CC1

Procedure:
The title compound was prepared in accordance with the general method 16 described in example 151 from 1-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea hydroiodide and cyclopropylamine; MS: m/e=358.4 (M+H+).