Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH:7]=O.Cl.[NH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]1[C:24]2[CH:25]=[CH:26][N:27]=[C:28]([Cl:33])[C:29]=2[CH:30]=[CH:31][CH:32]=1)(=[O:22])=[O:21].CCN(CC)CC.[BH4-].[Na+]>CO>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]1[C:24]2[CH:25]=[CH:26][N:27]=[C:28]([Cl:33])[C:29]=2[CH:30]=[CH:31][CH:32]=1)(=[O:21])=[O:22]
Reactant: O=CCOc1ccccc1C(F)(F)F
Reactant: NCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCNCCOc1ccccc1C(F)(F)F)c1cccc2c(Cl)nccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A 4.2 mL of the (2-trifluoromethyl-phenoxy)-acetaldehyde stock solution (˜0.69 mmol) is added to a stirred mixture of 1-chloro-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide hydrochloride (200 mg, 0.621 mmol), 4 Å molecular sieve (400 mg) and NEt3 (0.19 mL, 1.4 mmol) in anhydrous CH3OH (5 mL) at ambient temperature under nitrogen. The resultant mixture is stirred for 16 hours. The mixture is cooled to 0° C. before it is treated with powdered sodium borohydride (53 mg, 1.4 mmol). The mixture is stirred at 0° C. for 1 hour and at ambient temperature for another 1 hour. After filtration and subsequent concentration in vacuo, the crude product is chromatographed on silica (gradient 0-5% CH3OH in CH2Cl2) to give 92 mg (0.19 mmol, 31% yield) of 1-chloro-isoquinoline -5-sulfonic acid {2-[2-(2-trifluoromethyl-phenoxy)-ethylamino]-ethyl}-amide. ESIMS: m/z 474 [(M+H)+, 35Cl], 476 [(M+H)+, 37Cl].
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C>[Br:20][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(C(F)(F)F)c1F
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(C(F)(F)F)c1F
Reaction time: 2.5 h

Procedure:
To a solution of 2-fluoro-3-trifluoromethylaniline (5.0 g, 28 mmol) in DMF (25 mL) is added a solution of NBS (5.0 g, 28 mmol) in DMF (25 mL). After 2.5 h, the reaction is partitioned between ether and saturated aqueous NaCl. The separated organic phase is washed twice with fresh saturated aqueous NaCl, dried over Na2SO4, and concentrated under reduced pressure to give 4-bromo-2-fluoro-3-trifluoromethylaniline as an oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16](I)[N:11]3[N:10]=2)[CH:8]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:21][C:22]1[N:23]=[CH:24][C:25]([C:16]2[N:11]3[C:12]([S:13][C:9]([C:7]4[CH:8]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:4]([NH2:18])=[N:5][CH:6]=4)=[N:10]3)=[N:14][CH:15]=2)=[CH:26][CH:27]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Nc1ncc(-c2nn3c(I)cnc3s2)cc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(-c2nn3c(-c4ccc(F)nc4)cnc3s2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 53 %

Procedure:
3-(trifluoromethyl)-5-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyridin-2-amine (0.100 g, 0.243 mmol, 1 eq) was dissolved in dioxane (1.5 mL), then 2-fluoropyridine-5-boronic acid (0.055 g, 0.389 mmol, 1.6 eq) was added followed by 2M aq. Na2CO3 (0.5 mL, 4 eq). The suspension was degassed (N2, 15 min) and equipped with an argon balloon. Pd(Ph3P)2Cl2 (0.043 g, 0.061 mmol, 0.25 eq) was quickly added, and the reaction flask was placed in a pre-heated bath (115° C.). After stirring at reflux temperature for 3 h the mixture was cooled to RT and concentrated. The residue was suspended in EtOAc and water, and the clear water phase was removed. The remainder was concentrated to dryness and triturated with Et2O, filtered off, washed with Et2O and dried in vacuo to afford the desired product (0.049 g, 53%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.14 min, [M+H]+ m/z 381.0; 1H-NMR (DMSO-d6): δ=8.93 (1H ,bs), 8.84 (1H, bs), 8.67-8.58 (1H, m), 8.24 (1H, bs), 7.92 (1H, s), 7.42-7.34 (3H, m) ppm
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([SH:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])[CH3:8].N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:9][C:7]([C:10]1[CH:15]=[C:14]([S:16][CH2:2][C:3](=[O:5])[CH3:4])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:6])[CH3:8]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
Chloroacetone (2.0 mL, 25.2 mM) is added to a 0° C. of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.0 g, 12.6 mM) and pyridine (2.0 mL, 25.2 mM) in methylene chloride (100 mL). The reaction mixture is allowed to warm to room temperature then cooled again to 0° C., and an additional amount of chloroacetone (2.0 mL, 25.2 mM) and pyridine (2.0 mL, 25.2 mM) is added along with K2CO3 (100 mg). The reaction mixture is again allowed to warm to room temperature. The mixture is diluted with ethyl acetate and washed once with dilute aqueous hydrochloric acid, four times with water, and once with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is crystallized from ethyl acetate:hexane to give 2.8 g (75.5%) of white crystals, mp 105°-106° C.
Reaction SMILES: CC(C)[C@@H](N1CC2C(=CC=C(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)C=2)C1=O)C(O)=O.[CH3:38][CH:39]([CH3:76])[CH2:40][C@H:41]([N:46]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[C:51]([C:55]3[CH:60]=[CH:59][C:58]([NH:61][C:62]([NH:64][C:65]4[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:73])[F:72])[CH:66]=4)=[O:63])=[CH:57][CH:56]=3)[CH:52]=2)[C:47]1=[O:75])[C:42]([O:44]C)=[O:43]>>[CH3:38][CH:39]([CH3:76])[CH2:40][C@H:41]([N:46]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[C:51]([C:55]3[CH:56]=[CH:57][C:58]([NH:61][C:62]([NH:64][C:65]4[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:72])[F:73])[CH:66]=4)=[O:63])=[CH:59][CH:60]=3)[CH:52]=2)[C:47]1=[O:75])[C:42]([OH:44])=[O:43]
Reactant: COC(=O)[C@H](CC(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Product: CC(C)C[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Yield: 88 %

Procedure:
The compound of example 388 was prepared analogous to the compound of example 361 by hydrolysis of the compound of example 387.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[C:25]([F:28])([F:27])[F:26])[CH2:13][C@H:12]2[CH3:29])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>ClCCl.[Cu]I>[CH3:29][C@H:12]1[N:11]([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:30]3[CH:34]=[N:33][CH:32]=[N:31]3)[CH:3]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[C:25]([F:27])([F:28])[F:26])[CH2:13]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(-n2cncn2)c1
Temperature: 166 °C

Procedure:
A mixture of 4-{(3R)-4-[(3-fluorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(trifluoromethyl)benzonitrile (349 mg, 0.82 mmol), 1,2,4-triazole (112.6 mg, 1.64 mmol), K2CO3 (226.7 mg, 1.64 mmol), and CuI (15.6 mg, 0.082 mmol) were charged to a microwave vial. NMP (3 mL) was introduced under nitrogen atmosphere and the reaction mixture was heated at 166° C. for 3 hr in an oil bath. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via prep HPLC under neutral condition to yield 4-((3R)-3-methyl-4-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile as a light tan color solid (176.8 mg, 45.3% yield). HRMS: calcd for C21H19F3N6O2S+H+, 477.13150. found (ESI-FTMS, [M+H]1+), 477.13303.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][O:2]1.[S:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18]>>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:16]3[S:12][C:13](=[O:18])[NH:14][C:15]3=[O:17])=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: O=Cc1ccc2c(c1)COC2
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)COC3)S1

Procedure:
Following the general method as outlined in Example 1, starting from 1,3-dihydro-2-benzofuran-5-carbaldehyde (intermediate 4) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH2:26][OH:27].Cl>C(N(CC)CC)C>[OH:27][NH:26][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1ccc(Oc2ccccc2)cc1)NO
Yield: 44 %

Procedure:
Following the procedure described in Example 1, step 4, but substituting 4-phenoxybenzoic acid for 5, followed by Example 18, step 2, 3, but substituting 4-phenoxybenzoyl chloride for benzoyl chloride, and then the resulting carboxylic acid was substituted for 37 in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 104 obtained in 44% yield. 1H NMR (300 MHz, 20% CD3OD in CDCl3): δ 7.81 (d, J=8.7 Hz, 2H), 7.23 (m, 2H), 7.08 (m, 1H), 6.94 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.1 Hz, 2H), 2.81 (t, J=7.2 Hz, 2H), 1.99 (m, 2H), 1.59 (m, 2H), 1.52 (m, 2H), 1.25 (m, 4H). 13C NMR (75 MHz, 20% CD3OD in CDCl3): δ 24.00, 25.02, 28.56(2), 32.48, 37.96, 116.99, 119.89, 124.41, 129.79, 130.15, 131.15, 155.11, 161.83, 171.14, 199.86.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][C:11]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([N+]([O-])=O)[CH:15]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:16]1[CH:15]=[C:14]([O:13][C:12]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:31])[F:32])=[CH:29][C:11]=2[Cl:10])[CH:19]=[CH:18][C:17]=1[N+:20]([O-:22])=[O:21])[CH3:9]
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of ethyl 3-aminopropionate hydrochloride (10.29 gm, 0.067 mol), 4-(2-chloro-4-(trifluoromethyl)phenoxy)-1,2-dinitrobenzene (5.96 gm, 0.016 mol) and 150 ml of dry dioxane there was added 9.12 gm (0.066 mol) of anhydrous potassium carbonate. The mixture was stirred at room temperature for about 48 hours. The resultant bright-yellow suspension was poured into water and extracted with ether. The etheral solution was then washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. Filtration and evaporation of the filtrate gave an orange oil which, when mixed with methanol yielded orange crystals which were isolated by filtration and dried to give the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2/[C:14](/[NH:17][OH:18])=[N:15]\[H])=[N:2]1.N1C=CC=CC=1.[CH2:29]([O:31]C(Cl)=O)C.CC(C)([O-])C.[K+].C(O)(=O)/C=C/C(O)=O>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]2[NH:15][C:29](=[O:31])[O:18][N:17]=2)=[N:2]1
Reactant: CCOC(=O)Cl
Reactant: [H]/N=C(/NO)c1ccccc1C=Cc1n[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(-c2ccccc2/C=C/c2n[nH]c3ccccc23)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]-N-hydroxybenzamidine (0.06 g, 0.22 mmol) obtained in Step 1 of Example 175 was dissolved in DMF (1.0 mL), and pyridine (35 μL, 0.43 mmol) and ethylchloroformate (0.12 mL, 1.1 mmol) were added thereto, followed by stirring at 0° C. for 30 minutes. The mixture was added with water and the precipitated solid was collected by filtration and the solid was dried. The obtained solid was dissolved in toluene (2.0 mL) at 0° C. and added with potassium tert-butoxide (85 mg, 0.76 mmol), followed by stirring at 60° C. for 2 hours. Then, the mixture was neutralized using aqueous fumaric acid solution. The reaction mixture was extracted with ethyl acetate and the organic layer was concentrated. The residue was triturated in a mixed solvent of ethyl acetate/hexane to obtain Compound 178 (18 mg, 23%).
Reaction SMILES: [P:1]([O:28]C)([O:26]C)([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2].C[Si](Br)(C)C>C(Cl)Cl.CC#N.O>[P:1]([OH:26])([OH:28])([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])[N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2]
Reactant: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)nn(CC(=O)C(C)(C)C)c2c1
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2c(C(OP(=O)(O)O)=C(C)C)nn(CC(=O)C(C)(C)C)c2c1
Reaction time: 2.5 h

Procedure:
Dissolve 120 mg 1-[1-(3,3-dimethyl-2-oxobutyl)-6-methoxy-1H-indazol-3-yl]-2-methylprop-1-en-1-yl dimethyl phosphate from Example 1 in 0.75 mL anhydrous DCM. Cool the solution in an ice bath under nitrogen. Add 108 mg trimethylsilyl bromide and let the reaction mixture sit at room temperature for 2.5 hours. Remove solvent under reduced pressure. The residue was dissolved in a mixture of MeCN and water and purified by RP-HPLC using 10-100% MeCN gradient with about 0.05% TFA to give the title compound as a colorless solid after lyophilization. This reaction can also be carried out in MeCN. The title compound can also be purified by recrystallization in anhydrous MeCN.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[C:10]([O:17][CH2:18][CH3:19])(=[O:16])[C:11]([O:13]CC)=O.[NH4+].[Cl-]>C1COCC1>[CH3:8][CH:5]1[CH2:6][CH2:7][CH:2]([C:11](=[O:13])[C:10]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][CH2:4]1
Reactant: CC1CCC(Br)CC1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CCC(C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A Grignard reagent prepared from 1-bromo-4-methylcyclohexane (20.0 g, 0.11 mol) and magnesium (2.9 g, 0.12 mol) in THF (110 ml) was added dropwise (during a period of 80 min) to a mechanically stirred solution of diethyl oxalate (16.0 g, 0.11 mol) in THF (250 ml) at −78° C. The mixture was left stirring for 2 h and then slowly warmed up to 0° C. A saturated solution of NH4Cl (100 ml) was added and the formation of a white precipitate was observed. Extraction with diethyl ether (2×), washing with water, drying (Na2SO4) and concentrating afforded 22.6 g of the crude compound. Kugelrohr distillation of 10 g (100° C./2 mbar) gave 7.74 g (76%) of ethyl 2-(4-methylcyclohexyl)-2-oxoacetate as a slightly yellow oil (mixture of cis/trans isomers ca. 1:3).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(OCCO)C.C(OCC)C>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][N:17]=[C:4]2[OH:5]
Reactant: N=CN
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CC(=O)O
Solvent: CCOCCO
Solvent: CCOCC
Product: Oc1ncnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Preparation D12, Step 1: A mixture of 2-amino-5-bromobenzoic acid (5.7 g, 24.78 mmol) and formamidine acetate (5.2 g, 49.5 mmol) in 2-ethoxyethanol (50 mL) was heated at reflux for 4 h. The reaction was cooled to room temperature, allowed to stand overnight, then diluted with diethyl ether (20 mL) to further precipitate the product. The solids were collected by filtration, rinsed with 2-ethoxyethanol (10 mL), diethyl ether (2×50 mL), and air dried to yield 4.4 g of 6-bromoquinazolin-4-ol as a tan solid. MS (ES+)=225/227 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]([CH2:15][S:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6].N1C=CN=C1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].O>CN(C=O)C>[Si:41]([O:1][C@@H:2]([CH2:15][S:16][C:17]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC[C@H](C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3.72 g (7.88 mmol) of the crude product of Example 21 dissolved in 10 mL of DMF was added 2.68 g (0.039 mol) of imidazole followed by 2.85 g (0.019 mol) of t-butyldimethylsilyl chloride. The reaction mixture was stirred at room temperature for 2 h and then poured into 200 mL of H2O. The resulting solution was extracted with ether and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 10 mL of methanol/THF (1:1) and 5.0 mL of 1N NaOH solution was added. After stirring for 0.75 h at room temperature the reaction mixture was acidified with 5% HCl solution to pH 5 and then extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 4.76 g (100%) of the desired product as a colorless oil. Electrospray Mass Spec: 603.5 (M-H)-.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](=[O:10])([O:8][CH3:9])OC>>[CH3:9][O:8][C:5]([NH:3][CH2:2][CH2:1][NH:4][C:5]([O:8][CH3:9])=[O:10])=[O:10]
Reactant: COC(=O)OC
Reactant: NCCN
Product: COC(=O)NCCNC(=O)OC
Reaction time: 24 h

Procedure:
Ethylene diamine (6 g) and dimethyl carbonate (18 g) were mixed together in a round bottom flask at 20° C. TBD (0.1 g) was added and the mixture allowed to stand for 24h. After this time a white solid product was collected and recrystallised from methanol to give bis (methoxycarbonyl) ethylene diamine. NMR and IR spectra were consistent with the desired compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([NH:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][NH:20][C:19]3=[O:23])[N:8]=2)=[CH:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>ClCCl.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>[O:23]=[C:19]1[NH:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][NH:15][C:9]1[N:8]=[C:7]([C:5]2[S:6][C:2]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:3][CH:4]=2)[C:12]([C:13]#[N:14])=[CH:11][N:10]=1
Reactant: N#Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(Br)s1
Reactant: OB(O)c1cccs1
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: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(-c2cccs2)s1
Temperature: 130 °C

Procedure:
4-(5-Bromothiophen-2-yl)-2-(2-(2-oxoimidazolidin-1-yl)ethylamino)pyrimidine-5-carbonitrile (0.08 g, 0.2 mmol), thiophen-2-ylboronic acid (0.052 g, 04 mmol), sodium carbonate (1.5 mL of 2 M solution, 1 mmol) were added to a microwave tube containing ethanol (1.5 mL). The tube was flushed with nitrogen and tetrakis(triphenylphosphine)palladium (0.06 g, 0.054 mmol) was added. The tube was capped and heated to 130° C. for 30 min in a Personal Chemistry microwave. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and purified by flash chromatography on silica gel using a gradient of 0 to 10% methanol in dichloromethane to afford a yellow solid which recrystallized from ethyl acetate. Yield=0.066 g. MS (M+H)+ 397.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].Cl.Cl.[CH2:8]([NH:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[C:18]1([CH3:25])[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[CH2:8]([N:15]1[C:25]2[C:18](=[CH:19][CH:24]=[C:1]([OH:4])[CH:2]=2)[C:23]([CH2:22][CH2:21][CH3:20])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccccc1C
Reactant: NNCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCc1nn(Cc2ccccc2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Fluoro-4-hydroxyphenyl)butan-1-one (3.468 g) that can be produced by the method described in Reference Example 16 or the like, sodium acetate (7.57 g; manufactured by Wako Pure Chemical Industries, Ltd.), and benzylhydrazine dihydrochloride (5.48 g; manufactured by Wako Pure Chemical Industries, Ltd,) were suspended in xylene (200 mL; manufactured by Kanto Chemical Co., Inc.). The suspension was stirred overnight at reflux using a Dean-Stark apparatus. The reaction solution was cooled to room temperature, subsequently water was added thereto, and the mixture was extracted two times with ethyl acetate. The organic layer was washed two times with water and with brine, and was dried over anhydrous sodium sulfate. Subsequently, the solvent was evaporated under reduced pressure, and n-hexane was added to the residue. Precipitates were filtered, and thus the title compound (5.41 g) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[O:28]1[CH2:29][CH2:30][CH2:31][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1
Reactant: Fc1ccc2nnc(N3CCCOCC3)n2c1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCOCC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
To a solution of Intermediate A (145 mg, 0.614 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 74 mg, 1.84 mmol). The mixture was stirred at RT for 15 min, then a solution of Intermediate 49a (100 mg, 0.614 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 2.25 h. The cooled mixture was diluted with water and extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give the title compound as a pale brown gum (93 mg, 40%). LCMS (Method 3): Rt 0.43 min, m/z 380 [MH+].