Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4F)c3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccccc1-c1cccc2[nH]c3c(c12)CCN(Cc1ccccc1)CC3
Yield: 63.1 %

Procedure:
A solution of lithium aluminum hydride (0.25 g, 6.59 mmol) in tetrahydrofuran (5.0 mL) and a solution of 3-benzoyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.247 g, 0.642 mmol) in tetrahydrofuran (5.0 mL) were reacted in a manner similar to Example 1 to give 0.15 g (63%) of the title compound as pale yellow crystals: mp 157-159° C.; 1H NMR (400 MHz, CDCl3) δ 7.86, 7.37-7.24, 7.18-7.10, 6.91, 3.72, 3.00-2.90, 2.75-2.61, 2.57-2.48, 2.42-2.33; 13C NMR (100 MHz, CDCl3) δ 161.9, 159.4, 137.6, 135.3, 132.5, 130.0, 129.3, 128.7, 128.0, 127.5, 127.0, 124.1, 122.4, 121.0, 115.7, 115.4, 114.1, 110.7, 62.0, 56.1, 53.9, 28.8, 24.9; IR (drift) 3405, 2887, 2811, 1485, 1453, 1418, 1346, 1335, 1221, 1121, 924, 817, 782, 757, 740 cm−1; MS (EI) m/z 370 (M+); Anal. Calcd for C25H23FN2: C, 81.05; H, 6.26; N, 7.56. Found: C, 80.82; H, 6.35; N, 7.47.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH2:11][CH2:12][N:13]=1.C(N(C(C)C)CC)(C)C.[C:25](Cl)(Cl)=[S:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:15]=[C:25]=[S:26])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH2:11][CH2:12][N:13]=1
Reactant: S=C(Cl)Cl
Reactant: CN1CCN=C1Sc1ccc(N)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN=C1Sc1ccc(N=C=S)cc1Cl
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3-chloro-4-(1-methyl-4,5-dihydro-1H-imidazol-2-ylsulfanyl)-phenylamine (5.0 g, 21 mmol) and diisopropylethylamine (5.37 g, 41.6 mmol) in dry tetrahydrofuran at 0° C. under N2 inert atmosphere, thiophosgene (2.39 g, 21 mmol) in tetrahydrofuran was added dropwise and stirred for 20 minutes. When the reaction was completed, the reaction mixture was concentrated at room temperature and taken in dichloromethane (100 mL), washed with water (2×50 mL) and dried over anhydrous MgSO4 to get the product as a brown solid (5.8 g, 99%). TLC: pet ether/ethyl acetate (8/2) Rf-0.4. LCMS (method A): mass found (M+H+, 282.0), Rt (min): 3.43, area % 71.5 (max); 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J=2.16 Hz, 1H), 7.57 (s, 1H), 7.31 (m, 1H), 7.28 (m, 1H), 6.43 (d, J=8.56 Hz, 1H), 3.61 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][C:8]=1[CH3:16])[CH3:2].FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[CH2:39][CH:40]([F:42])[F:41])=[CH:9][C:8]=1[CH3:16])[CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[CH3:2]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2[nH]ncc2cc1C
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2c(cnn2CC(F)F)cc1C
Yield: 65.2 %

Procedure:
Using the compound (1.46 g, 3.32 mmol) of Example 259, step B, and 2,2-difluoroethyl trifluoromethanesulfonate (957 mg, 4.47 mmol), and according to the method of Example 241, step C, the title compound (1.09 g, yield 65%) was obtained as a colorless amorphous solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]4[N:24]([CH3:25])[N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:29]([N:31](CC)CC)C.[ClH:36].CN.C(OP(C#N)(=O)OCC)C>O.CN(C=O)C>[ClH:36].[CH3:29][NH:31][C:26]([C:22]1[CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:6]3[C:3]4[CH:4]=[CH:5][S:1][C:2]=4[CH:9]=[CH:8][CH:7]=3)[CH2:11][CH2:12]2)[N:24]([CH3:25])[N:23]=1)=[O:28]
Reactant: CCN(CC)CC
Reactant: Cn1nc(C(=O)O)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: CCOP(=O)(C#N)OCC
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)n(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
A DMF solution of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylic acid (0.3 g, 0.75 mmol) was cooled on ice and triethylamine (0.73 ml, 5.2 mmol), methylamine hydrochloride (0.3 g, 4.5 mmol) and diethylphosphorocyanidate (DEPC)(0.25 ml, 1.4 mmol) were added thereto, and then, the mixture was stirred at room temperature for 24 hours. To the reaction solution, triethylamine (0.73 ml, 5.2 mmol), methylamine hydrochloride (0.3 g, 4.5 mmol) and DEPC (0.25 ml, 1.4 mmol) were added and the mixture was stirred at room temperature for 4 days. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extracted material was washed with water and dried over magnesium sulfate. The solution was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1-+ethyl acetate). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and a solution of 4N-hydrochloric acid/ethyl acetate was added thereto. The insoluble matter precipitated was obtained by filtration and dried to obtain N-methyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxamide hydrochloride (0.24 g) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][S:7][CH2:8][CH2:9][O:10][P:11]([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])=[O:12])[NH2:5].C(N(C(C)C)CC)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][S:7][CH2:8][CH2:9][O:10][P:11]([N:13]([CH2:14][CH2:15][Cl:16])[CH2:17][CH2:18][Cl:19])([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])=[O:12])[NH:5][S:38]([CH3:37])(=[O:40])=[O:39]
Reactant: COC(=O)[C@@H](N)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)NS(C)(=O)=O
Reaction time: 8 h

Procedure:
3-[[2-[[Bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-L-alanine methyl ester, 400 mg (0.8 mmol), was dissolved in 4 mL anhydrous tetrahydrofuran, and 550 μL (3.2 mmol) diisopropylethylamine added, followed by methanesulfonyl chloride, 181 mg (1.6 mmol). The reaction mixture was purged with argon and stirred overnight. After adding a further 275 μL (1.6 mmol) diisopropylethylamine, then tris(2-aminoethyl)amine-polystyrene resin, 480 mg (1.6 mmol), the mixture was agitated for 6 hours, then filtered and the filtrate evaporated to dryness under vacuum, giving N-(methanesulfonyl)-3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-L-alanine methyl ester, 397 mg. Purity was verified with ELSD and identity verified with 1H and 31P NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:22][NH:23][C:24]3[N:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][N:25]=3)=[O:15])=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:22][NH:23][C:24]3[N:25]=[CH:26][C:27]([CH:30]([OH:32])[CH3:31])=[CH:28][N:29]=3)=[O:15])=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1cnc(NC[C@@H]2CCCCN2C(=O)c2nn(C)cc2-c2ccc(F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1cnc(NC[C@@H]2CCCCN2C(=O)c2nn(C)cc2-c2ccc(F)cc2)nc1
Reaction time: 8 h

Procedure:
1-{2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone (0.2 g) was dissolved in methanol 20 ml) and sodium borohydride (0.4 g) added. The reaction was stirred overnight, water was added and stirring continued for 30 min. The reaction mixture was extracted with ethyl acetate (×3), the organic extracts combined, dried (MgSO4) and solvent removed at reduced pressure to give the title compound as a colourless foam.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:16])(=[O:3])[CH3:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:18]([Cl:17])(=[O:20])=[O:19])[C:7]=1[OH:16])(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)NCc1cc(C(C)(C)C)ccc1O
Product: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15.5 g (0.059 mole) of 2-acetamidomethyl-4-(1,1-dimethylethyl)-phenol are introduced at room temperature into 100 ml of chlorosulfonic acid. Stirring is continued for a further 15 minutes and the solution is stirred into ice water. The precipitate is filtered off with suction and recrystallized from toluene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:5].[N:13](OCCC(C)C)=O.C(O)(=O)C>C1C=CC=CC=1>[N+:5](=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3]([O:2][CH3:1])=[O:12])=[N-:13]
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: CC(C)CCON=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CCC(=[N+]=[N-])C(=O)OC

Procedure:
A solution of L-glutamic acid dimethyl ester (2.6 g, 14.8 mmol), isoamyl nitrite (2.13 mL, 15.9 mmol) and acetic acid (0.22 mL) in benzene (150 mL) is heated to reflux for one hour. The solution is washed with IN aqueous sulfuric acid, water, saturated sodium hydrogen carbonate solution, water and brine (50 mL each). The solvent is removed in vacuo to yield dimethyl 2-diazopentane-1,5-dioate which can be further purified by column chromatography.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]=1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]3([CH2:28][CH2:27][CH2:26][CH2:25]3)[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1>C(O)C>[CH3:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:2][NH2:3])=[O:11])=[CH:7][C:6]=1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]3([CH2:28][CH2:27][CH2:26][CH2:25]3)[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(c2)NC(=O)C32CCCC2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
Hydrazine monohydrate (0.67 mL, 13.8 mmol) was added to a stirred solution of methyl 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzoate (preparation 53a, 0.46 g, 1.3 mmol) in ethanol (6 mL) and the mixture was stirred at 80° C. After 3 days, the mixture was cooled and concentrated in vacuo. The crude material was purified by flash chromatography (50:1 dichloromethane/methanol) to give the title compound (0.16 g, 19%) as a solid.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16].Cl>C1(C)C=CC=CC=1>[CH2:1]([NH:6][C:15](=[O:16])[O:17][CH2:18][Cl:19])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)OCCl
Reactant: CCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCNC(=O)OCCl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3.84 ml of n-pentylamine and 5.02 ml of triethylamine in 38 ml of toluene was added dropwise to 24 ml of a solution of 2.39 ml of chloromethyl chloroformate in toluene while cooling in an ice bath over a period of 15 min, and the mixture was stirred at room temperature for 15 hr. 1 N hydrochloric acid (60 ml) was added thereto, followed by separation. The organic layer was washed with 60 ml of a 5% aqueous sodium hydrogencarbonate solution and 60 ml of 20% brine, was dried over anhydrous magnesium sulfate, and was filtered. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give 3.31 g of chloromethyl N-pentan-1-ylcarbamate.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[NH2:22][C@H:23]1[CH2:27][C:26](=[O:28])[N:25]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]1=[O:37].CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:30]([O:29][N:25]1[C:26](=[O:28])[CH2:27][C@H:23]([NH:22][S:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)(=[O:17])=[O:16])[C:24]1=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N[C@H]1CC(=O)N(OCc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C[C@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1OCc1ccccc1
Temperature: 25 °C
Yield: 35 %

Procedure:
4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl chloride (256 mg; 0.78 mmol), (3S)-3-Amino-1-benzyloxy-pyrrolidine-2,5-dione hydrochloric acid (112 mg; 0.44 mmol), Et3N (230 ul; 1.65 mmol) and DMAP (43 mg; 0.35 mmol) was dissolved in DMF (2 ml). The mixture was heated in a microwave oven at 200 W for 2×10 seconds, allowed to cool to room temperature and then heated for another 10 seconds at 200 W. Evaporation of solvent and the residue was partitioned between EtOAc and 5% KHSO4, separation. Organic phase were washed with H2O and brine, the combined waterphases was extracted twice with warm DCM. Organic phases were combined and evaporated directly onto Si-60 gel. Purified by flash chromatography on 20 g of Si-60 gel using a gradient solvent system of 100% iso-Hexane to 100% EtOAc. Fractions containing the product was evaporated to give the title compound as a slightly yellow solid. Obtained 78 mg (35% yield). Purity by H-nmr was 90%, considered pure enough to use in next step.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][S:6][C:5]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4]1>O.C(O)C>[O:3]1[CH2:8][CH2:7][S:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[CH:4]1
Reactant: CCOC(=O)CC1=COCCS1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1=COCCS1
Temperature: 60 °C
Yield: 78 %

Procedure:
A solution of sodium hydroxide (3.2 g.) in water (18 cc.) is added to a solution of ethyl (5,6-dihydro-1,4-oxathiin-3-yl )acetate (13.4 g.) in ethanol (134 cc.). The reaction mixture is heated for one hour at 60° C. and is then concentrated to dryness under reduced pressure (20 mm.Hg). The resulting residue is taken up in water (250 cc.), and the mixture extracted with diethyl ether (200 cc.), decanted and the ether phase is discarded. The aqueous phase is acidified to pH 1 by addition of 4N hydrochloric acid and is then extracted three times with diethyl ether (total 600 cc.). The ether fractions are combined, washed twice with water (total 200 cc.), dried over sodium sulphate and treated with decolourizing charcoal. After filtration and concentration to dryness under reduced pressure (20 mm.Hg), (5,6-dihydro-1,4-oxathiin-3-yl )acetic acid (8.9 g.) is obtained in the form of an oil which is used as it is.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[H-].[Na+].[Cl:33][C:34]1[N:39]=[C:38](Cl)[CH:37]=[CH:36][N:35]=1.C(OCC)(=O)C>O1CCCC1>[Cl:33][C:34]1[N:39]=[C:38]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)[CH:37]=[CH:36][N:35]=1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Oc2ccc3nc(Nc4ccnc(Cl)n4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.5 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (103 mg, 0.25 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (60% in oil, 80 mg, 2.0 mmol), and the mixture was stirred at room temperature for 10 min. 2,4-Dichloropyrimidine (149 mg, 1.00 mmol) was added to the reaction mixture, and the mixture was heated to 60° C. After 1 hr, the reaction mixture was cooled to room temperature and ethyl acetate was added thereto. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone) and the obtained solid was washed with ethyl acetate/hexane (=1/2) to give the title compound (27 mg, 21%) as a light blue solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]([CH2:19][CH3:20])[CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>C1COCC1.C(O)(=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([N:17]([CH2:19][CH3:20])[CH3:18])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: CCN(C)c1nc(Cl)nc2c1CCC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(C)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
2-Chloro-N-ethyl-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (160 mg, 0.556 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (124 mg, 0.556 mmol) in THF (1.5 mL) and acetic acid (1.5 mL). The reaction mixture was stirred overnight at 80° C. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (85.3 mg, 0.171 mmol, 30.7% yield). LC-MS (M+H)+=475.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.49-7.61 (1H, m), 7.38 (1H, br. s.), 7.23-7.34 (6H, m), 7.13 (1H, d, J=8.5 Hz), 7.05 (1H, s), 4.35 (1H, dd, J=9.3, 4.1 Hz), 3.69-3.82 (4H, m), 3.47 (2H, br. s.), 3.27-3.38 (4H, m), 3.11-3.23 (1H, m), 2.56-2.72 (1H, m), 2.24 (1H, ddd, J=9.0, 4.4, 4.3 Hz), 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Br:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>O1CCCC1>[Br:12][C:13]([F:20])([F:19])[C:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9])=[O:15]
Reactant: Nc1ccc(F)cc1O
Reactant: CCOC(=O)C(F)(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1O)C(F)(F)Br
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 105.6 %

Procedure:
To 2-amino-5-fluorophenol (14 g, 110 mmol) in dry tetrahydrofuran at 0° C. was added sodium hydride (55 wt % in mineral oil; 4.81 g, 110 mmol). The resulting mixture was stirred for 15 minutes at −15° C. Subsequently ethyl 2-bromo-2,2-difluoroacetate (24.59 g, 121 mmol) was added dropwise and the resulting mixture was stirred at 0° C. for two hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried with Na2SO4 and concentrated to yield 33 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=[O:19])[CH:13]([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Si](OS(C(F)(F)[F:34])(=O)=O)(C(C)(C)C)(C)C.[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl.C(#N)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=[O:19])[C:13]([F:34])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(=O)C(F)C3
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(=O)C(F)(F)C3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into a 500 ml flask, the product from step (a) (6.01 g, 20.65 mmol) dissolved in DCM (100 ml) was added. The solution was cooled to 0° C. and TEA (17.27 ml, 123.91 mmol) was added, followed by TBDMS-triflate (14.222 ml, 61.95 mmol). After 10 minutes, the ice bath was removed and the mixture was stirred at room temperature for 16 hours. The contents were washed with saturated aqueous NaHCO3, 1M citric acid, saturated aqueous NaHCO3, brine, and dried over Na2SO4. Evaporation of solvent yielded a brown liquid which was immediately dissolved in acetonitrile (100 ml). The solution was cooled to 0° C. and Selectfluor (14.6 g, 41.3 mmol) was added portion-wise at 0° C. over 30 minutes. The flask was then warmed to room temperature and stirred for 1 hour. The contents were partitioned between DCM and water and the aqueous layer was extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 40% EtOAc) gave the sub-title product an off-white solid (5.1 g). 1H NMR (300 MHz, CDCl3) δ7.45 (d, J=7.8 Hz, 1H); 7.23 (d, J=7.5 Hz, 1H); 4.16 (t, J=6.9 Hz, 2H); 3.63-3.57 (m, 6H); 3.46 (t, J=12.9 Hz, 2H); 3.01-2.98 (m, 2H); 1.27 (t, J=7.2 Hz, 3H); MS: ESI (positive): 310 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19]([C:21]1[CH:29]=[CH:28][C:24]2=[N:25][O:26][N:27]=[C:23]2[CH:22]=1)=[O:20]>C1COCC1>[N:25]1[O:26][N:27]=[C:23]2[CH:22]=[C:21]([C:19](=[O:20])[C:7]#[C:6][C:4]([CH3:8])([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])[CH3:5])[CH:29]=[CH:28][C:24]=12
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CON(C)C(=O)c1ccc2nonc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc2nonc2c1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a −78° C. stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (0.49 g, 2.367 mmol) in dry THF (20 mL), n-BuLi (3.70 mL, 5.917 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of N-methoxy-N-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide (0.557 g, 3.550 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.45 g, 63%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:9][S-:10].[Na+].O>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([S:10][CH3:9])[CH:7]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cnnc(Cl)c1
Yield: 76 %

Procedure:
3,5-Dichloropyridazine, which is known in the art, (2.0 g, 0.0135 moles) and sodium thiomethoxide (1.14 g, 0.0162 moles) were stirred in THF (50 mL) at RT under N2 for 2 h. The mixture was then poured into water and extracted 2×100 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated in-vacuo to give a crude solid which was recrystallized from cyclohexane/ethyl acetate to give 3-chloro-5(methylthio)pyridazine (1.64 g, 76% yield) as a brown solid, mp=98° C.-100° C.