Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].Cl[CH2:21][CH2:22][CH2:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])(=[O:29])[O:26][CH2:27][CH3:28]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:21][CH2:22][CH2:23][CH2:24][P:25](=[O:29])([O:30][CH2:31][CH3:32])[O:26][CH2:27][CH3:28])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Product: CCCCn1c(=O)c2c(ncn2CCCCP(=O)(OCC)OCC)n(CCCC)c1=O

Procedure:
The title substance was prepared from 1,3-dibutylxanthine and diethyl 4-chlorobutanephosphonate analogously to Example 9.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:33]=1.[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:41]([O:43]CC)=[CH2:42])CCC.Cl.CCOCC>CN1C(=O)CCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:7]2[C:6]3[CH:33]=[C:2]([C:41](=[O:43])[CH3:42])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:18])([F:17])[F:19])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:21])=[O:22])=[CH:24][CH:25]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (270 mg, 0.5 mmol, from intermediate 53, Pd(dppf)Cl2 (165 mg, 0.2 mmol), and LiCl (21 mg, 0.5 mmol) were dissolved in NMP (1.5 mL) under N2 was added tri-n-butyl(1-ethoxyvinyl)tin (180 mg, 0.5 mmol), and the resulting mixture was stirred at 90° C. for 1 h. The cooled reaction mixture was poured into 1M HCl/Et2O (5 mL) and stirred vigorously for 2 h. The product was extracted with EtOAc and the combined extracts were washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by SiO2 column chromatography to provide the title compound. LC/MS: m/e 504.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.19 (1H, s), 7.92 (1H, d, J=8.4 Hz), 7.64 (1H, d, J=7.6 Hz), 7.15 (1H, d, J=7.5 Hz), 7.12 (2H, d, J=8.4 Hz), 7.01 (1H, s), 6.94 (2H, d, J=8.2 Hz), 6.83 (1H, d, J=8.4 Hz), 4.65-4.9 (2H, br), 2.64 (3H, s), 1.25 (9H, s).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:26][O:27][C:28](=[O:56])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]1[C@H:39]([CH:40]=[CH:41][Sn](CCCC)(CCCC)CCCC)[CH2:38][CH2:37][C:36]1=[O:55]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][O:27][C:28](=[O:56])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]1[C@H:39]([CH:40]=[CH:41][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:38][CH2:37][C:36]1=[O:55]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of benzoyl chloride (0.224 mL, 1.94 mmol) in tetrahydrofuran (20 mL) was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(DBA)3) (8.8 mg, 0.01 mmol) and tri-2-furylphosphine (9.2 mg, 0.04 mmol). The mixture was stirred for 10 minutes and trans-7-[2-oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl]-heptanoic acid methyl ester (the compound of Preparation 1, Step D, 1.0 g, 1.85 mmol) was added. The reaction was stirred for 24 h and was concentrated in vacuo. Radial chromatography (hexanes to 20% hexanes in ethyl acetate) provided the title compound of Step A as a clear and colorless oil (569 mg). 1H NMR (CDCl3, 250 MHz) d 7.94 (m, 2H), 7.62-7.42 (m, 3H), 7.00 (m, 2H), 3.64 (s, 3H), 2.75 (m, 1H), 2.44 (m, 1H), 2.23 (m, 5H), 2.03 (m, 1H), 1.86-1.16 (m, 8H), 0.90 (t, 2H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C@H:16]2[C:21](=[O:32])[NH:22][C:23]2[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[O:25][N:24]=2)=[CH:11][CH:10]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:28]([C:26]1[O:25][N:24]=[C:23]([NH:22][C:21]([C@@H:16]2[CH2:17][CH2:18][C:19](=[O:20])[N:15]2[C:12]2[CH:13]=[CH:14][C:9]([NH:7][CH3:6])=[CH:10][CH:11]=2)=[O:32])[CH:27]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(N2C(=O)CC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(N2C(=O)CC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)cc1

Procedure:
A solution of {4-[(S)-2-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-5-oxo-pyrrolidin-1-yl]-phenyl}-methyl-carbamic acid tert-butyl ester (550 mg, 1.21 mmol) in dichloromethane (5 mL) is cooled in an ice bath. A pre-cooled trifluoroacetic acid (15 mL) is added and the mixture is kept in ice-bath for 30 minutes. Trifluoroacetic acid is evaporated in vacuo, and the residue is treated with ice and sodium bicarbonate solution. Extracted with ethyl acetate (1×150 mL) and the combined extracts washed with brine (50 mL) dried over anhydrous Na2SO4 and solvent removed in vacuo to give the title compound, ESI m/z 357 [M+H]+.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:9][CH:8]=1)(=O)=O.[CH:23]([N:26](CC)[CH:27](C)C)(C)C.CNC>O1CCCC1>[CH3:23][N:26]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:8]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(COS(C)(=O)=O)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.9 %

Procedure:
To a stirred suspension of 4-(2-(tert-butoxycarbonylamino)ethyl)benzyl methanesulfonate (0.33 g, 1.0 mmol) and N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) in tetrahydrofuran (50 mL) was added a 2M solution of dimethylamine in tetrahydrofuran (5.0 mL, 10 mmol). The resulting mixture was stirred in an oil bath set to 60° C. for 6 hours. The solution was cooled to ambient temperature and concentrated. The residue was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 99/1 to 98/2 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford tert-butyl 4-((dimethylamino)methyl)phenethylcarbamate as a colorless oil (0.15 g, 54% yield).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)CCC.[CH:24]([C:26]1[CH:30]=[C:29](I)[S:28][C:27]=1[CH2:32][OH:33])=[O:25]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O1CCCC1>[CH:24]([C:26]1[CH:30]=[C:29]([C:6]2[S:10][C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][CH:7]=2)[S:28][C:27]=1[CH2:32][OH:33])=[O:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2cccs2)s1
Reactant: O=Cc1cc(I)sc1CO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(-c3cccs3)s2)sc1CO
Yield: 37.6 %

Procedure:
In a two-necked round bottomed flask was added 5-tributylstannyl-2,2'-bithiophene (2.04 g), bis(triphenylphosphine)palladium (II) chloride (0.19 g), 3-formyl-2-hydroxymethyl-5-iodo-thiophene (1.0 g) and tetrahydrofuran (20 ml). The reaction mixture was refluxed for 16 hours. Extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was separated by silica gel chromatography, eluted with n-hexane/ethyl acetate (9:1→1:1 gradient) to give brownish solid product (0.43 g, 38%), melting point 108°-110° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:34]=[CH:33][C:12]([CH2:13][O:14][C:15]3[C:24]4[C:19](=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:29]([F:32])([F:31])[F:30])[CH:16]=3)=[CH:11][CH:10]=2)O1.[CH3:36][O:37][C:38](=[O:54])[CH:39]([NH:43][S:44]([C:47]1[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=1)(=[O:46])=[O:45])[CH:40]([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:36][O:37][C:38](=[O:54])[CH:39]([NH:43][S:44]([C:47]1[CH:48]=[CH:49][C:50]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]3[C:24]4[C:19](=[C:20]([C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:29]([F:30])([F:31])[F:32])[CH:16]=3)=[CH:33][CH:34]=2)=[CH:51][CH:52]=1)(=[O:46])=[O:45])[CH:40]([CH3:42])[CH3:41]
Reactant: CC1(C)OB(c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)OC1(C)C
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Br)cc1)C(C)C
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: COCCOC
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Step 2B [Intermediate 5, G9591-162]: To 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-2,8-bis-trifluoromethyl-quinoline (1.5 g, 3.0 mmol, 1 equiv.) in 45 mL of ethylene glycol dimethyl ether was added 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester (1.06 g, 3.0 mmol, 1.0 equiv.) and Pd(PPh3)4 (174 mg, 0.15 mmol, 0.05 equiv.) under N2. The reaction mixture was stirred for 0.5 hr, then an aqueous solution of K2CO3 (834 mg, 6.0 mmol, 2 equiv.) was added. The mixture was heat to reflux overnight. After cooling to room temperature, solvent was removed under vacuum. The residue was diluted with EtOAc (100 mL) and washed with brine solution. The organic layer was dried over anhydrous MgSO4, solvent evaporated under vacuum, and the crude product was purified on silica gel column (30% EtOAc/Hexane) to give 1.026 g of 2-[4′-(2,8-Bis-trifluoromethyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester in 53% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22](I)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3ccccn3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in toluene (2 ml), then thereto are added 2-tributylstannylpyridine (105 μl) and tetrakis(triphenylphosphine)palladium (16 mg), and the mixture is stirred at 100° C. under nitrogen flow overnight. After allowing to cool to room temperature, 10% aqueous potassium fluoride solution is added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is washed with a 10% aqueous potassium fluoride solution and a saturated brine successively, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyridin-2-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (138 mg). MS (m/z): 661 [M+H]+
Reaction SMILES: [BH4-].[Na+].O.C(=O)(O)[O-].[Na+].[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]=[C:17]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1>C(OCC)(=O)C>[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH:17]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc2c(c1)C(c1ccc(C(F)(F)F)cc1)=NCC2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc2c(c1)C(c1ccc(C(F)(F)F)cc1)NCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 7-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (0.6 g, 2.1 mmol) in methanol (10 mL) from step 2 was cooled to 0° C. and sodium borohydride (0.2 g, 6.2 mmol) was added in small portions over 5 min and the reaction mixture was stirred at RT for 16 h. The reaction was quenched with ethyl acetate (10 mL) and concentrated to yield a light-yellow residue which was dissolved in ethyl acetate (40 mL), water (10 mL), and saturated sodium bicarbonate (20 mL). After stirring for 15 min, it was transferred to a separatory funnel, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 7-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a pale-yellow solid. MS (ESI pos. ion) m/z: 296 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[C:10]1[C:15](=[O:16])OC(C)(C)OC1=O.CCCCCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:9]=[CH:10][C:15]2=[O:16]
Reactant: CC1(C)OC(=O)C(=CNc2ccccc2Br)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: O=c1cc[nH]c2c(Br)cccc12
Temperature: 210 °C
Yield: 84.9 %

Procedure:
A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) in isopropanol (240 ml) was heated to reflux for 1 hour. After cooling, the deposit was filtrated to obtain 5-((2-bromophenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). A suspension of the obtained 5-((2-bromophenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.8 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution. The deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). 4-Chloro-8-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline was obtained according to Example 3(2) using the obtained 8-bromoquinolin-4(1H)-one instead of compound (3a). Compound (130) was obtained as a pale yellow solid (yield based on 6 steps: 3.4%) according to Example 3(3) using 3-(tert-butylamino)-4-cyanophenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]([CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)C)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[CH3:2][NH:9][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN(CCCN1CCCCC1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
To a solution of 1-(3-(N-benzyl-N-methylamino)propyl)piperidine hydrochloride (0.82 g, 2.6 mmol) in methanol (50 mL) was added 5% palladium/carbon (0.16 g), and the mixture was stirred under hydrogen atmosphere at room temperature overnight. After filtrating the reaction mixture through Celite, the filtrate was concentrated to afford the title compound (0.58 g, yield: 99%) as white crystals.
Reaction SMILES: [NH:1]([C:8](=[O:47])[CH:9]([C:19]1[CH:46]=[CH:45][C:22]([C:23]([NH:25][C:26]2[C:30]([NH:31]C(=O)OC(C)(C)C)=[CH:29][N:28]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:27]=2)=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CO.O1CCOCC1>[NH2:31][C:30]1[C:26]([NH:25][C:23]([C:22]2[CH:45]=[CH:46][C:19]([CH:9]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[C:8]([NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:47])=[CH:20][CH:21]=2)=[O:24])=[N:27][N:28]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of tert-butyl [3-({4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]carbamate (crude from above) in ethyl acetate (20 mL) and methanol (20 mL) was added 4M HCl in dioxane (10 mL) and the resulting solution was stirred at ambient temperature for 16 hours. The reaction was evaporated to dryness and purified by reverse phase LC to give 0.22 g (52%, 2 steps) of 2-(4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]-carbonyl}phenyl)-N,N′-diphenyl-malonamide as a white solid. 1H NMR (600 MHz, CD3OD) δ 10.30 (s, 1H), 8.44 (s, 1H), 8.08 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.8 Hz, 21-1), 7.74 (d, J=8.5 Hz, 2H), 7.58 (m, 4H), 7.51 (m, 2H), 7.36 (m, 1H), 7.32 (m, 4H), 7.11 (t, J=7.33 Hz, 2H); ESIMS calcd 531.2 (M++H), found 531.2 (M++H).
Reaction SMILES: O1C2(CC[N:8]([C:11](=[O:31])[CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:30][CH2:29][C:24]5([O:28][CH2:27][CH2:26][O:25]5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=O)CC2)OCC1.[NH2:32]N>C(O)C.O1CCCC1>[O:28]1[C:24]2([CH2:29][CH2:30][N:21]([C:18]3[CH:17]=[CH:16][C:15]([C:13]4[NH:32][NH:8][C:11](=[O:31])[CH:12]=4)=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[O:25][CH2:26][CH2:27]1
Reactant: NN
Reactant: O=C(CC(=O)N1CCC2(CC1)OCCO2)c1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)[nH][nH]1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-propane-1,3-dione (which was obtained in Example 143) (0.43 g, 1 mmol) was dissolved in a mixture of ethanol (10 mL) and tetrahydrofuran (4 mL). The solution was treated with 0.08 mL (2.4 mmol) of hydrazine and heated at reflux for 4 days. After cooling to room temperature, the resulting suspension was filtered, and the precipitate was washed with ethanol and dried in vacuo to give 0.24 g of light yellow solid; 1H NMR (DMSO-d6) δ 1.67-1.71 (t, 4H), 3.29-3.32 (t, 4H), 3.91 (s, 4H), 5.72 (s, 1H), 6.97 (d, 2H), 7.48 (d, 2H), 9.50 (brs, 1H), 11.80 (brs, 1H); MS (ES) m/z: 302 (MH+).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[Si:10](Cl)([C:13](C)(C)C)([CH3:12])[CH3:11]>C1COCC1>[CH3:11][Si:10]([CH3:13])([CH3:12])[O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,5-pentandiol (44 mmol) in THF (15 mL) is cooled to 0° C. and treated with sodium hydride (44 mmol) followed by tert-butyldimethylsilyl chloride (44 mmol). The reaction mixture is stirred at room temperature overnight. Concentration in vacuo and flash chromatography affords 5-trimethylsiloxy-1-pentanol. To a solution of 5-trimethylsiloxy-1-pentanol (11.6 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 5-trimethylsiloxy-1-pentyl triflate (45) which is used without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:27])[NH:14][C:15](=[O:26])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[CH:4]1.C[Si](Cl)(C)C.[CH2:33]1[O:36][CH:34]1[CH3:35]>CN(C=O)C.O>[OH:36][CH:34]([CH3:33])[CH2:35][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:27])[NH:14][C:15](=[O:26])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:33][CH:34]([OH:36])[CH3:35])[CH:18]=2)=[CH:4]1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Reactant: CC1CO1
Agent: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)Cn1cc(C2=C(c3cn(CC(C)O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
40 mg of a 60% suspension of sodium hydride in mineral oil was added to a solution of 327 mg of 3,4-bis-(3-indolyl)-1H-pyrrole-2,5-dione in 5 ml of DMF at 0° C. under nitrogen. After 0.5 hour the mixture was cooled to -20° C. and 108 mg of trimethylsilyl chloride were added. The mixture was allowed to warm to room temperature, then cooled to 0° C. and then a further 80 mg of sodium hydride were added thereto. After 0.5 hour at 0° C. 116 mg of propylene oxide were added and the mixture was stirred overnight. 5 ml of water were added and the mixture was extracted with dichloromethane. The organic phase was dried and evaporated. The residue was purified on silica gel with ethyl acetate/petroleum ether. Recrystallization from diethyl ether/petroleum ether gave 30 mg of 3,4-bis[1-(2-hydroxypropyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@@H:18](O)[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:28])CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@H:18]([F:28])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCN(CC)S(F)(F)F
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](F)[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile prepared according to example 1 (30 mg, 0.0983 mmol) in DCM (2 mL) at 0° C. was added DAST (0.02 mL, 0.1475 mmol) and the reaction mixture was stirred at same temperature for 2 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with DCM, water and extracted. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by preparative TLC method (40% EtOAc in hexane) provided the title compound.