Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])C)[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].C(N(C(C)C)CC)(C)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CC#N>[CH:15]([NH:13][C@H:10]1[CH2:9][C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:16])[CH3:17]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N[C@@H]1C[C@H](NC(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
Example 1, Alternative Preparation, Step 8: To a mixture of acetamide 11 (28.5 g, HCl salt, 73.6% free base assay), acetonitrile (100 mL), N,N,-di-isopropyl-N-ethylamine (61 mL) at room temperature was added a solution of 13 (˜21.2 g) in MeCN (˜450 mL). The homogeneous mixture was held overnight. Upon reaction completion (HPLC), the mixture was concentrated in vacuo to approx. 125 mL. A 9.5% aqueous solution of acetic acid (240 mL) was added and the aqueous phase was extracted with methylene chloride. The aqueous phase was separated and methyl tert-butyl ether (450 mL) was added, followed by 2N aqueous lithium hydroxide solution to adjust to pH>11.5. The organic layer was separated, washed with water and filtered. Approx. half of the ether phase was diluted with methyl tert-butyl ether (˜250 mL) and concentrated in vacuo. Heptane (45 mL) was added slowly below 60° C., followed by seed crystals of Example 1 (0.4 g). Additional heptane (125 mL) was added and the mixture was slowly cooled to room temperature and the resulting slurry was held overnight. The product was isolated by filtration, the cake was washed with heptane and dried in vacuo to constant weight to give N-((1R,2S,5R)-5-(isopropylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)-quin-azolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide 14 (15.0 g, 85% yield).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37](Br)=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH2:60]CCC.IC>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([CH3:60])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2C)CCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the intermediate 17 (0.95 g, 1.13 mmol) in anhydrous THF (12.0 mL) were added dropwise n-BuLi (2.5 M in hexane, 0.72 mL, 1.81 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 0.5 h at the same temperature. Then a solution of iodomethane (0.13 mL, 2.03 mmol) in THF (1.0 mL) was added dropwise, and the mixture was slowly warmed up to 0° C. for 3 h. The reaction mixture was quenched with 1 M HCl solution (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 20, which was used without further purification (0.88 g, 1.13 mmol, 100%).
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:11](Cl)(=[O:20])[C:12]1[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([O:1][CH2:2][P:3]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:10])=[O:20]
Reactant: CCOP(=O)(CO)OCC
Reactant: COc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)c1ccccc1OC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of diethyl (hydroxymethyl)phosphonate (1.2 mmol), 2-anisoyl chloride (1 mmol) and pyridine (2 mmol) in 5 mL CH2Cl2 were stirred at rt for 4 h. Extraction and chromatography provided diethylphosphonomethyl 2-methoxybenzoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:23]>C1(C)C=CC=CC=1>[Cl:23][C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Clc1ccc2cc(Cl)[nH]c2c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a stirred solution of 6-chloroindolin-2-one 1 (500 mg, 2.99 mmol) in toluene (25 mL) under inert atmosphere were added N,N-dimethylaniline (362 mg, 2.99 mmol) and POCl3 (918 g, 5.98 mmol) at RT; heated to 110° C. and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 10% aq. NaHCO3 solution (30 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 5% EtOAc/Hexanes to afford compound 2 (350 mg, 63%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.09 (br s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.28 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.39 (s, 1H); MS (ESI): m/z 184 (M−H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[C:5]([OH:12])[CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[C:5]([OH:12])[CH:4]=1
Reactant: COc1ccc(C(C)=O)c(O)c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(OC)cc1O
Reaction time: 24 h
Yield: 99.3 %

Procedure:
1-(4-Methoxy-2-hydroxy-phenyl)-ethanone (11.0 g) was dissolved in MeOH (100 mL), treated with 10 wt % Pd/C (4.0 g, Degussa type) and stirred under a balloon of H2 for 24 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to give the product as an oil (10.0 g). 1H NMR (300 MHz, CDCl3): δ 1.20 (t, J=7.85 Hz, 3H) 2.60- (q, J=6.22 Hz 2H), 3.75 (s, 3H), 6.40 (dd, J=9.04 Hz, 2.64 Hz, 1H), 6.45 (d, J=2.64 Hz, 1H) 7.00 (d, J=8.29 Hz, 1H), 12.90 (s, 1H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]3[C:22]([CH:23]=[O:24])=[CH:21][N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1>CCOCC>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]3[C:22]([CH:23]([CH2:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[OH:24])=[CH:21][N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc2c(c1)sc1ncc(C=O)n12
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc2c(c1)sc1ncc(C(O)CCc3ccccc3)n12

Procedure:
Magnesium (0.146 g) in anhydrous ether (15 mL) was treated with (2-bromoethyl)benzene (0.82 mL) and reacted for 2.5 hours. Solid 7-Methoxy-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3) (0.46 g) was added and reacted for 24 hours. The reaction mixture was quenched with 5% ammonium chloride solution and product was extracted into ethyl acetate. Drying and evaporation of solvent gave crude 7-Methoxy-α-(2-phenylethyl) imidazo[2,1-b]benzothiazole-3-methanol (Formula M-4) which was recrystallized from acetonitrile solution to provide pure 7-Methoxy-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol (Formula M-4) (0.60 g), m.p. 166-167°.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)=[CH:17][CH:16]=3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>ClCCl>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:13]([N:10]3[CH2:11][CH2:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)=[O:14])=[CH:16][CH:17]=2)[S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[CH:30][CH:29]=1)#[N:28]
Reactant: N#Cc1ccc(CNc2ccc(C(=O)N3CCN(c4ccccc4)CC3)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(CN(c2ccc(C(=O)N3CCN(c4ccccc4)CC3)cc2)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 23.5 %

Procedure:
A mixture of 4-{[4-(4-Phenyl-piperazine-1-carbonyl)-phenylamino]-methyl}-benzonitrile (50 mg, 0.13 mmol), phenylsulfonylchloride (80 mg, 0.42 mmol) and pyridine (0.04 mL, 0.44 mmol) in dichloromethane (5 ml) was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and the quenched by the addition of water (4 ml). The organics were collected, dried over magnesium sulfate and concentrated in vacuo The residue was purified by preparative thin layer chromatography (dichloromethane/ethyl acetate 1:1) to afford the title compound as a white solid (16.4 mg, 27% yield). HPLC retention time 6.71 min. Mass spectrum (ES+) m/z 475 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)([O-])[O-].C1(C)C=CC(S([CH2:37][C@@H:38]2[NH:42][C:41](=[O:43])[CH2:40][CH2:39]2)(=O)=O)=CC=1>CN(C=O)C>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:37][C@@H:38]5[NH:42][C:41](=[O:43])[CH2:40][CH2:39]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: Cc1ccc(S(=O)(=O)C[C@H]2CCC(=O)N2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CCC(=O)N1
Temperature: 90 °C
Yield: 6.7 %

Procedure:
To a solution of 7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (800 mg, 2.6 mmol), (prepared as described for the starting material in Example 107), in DMF (20 ml) was added powdered potassuim carbonate (1.08 g, 7.8 mmol) and (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (1.13 g, 4.2 mmol). The reaction was then heated at 90° C. for 4 hours. The inorganic material was filtered off and the DMF removed by evaporation. The residue was then purified by chromatography eluting from methylene chloride to 12% methanol/88% methylene chloride (+1% ammonium hydroxide). A small portion was recolumned using the same gradient. The product was evaporated, triturated with ether and filtered to give (5R)-4-(1H-indol-5-yloxy)-6-methoxy-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (70 mg, 6.5%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:19]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:19]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)c1
Yield: 91.9 %

Procedure:
Following general procedure F, {6-Bromo-4-[3-(2-(dimethylamino)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (54 mg, 0.123 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.185 mmol) to afford the desired product (57 mg, 92%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.44 (s, 1H), 8.21 (dd, J=8.8, 1.9 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.66-7.57 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.50 (s, 1H), 7.39 (dd, J=7.8, 2.2 Hz, 1H), 7.12 (d, J=11.5 Hz, 1H), 6.96 (s, 1H), 3.40-3.32 (m, 2H), 3.18-3.11 (m, 2H), 2.97-2.86 (m, 8H), 1.26-1.15 (m, 4H); ESI MS m/z 504 [C29H27ClFN3O2+H]+; HPLC 96.4% (AUC), tR=11.15 min.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]([CH2:19][CH2:20][CH3:21])=[C:14](Cl)[C:13]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>C(O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[C:13]=2[CH:23]=1
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCc1c(NCCOC)c2cc(Br)ccc2oc1=O

Procedure:
Triethylamine was added to a solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (0.5 g), in dry ethanol (10 ml) followed by 2-methoxyethylamine (0.16 ml). The mixture was heated at reflux under nitrogen overnight, evaporated and the residue extracted with ethyl acetate and the extract washed with dilute hydrochloric acid, brine, dried and evaporated under reduced pressure. The residue was triturated with ethanol and light petroleum (b.p. 40-60° C.) to give 6-bromo-4-(2-methoxyethylamino)-3-propyl-2H-1-benzopyran-2-one, m.p. 75-7° C. (compound 21).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[O:30]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>>[O:30]1[C:34]2([CH2:39][CH2:38][N:37]([C:2]3[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=3)[C:5]([NH:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:10][CH:9]=3)=[O:6])[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCC3(CC2)OCCO3)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and 1,4-dioxa-8-aza-spiro[4.5]decane under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.29 (d, 1H), 8.20 (m, 1H), 7.88 (m, 1H), 7.59 (m, 2H), 7.42 (d, 2H), 7.19 (d, 1H), 7.01 (d, 1H), 4.31 (t, 2H), 3.95 (s, 4H), 3.75 (m, 4H), 3.61 (m, 4H), 2.88 (t, 2H), 2.60 (m, 4H), 2.66 (m, 4H). MS: 519.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]([CH3:61])([CH3:60])[CH3:59])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:58]([NH:55][C:56]([N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1)=[O:57])([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)N=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 32 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-isocyanato-2-methyl-propane as starting materials in 32% yield. LCMS for C29H36ClN8O2 (M+H)+: m/z=563.3.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[O:8][C@@H:7]([CH2:9][OH:10])[C@H:6]([CH2:11][OH:12])[O:5]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C>CN(C)C=O>[CH2:14]([O:12][CH2:11][C@@H:6]1[O:5][C:4]([CH3:13])([CH3:3])[O:8][C@H:7]1[CH2:9][OH:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)O[C@@H](CO)[C@H](CO)O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(C)O[C@@H](CO)[C@H](COCc2ccccc2)O1
Reaction time: 1 h
Yield: 73.2 %

Procedure:
7.71 g of sodium hydride (content: 60%) (193 mmol) was added portionwise to a solution of 30.92 g of (+)-2,3-O-isopropylidene-L-threitol (191 mmol) in N,N-dimethylformamide (285 ml) under a nitrogen atmosphere and under ice-cooling over 45 minutes, and the mixture was stirred at the same temperature for one hour. 23.8 ml of benzyl bromide (200 mmol) was added to the reaction mixture over 30 minutes, and the mixture was stirred at the same temperature for three hours. 2.2 ml of acetic acid (38 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=2/1-1/1) to obtain 35.27 g of the title compound (yield: 73%).
Reaction SMILES: [CH2:1]([C:4]1([CH2:16][CH2:17][CH3:18])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[CH:15])[CH:12]=2)[S:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.I[C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>[Cu]I.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>[CH2:16]([C:4]1([CH2:1][CH2:2][CH3:3])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[C:15][C:27]3[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=3)[CH:12]=2)[S:7][CH2:6][CH2:5]1)[CH2:17][CH3:18]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(CCC)(CCC)CCS2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC1(CCC)CCSc2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A mixture of 0.338 g (1.47 mmol) of 4,4-dipropylthiochroman-6-yl)acetylene (Compound 31), 24 mg, (0.13 mmol) of copper (I) iodide, and 2.54 g (25 mmol of triethylamine were degassed with argon for 15 minutes. To the suspension was added 0.57 g (2.07 mmol) of ethyl 4-iodobenzoate (compound 22) and then 0.12 g (0.17 mmol) of bis(triphenylphosphine)palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 55° C. for 16 hours.
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].[C:26](Cl)(=[O:28])[CH3:27]>ClCCl.N1C=CC=CC=1>[Cl:25][C:8]1[CH:9]=[C:10]([F:24])[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])=[CH:12][C:7]=1[N:6]([S:3]([CH2:2][Cl:1])(=[O:5])=[O:4])[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(c1cc(N2C(=O)[C@H]3C[C@H](F)CN3C2=O)c(F)cc1Cl)S(=O)(=O)CCl

Procedure:
To a solution of the title compound of Example 1, Step H (4.14 g, 10 mmol) in anhydrous dichloromethane (200 mL) and pyridine (5 mL) was added a solution of acetyl chloride (0.863 g, 11 mmol) in dichloromethane (10 mL) dropwise at room temperature. After completion of the reaction (monitored by tlc), the organic phase was washed with water (50 mL) and diluted with HCl (5%, 50 mL). The organic layer was separated, dried (MgSO4), and the solvent was removed in vacuo to give the title compound of Step A, a compound of this invention, as a white solid (4.3 g, 94%) melting at 198-200° C. 1H NMR (CDCl3) δ 7.56 (m, 2H), 5.52 (m, 1H), 5.40 (dd, 1H), 4.84 (d, 1H), 4.62 (dd, 1H), 4.08 (m, 1H), 3.62 (m, 1H), 2.68 (m, 1H), 2.05 (s, 3H), 1.98 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11]([CH2:22][C:23]([OH:25])=O)=[N:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]1=2.[C:26](N1C=CN=C1)([N:28]1C=CN=[CH:29]1)=O.CNC>O1CCCC1>[CH3:26][N:28]([CH3:29])[C:23](=[O:25])[CH2:22][C:11]1[C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[N:2]([CH3:1])[C:3]=2[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c2ccccc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1nn(-c2ccccc2)c(=O)c2c1c1ccccc1n2C
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.7 %

Procedure:
A suspension of 1 g (3 mmol) of 5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and of 0.7 g (4.3 mmol) of 1,1′-carbonylbis-1H-imidazole in 200 ml of tetrahydrofuran is stirred for 2 h at 60° C. The reaction mixture is cooled to 25° C., an excess of liquefied dimethylamine in solution in tetrahydrofuran is added and the reaction mixture is stirred for 72 h at room temperature. It is concentrated under reduced pressure, 300 ml of water are added and the precipitate is collected by filtration, washed with water and with ether and recrystallized from propan-2-ol. 0.75 g (2 mmol) of solid is isolated.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH2:8]([SH:10])[CH3:9].[NH2:11][C:12]1[N:20]=[C:19](Cl)[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[Cl-].[Na+].O>[NH2:11][C:12]1[N:20]=[C:19]([S:10][CH2:8][CH3:9])[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 110 °C
Yield: 80.9 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added ethanethiol (2 ml, 27 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 110° C. for 3.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (90 mg, yield 82%).