Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([NH:19][CH3:20])=[CH:15][CH:14]=1>>[CH3:12][C:4]1[N:3]=[C:2]([N:19]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccncc1
Product: Cc1nc(N(C)c2ccncc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (0.178 g, 2.13 mmol) and (pyridin-4-yl)-methyl-amine (0.108 g, 1.84 mmol) by a procedure similar to Examples 125c (0.224 g, 49%). 1H NMR (CDCl3): 8.39 (m, 2H), 7.91 (d, J=8.4, 1H), 7.73 (ddd, J=1.2, 6.6, 8.4, 1H), 7.41 (m, 1H), 7.23-7.29 (m, 1H), 6.79-6.82 (m, 2H), 3.70 (s, 3H), 2.83 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]1>>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: O[C@H]1CCNC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CC[C@H](O)C3)cc2c1=O
Yield: 69 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (S)-pyrrolidin-3-ol according to the GPA affording 25 mg (69%) of a red powder. Rt=3.11 min.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[N:32]=[C:33]=[O:34])([CH3:24])[CH3:23]>O1CCCC1>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[NH:32][C:33](=[O:34])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1)([CH3:24])[CH3:23]
Reactant: Cc1cccc(C(C)C)c1N=C=O
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)Nc3c(C)cccc3C(C)C)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-isopropyl-6-methylphenyl isocyanate (558 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 30 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:19) to afford 10d as solid. Yield: 520 mg, 67.16%.
Reaction SMILES: Cl[CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].Cl.[Cl:12][C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1>ClCCl>[O:4]([CH:2]([N:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[N:15][C:16]1=[O:19])[CH3:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Cl)Oc1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Product: CC(Oc1ccccc1)n1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 by adding a solution of α-chloroethoxybenzene [see Preparation 8] (4.5 mmol) in dichloromethane (5 ml) to a solution from 5-chloropyrimidin-2-one hydrochloride (4.5 mmol) in dichloromethane (15 ml) at 5° C., and the mixture was stirred at room temperature for 2 h before being worked up. The product was a mixture of the desired N-isomer and the O-isomer in the ratio 3:2; yield 0.85 g (76%). The isomers were separated by chromatography on silica gel using chloroform as above; m.p. 92° C. (CH2Cl2 /Pet.ether). (Found: C58.02; H 4.51 Calc. for C12H11ClN2O2 : C57.49; H4.43) 1H NMR (CDCl3): δ 1.72 (Me, d, J 5 Hz), 6.47-7.3 (Ph,H-δ), 7.79 and 8.40 (H-4 and H-6, respectively, J 3 Hz). IR (KBr): 1665 cm-1 (CO). MS [70 eV, m/z (% rel. int.)]: 250 (l,M), 159 (30)), 157 (100), 121 (23), 77 (30), 65 (17).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[CH:16][CH:15]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(-c2ccc3ncccc3c2)cc1

Procedure:
N,N-Dimethyl-4-(quinolin-6-yl)aniline T505 was prepared using general procedure A from 6-bromoquinoline (52 mg, 0.25 mmol) and (4-(dimethylamino)phenyl)boronic acid (41 mg, 0.25 mmol). The product T505 was obtained as a yellow solid (42 mg, 67%). 1H NMR (400 MHz, CDCl3): δ 8.85 (dd, J=4.4, 1.6 Hz, 1H), 8.15 (m. 2H), 7.97 (dd, J=8.4, 1.6 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.63 (m, 2H), 7.38 (dd, J=8.4, 4.4 Hz, 1H), 6.84 (m, 2H), 3.01 (s, 6H); MS (ESI): 249 (M+H+).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:5]3[CH:6]=[N:7][C:8]4[C:4]3=[N:3][CH:2]=[N:1][CH:9]=4)=[CH:12][CH:13]=2)=[O:29])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: c1ncc2[nH]cnc2n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(-n2cnc3cncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from purine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 1.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Ni]>[N:10]1([C:7]2[CH:8]=[N:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cn1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCCCC2)cn1
Reaction time: 4 h
Yield: 121.3 %

Procedure:
6′-Nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (4.69 g, 22.6 mmol) was dissolved in THF (100 mL) to which Raney Nickel (1.08 g) was added. The reaction was shaken under a hydrogen atmosphere (50 psi) for 4 hours. The catalyst was removed by filtration and the solvent evaporated to give 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine as a purple solid (4.86 g, 85.7%). 1H NMR δ (400 MHz, CDCl3) 7.76 (d, J=2.4 Hz, 1H), 7.19 (dd, J=2.9, 8.8 Hz, 1H), 6.47 (dd, J=0.7, 8.8 Hz, 1H), 4.18 (s, 2H), 2.97 (m, 4H), 1.71 (m, 4H), 1.53 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[C:18]([OH:24])=[CH:19][CH:20]=[C:21]([F:23])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].CC1C=CC(S(O[C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][C@@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2cc(F)ccc2O)cc1Cl
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Product: COC(=O)[C@H](C)Oc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 11 step (vii) using the product of step (iii) and the product of example 11 step (vi).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](N)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:12]([O:15]C(=O)C)(=O)[CH3:13].O.[N:20]1C=CC=CC=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:13][C:12]([NH2:20])=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: c1ccncc1
Solvent: O
Product: NC(=O)Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 1,4-benzodioxan-6-amine (2.0 g, 13.2 mmol) in 5 mL of anhydrous pyridine at 0° C. was added acetic anhydride (1.87 mL, 19.9 mmol) and the solution was stirred at rt overnight. The solution was then added to 50 mL of water and was extracted with 2×50 mL of EtOAc. The extract was washed with 1N HCl, water and brine, then dried over MgSO2 and concentrated in vacuo to yield the title compound (1.82 g, 71%). 1H NMR (CDCl3): 7.13 (m, 2H), 6.88 (dd, 1H), 6.80 (d, 1H), 4.25 (s, 4H), 2.15 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][NH2:41]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: COCCCN
Product: COCCCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (488 mg, 0.96 mmol) and 3-methoxypropylamine (325 mg, 3.84 mmol) as starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O-:7])=[O:6].[NH2+:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc(O)c1
Solvent: CCO
Product: C1COCC[NH2+]1
Product: O=C([O-])c1cccc(O)c1
Yield: 70 %

Procedure:
In a conical flask, cold absolute ethanol (ca. 40 ml) was added to 99% pure 3-hydroxybenzoic acid (1.8495 g; 13.39 mmol). Dissolution of the acid was achieved at room temperature by constant stirring. Morpholine (1.1653 g, 13.39 mmol) was added dropwise to the acid solution. The reaction was exothermic and some white fumes were observed; the turbid white solution of the acid turned yellow on addition of the colourless morpholine. The opening of the conical flask was covered with parafilm which was then punctured to allow slow evaporation of the solvent at room temperature. Transparent white polyhedral crystals of morpholinium 3-hydroxybenzoate were formed within 24 hrs. The crystals were filtered and washed with small aliquots of cold ethanol. Yield >70% (not optimised).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[CH2:10]2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]
Reactant: COc1cc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NO2)cc(OC)c1O
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1c(OC)cc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NO2)cc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 78.3 %

Procedure:
2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenol (11b) (389.40 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.31 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (16d) (570 mg, 80% yield).
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[O:11][C:12]([F:15])([F:14])[F:13])([O-])=O.[N+:16](C1C=C(OC(F)(F)F)C=CC=1Br)([O-:18])=[O:17]>>[N+:16]([C:8]1[CH:9]=[CH:4][C:5]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:6][CH:7]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(Br)ccc1OC(F)(F)F
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1Br
Product: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1

Procedure:
2-nitro-4-bromotrifluoromethoxybenzene and 3-nitro-4-bromotrifluoromethoxybenzene: 48%
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1C1CCCNC1
Product: O=c1[nH]c2cnc3[nH]ccc3c2n1C1CCCN(S(=O)(=O)c2cccs2)C1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 1-piperidin-3-yl-3,6-dihydroimidazo-[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in pyridine, 1.00 mL), thiophene-2-sulfonyl chloride (7.3 mg) was heated at 90° C. for 16 hours. The reaction mixture was concentrated and redissolved in N,N-dimethylformamide. PS-Trisamine (50 mg), PS-Isocyanate (50 mg) was added and the mixture agitated at ambient temperature for 6 hours then filtered. The filtrate was concentrated in vacuo and purification by preparative high performance liquid chromatography gave 1-[1-(2-thienylsulfonyl)piperidin-3-yl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.3 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=O)[C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:16]=[CH:17][C:18]=3[O:19][C:10]=2[CH:9]=[CH:8][N:7]=1.[CH3:29][Mg]Br.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:28][C:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[CH2:29])[C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:16]=[CH:17][C:18]=3[O:19][C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)CCOc1nccc2oc3ccc(-c4cncnc4)cc3c(=O)c12
Reactant: C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1c2cc(-c3cncnc3)ccc2Oc2ccnc(OCCC(C)(C)C)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(3,3-dimethylbutoxy)-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridin-10-one (0.320 g, 0.852 mmol) in THF (8.00 mL) was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether) (0.483 mL, 1.449 mmol) was added dropwise. The mixture stirred at 0° C. for 1 h. The mixture was quenched at 0° C. with saturated aqueous ammonium chloride solution and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow film. This material was dissolved in chloroform (8.00 mL), pyridinium p-toluenesulfonate (10.71 mg, 0.043 mmol) was added, and the mixture was heated at reflux for 2 h. The reaction mixture was diluted with DCM and the solution was partitioned between DCM and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-(3,3-dimethylbutoxy)-10-methylene-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridine as a yellow solid. MS m/z=374.2 [M+H]+. Calcd for C23H23N3O2: 373.4.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18](OC(F)(F)F)=[CH:17][CH:16]=2)[C:3]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:41]1[CH2:45]OC[CH2:42]1.I[CH2:47][CH2:48][CH3:49]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[C:20]3[C:2](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:7]([CH2:47][CH2:48][CH3:49])[C:6]=2[CH3:5])[C:3]=1[CH:26]([CH2:42][CH2:41][CH3:45])[C:27]([O:29][CH3:30])=[O:28]
Reactant: C1CCOC1
Reactant: CCCI
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(OC(F)(F)F)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1c(C)n(CCC)c2ccccc12)CCCC3
Yield: 92.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.233 g; 0.57 mmol), LHMDS 1N in THF (0.85 mL; 0.85 mmol), 1-iodopropane (0.111 mL; 1.14 mmol) in DMF (2.8 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.129 g (50%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:57])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[O:46][C:47]=3[CH3:48])=[C:37]([O:55][CH3:56])[CH:36]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[CH3:56][O:55][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][C:38]=1[O:41][CH2:42][C:43]1[N:44]=[C:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:46][C:47]=1[CH3:48])[C:34]([NH:33][C:23]1[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:24]=1)=[O:57]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(C(=O)Nc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (215 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 38 mg), and the mixture was stirred at room temperature for 20 min. A solution of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzamide (433 mg) in N,N-dimethylformamide (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless amorphous form (205 mg, yield 38%) from a fraction eluted with ethyl acetate-hexane (1:1 to 1:0, v/v).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]3[NH:14][N:15]=[CH:16][C:9]=23)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[N:23][CH:22]=[CH:21][C:20]=2[C:19]=1[NH2:39].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].N.CO>C1COCC1.CC(O)=O.CO>[NH:14]1[C:10]2=[N:11][CH:12]=[N:13][C:8]([C:7]3[C:2]([NH:39][C:19]4[C:20]5[CH:21]=[CH:22][N:23]=[C:24]([NH:28][C:29]6[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=6)[C:25]=5[CH:26]=[CH:27][C:18]=4[CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=3)=[C:9]2[CH:16]=[N:15]1
Reactant: Fc1ncccc1-c1ncnc2[nH]ncc12
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1Nc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (30 mg, 139 μmol) and 6-methyl-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (49 mg, 153 μmol) in THF (3 mL) was treated with lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 627 μL, 627 μmol). The mixture was stirred at it for 3 h and then heated in a microwave at 100° C. for 20 min. The mixture was poured into MeOH (15 mL) and AcOH (0.5 mL) and then 2M NH3/MeOH (30 mL) was added. Solvent was removed in vacuo. The product was purified by flash chromatography eluting with MeOH/DCM (1-5%) to give N5-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-6-methyl-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine. MS (ESI, pos. ion) m/z: 513.2 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26].CC#N.O.CC#N>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])[C@H:10]([C:15]([CH3:22])([CH3:23])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Reactant: CC(C)CN
Solvent: O
Solvent: CC#N
Product: CC(C)CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C

Procedure:
The title compound is prepared as described above for Example 9/step F (Scheme 5) from (3S*,4S*)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and isobutylamine. MS (LC-MS): 401.1 [M+H]+; tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 3.70 min.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH:19](C#N)[C:18](=[O:22])[NH:17][C:16]3=[O:23])[C:8]2=[O:24])=[C:4]([F:27])[CH:3]=1.Br.O>C(O)(=O)C>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][C:18](=[O:22])[NH:17][C:16]3=[O:23])[C:8]2=[O:24])=[C:4]([F:27])[CH:3]=1
Reactant: N#CC1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Yield: 26.6 %

Procedure:
1'-(4-bromo-2-fluorobenzyl)-4-cyano-spiro-[pyrrolidine-3,3'-indoline]-2,2',5-trione (1.0 g.) was heated under reflux in 48% w/w hydrogen bromide in acetic acid (30 ml.) for 90 minutes. The solution was poured into water (120 ml.). The precipitate was collected, washed with water (100 ml.), air dried and recrystallised twice from 2-propanol to give 1'-(4-bromo-2-fluorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.25 g.), m.p. 218°-220° C.