Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:14]1([C:20]2[CH:24]=[C:23]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]3)[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([NH:33][CH2:32][CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:23]2[O:22][N:21]=[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:24]=2)[CH2:31][CH2:30]1)=[O:9]
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: CCOc1ncc(N)cc1C(=O)O
Product: CCOc1ncc(N)cc1C(=O)NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 288 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH3:20])[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: COc1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1ccccc1OCCCOc1cccc(CC(OC)C(=O)O)c1

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-methoxyphenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C20H24O6 [M+Na]+: 383.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[Li]CCCC.[Br:15][C:16]1[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=1>C1COCC1>[Br:15][C:16]1[N:21]=[C:20]([CH:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=2)[OH:23])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(Br)n1
Reactant: O=Cc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2cccc(Br)n2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-bromo-6-methoxy-pyridine (5.00 g, 26.59 mmol) in anhydrous THF (100 mL) @ −78° C. under N2 was added n-BuLi (11.701 mL, 2.5 M) dropwise. The mixture was stirred for 20 min and 6-Bromo-2-pyridine carboxaldehyde (4.95 g, 26.93 mmol was added. The mixture was warmed to 0° C. and stirred for 1 hr. The resulting mixture was quenched with saturated aqueous NH4Cl, and extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (15% EtOAc in hexanes) to give (6-bromopyridin-2-yl)(6-methoxypyridin-2-yl)methanol. 1H NMR (500 MHz, CDCl3) δ 7.60-7.49 (m, 3H), 7.37 (dd, 1H, J=7.1, 1.5), 7.12 (d, 1H, J=7.3), 6.64 (d, 1H, J=8.3), 5.78 (d, 1H, J=5.4), 5.27 (d, 1H, J=5.4), 3.97 (s, 3H), LRMS m/z, (M+H) Calcd.: 295.0, found 295.1.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:58][CH2:59][CH3:60])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][O:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[O:11])([CH3:4])[CH3:3]>C(O)(=O)C>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:58][CH2:59][CH3:60])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][O:14][C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])=[O:11])([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 61(b), 0.78 g of isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] was detritylated by heating it with 75% v/v aqueous acetic acid, to give 0.48 g of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]2)=[S:18])=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:31](Cl)(Cl)=[S:32]>C(Cl)Cl>[F:1][C:2]1[C:15]([N:16]=[C:17]2[N:19]3[N:20]([CH2:21][CH2:22][CH2:23][CH2:24]3)[C:31](=[S:32])[S:18]2)=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCCN1C(=O)COc2cc(F)c(NC(=S)N3CCCCN3)cc21
Reactant: S=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1C(=O)COc2cc(F)c(N=c3sc(=S)n4n3CCCC4)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
To a stirred, cold (-20°) solution of 12.0 g (0.0340 mole) of N-(7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl)aminothiocarbonylperhydropyridazine and 8.69 g (0.110 mole) of pyridine in 300 mL of methylene chloride was added dropwise 3.90 g (0.0340 mole) of thiophosgene. The resulting mixture was stirred at room temperature for approximately 18 hours. The reaction mixture was washed with dilute hydrochloric acid followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was treated with decolorizing charcoal and was filtered through a pad of silica gel. The filtrate was evaporated under reduced pressure leaving a solid residue. This residue (10.4 g) was combined with 3.6 g of a similar residue prepared in a similar manner. The resultant solid (14.0 g) was recrystallized from ethyl acetate and n-heptane to yield 11.7 g of 9-(7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, mp 112°-114° C. (corresponding to Compound 5 of Table 1).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]2[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=2)[CH:9]=1)=[O:30]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccccc2Cl)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (51.4 mg, 0.187 mmol) in CH2Cl2 (2 mL) was added 2-chlorophenyl isocyanate (0.25 μL, 0.207 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 140 as a colorless solid (76.5 mg, 95%). LCMS m/z (%)=428 (M+H35Cl, 100), 430 (M+H37Cl, 37) 1H NMR (400 MHz, DMSO-d6) δ: 9.36 (bs, 1H), 8.25 (bs, 1H), 8.15 (dd, J=8.33, 1.48 Hz, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J=2.70 Hz, 1H), 7.31-7.26 (m, 1H), 7.11 (d, J=8.92 Hz, 1H), 7.05-6.99 (m, 1H), 6.25 (d, J=1.84 Hz, 1H), 3.98 (t, J=6.36 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.FC1C=C(C=CC=1OCCN1CCCCC1)C(O)=O.[CH2:44]([N:46]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([O:74][CH2:75][CH2:76][N:77]2[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]2)=[C:70]([F:83])[CH:69]=1)[C:47]1[CH:52]=[C:51]([O:53]C)[CH:50]=[CH:49][C:48]=1[CH:55]1[CH2:64][CH2:63][C:62]2[C:57](=[CH:58][CH:59]=[C:60]([O:65]C)[CH:61]=2)[CH2:56]1)[CH3:45]>>[CH2:44]([N:46]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([O:74][CH2:75][CH2:76][N:77]2[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]2)=[C:70]([F:83])[CH:69]=1)[C:47]1[CH:52]=[C:51]([OH:53])[CH:50]=[CH:49][C:48]=1[CH:55]1[CH2:64][CH2:63][C:62]2[CH:61]=[C:60]([OH:65])[CH:59]=[CH:58][C:57]=2[CH2:56]1)[CH3:45]
Reactant: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 92.4 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (276 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (242 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([Sn](CCCC)(CCCC)CCCC)=[N:3]1.[C:25]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38](Br)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.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.[Cu]I>[C:25]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:4]3[C:5]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[N:2]([CH3:1])[N:3]=3)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2c1CCCCC2
Temperature: 80 °C
Yield: 60.4 %

Procedure:
To a solution of 1-methyl-3-tributylstannyl-1,4,5,6,7,8-hexahydrocycloheptapyrazole (74 mg, 0.17 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (60 mg, 0.14 mmol) in DMF (2 mL) were added Pd(PPh3)4 (8 mg, 0.007 mmol) and copper(I) iodide (5 mg, 0.028 mmol). The reaction mixture was heated at 80° C. for 1.5 h then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was absorbed on SiO2 and chromatographed with 20% to 50% EtOAc/hexanes to isolate 42 mg (60%) of 2-(1-methyl-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a pale orange-yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:28][CH3:29])[CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Reactant: CCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and iodoethane.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C[C:29]1[CH:33]=[C:32](CC(O)=O)[O:31][N:30]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:31])[CH2:33][C:29]#[N:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (9 mg, 32%), MS (ISP) m/z=399.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-(3-methylisoxazol-5-yl)acetic acid
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Li]CCCC.[F:14][C:15]([F:20])([F:19])[C:16](=[O:18])[CH3:17]>CCOCC>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:16]([OH:18])([CH3:17])[C:15]([F:20])([F:19])[F:14])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
A 500-mL round-bottomed flask was charged with 5-bromo-2-chloropyrimidine (8.53 g, 44.1 mmol, Combi-Blocks, San Diego, Calif.) and 100 mL of ether. After cooling to −78° C., n-BuLi (2.5 M in hexanes, 27.6 mL, 44.1 mmol) was added. This mixture was stirred at −78° C. for 10 min, then 1,1,1,tri-fluoro-2-propanone (14.82 g, 132 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After stirring for an additional 10 min at −78° C., the reaction was quenched with saturated aqueous NH4Cl. The solution was extracted with EtOAc, dried (MgSO4), filtered, and concentrated. Purification via column chromatography on silica gel (0 to 85% EtOAc in hexanes) gave 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (1.70 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH:16]([CH2:20][Cl:21])[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Cl:15][CH:16]([CH2:20][Cl:21])[C:17]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1)C(Cl)CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a stirred solution of 12.8 grams (0.10 mole) of 4-chloroaniline in 85 ml of chloroform was added 8 ml of pyridine. The mixture was cooled to 10° and 16.1 grams (0.10 mole) of 2,3-dichloropropionyl chloride was added dropwise at such a rate that the reaction mixture temperature did not exceed 35°. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to a solid residue. The solid was slurried with water and collected by filtration. The dried solid was recrystallized from methylcyclohexane-ethyl acetate using silica gel as a decolorant to give 19.7 grams of 2,3-dichloro-N-(4-chlorophenyl)propanamide; mp 127.5°-129°.
Reaction SMILES: [SH:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[C:5]([C:10]2([CH2:13][CH3:14])[CH2:12][CH2:11]2)=[N:4][N:3]=1.O.[CH3:16]I.CO>[OH-].[Na+]>[CH3:16][S:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[C:5]([C:10]2([CH2:13][CH3:14])[CH2:12][CH2:11]2)=[N:4][N:3]=1
Reactant: CCC1(c2nnc(S)n(N)c2=O)CC1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1(c2nnc(SC)n(N)c2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6 g of 3-mercapto-4-amino-6-(1-ethylcyclopropyl)-1,2,4-triazin-5(4H)-one is dissolved in 14.2 ml of 2 N NaOH and 20 ml of H2O in the cold state. To the solution is added a solution consisting of 4.8 g of methyl iodide and 35 ml of CH3OH. The solution is stirred for 3 hours at room temperature; H2O is added and the solution is subsequently extracted 3 times with 50 ml of ethyl acetate each time. The organic phase is separated, dried, and evaporated to dryness. The residue (5.7 g) is recrystallized from 0 ml of toluene/petroleum ether (40°-65° C.)=1:1. There is thus obtained 4 g of white crystals of the formula ##STR3## having a melting point of 93°-95° C. The n-propyl derivative can be prepared in a similar manner.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[C:9]([C:11]#[N:12])=[CH:10][C:5]2=[N:4][CH:3]=1>C1COCC1>[NH2:12][CH2:11][C:9]1[C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:7][N:6]2[C:2]([NH2:1])=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: N#Cc1cc2ncc(N)n2cc1-c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: NCc1cc2ncc(N)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A solution of 3-amino-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (517 mg, 1.71 mmol) in anhydrous THF (10 mL) was cooled to 0° C. (ice bath), treated with a 1M BH3 solution in THF (8.5 mL, 8.5 mmol) and stirred at 40° C. for 1 h. The reaction mixture was cooled to 0° C. (ice bath), quenched by the cautious addition of MeOH until gas evolution ceased and concentrated to dryness. The residue was suspended into a 2M HCl solution in water, stirred at RT for 10 min and evaporated to dryness. The resulting HCl salt was suspended into a 2M NaOH solution in water then extracted with DCM and AcOEt. The combined organic fractions were dried over Na2SO41 filtered, and evaporated under vacuum to give the crude 7-aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-3-ylamine (277 mg). HPLC: AtRet=0.81.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@@H:12]([OH:23])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:30][S:31]([O:23][C@@H:12]1[CH2:13][C@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[C@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](O)C[C@H]1COCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1COCc1ccccc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 55.3 %

Procedure:
To a stirred solution of (1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentanol (2.04 g, 0.00606 mol) in CH2Cl2 (96 mL) was added pyridine (2.4 mL, 0.030 mol), DMAP (100 mg, 0.001 mol), and methanesulfonyl chloride (700 μL, 0.0091 mol) under an atmosphere of nitrogen, The mixture was stirred 23° C. for 45 minutes, then warmed to 40° C. for 3 hours. To the reaction was added DMAP (100 mg, 0.001 mol) and methanesulfonyl chloride (700 μL, 0.0091 mol). After stirring for 40 min, the reaction was cooled then concentrated in vacuo. The residue was purified by flash chromatography (0 to 15% EtOAc/hexanes) to obtain 1.39 g (55%) of the title compound as one diastereomer (separated undesired diastereomer from step a).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:7]=2[N:8]=1.[CH2:24]([NH:26][CH2:27]C)C>ClCCl>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C:5]2[C:6]3[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:7]=3[N:8]=[C:3]([CH2:2][N:26]([CH3:27])[CH3:24])[N:4]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CCNCC
Reactant: COc1ccc(-c2nc(CCl)nc3sc(C)c(C)c23)cc1OC
Solvent: ClCCl
Product: COc1ccc(-c2nc(CN(C)C)nc3sc(C)c(C)c23)cc1OC
Reaction time: 16 h
Yield: 44 %

Procedure:
A mixture of 2-chloromethyl-4-(3,4-dimethoxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidine (1.0 g), diethylamine (1.2 ml) and dichloromethane (30 ml) was stirred for 16 hours under reflux. The reaction mixture was concentrated under reduced pressure, which was dissolved in ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-methanol (5:1, v/v), was obtained 4-(3,4-dimethoxyphenyl)-5,6-dimethyl-2-(N,N-dimethylamino-methyl)thieno[2,3-d]pyrimidine (0.49 g, 44%). Recrystallization from isopropyl ether gave colorless prisms, m.p.118°-120° C.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.I[C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=1>>[CH2:50]([O:49][C:48]1[CH:47]=[C:46]([C:57]#[C:58][C:60]2[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=2)[N:45]=[N:44][C:43]=1[O:42][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: N#Cc1ccc(I)cc1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: N#Cc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 73 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 4-iodobenzonitrile in 73% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH:53][C:54]([C:56]3[S:57][C:58]([C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:59][CH:60]=3)=[O:55])[C:42]([N:44]3[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]3)=[O:43])=[CH:36][CH:35]=2)=[N:32][CH:33]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CC#N>[C:61]([C:58]1[S:57][C:56]([C:54]([NH:53][C@@H:41]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:31]3[N:30]=[CH:29][C:28]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)=[CH:33][N:32]=3)=[CH:35][CH:36]=2)[C:42]([N:44]2[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]2)=[O:43])=[O:55])=[CH:60][CH:59]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: OB(O)c1ccc(O)cc1
Reactant: COC(=O)[C@H]1CCN(C(=O)[C@H](Cc2ccc(-c3ncc(Br)cn3)cc2)NC(=O)c2ccc(C(C)(C)C)s2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CCN(C(=O)[C@H](Cc2ccc(-c3ncc(-c4ccc(O)cc4)cn3)cc2)NC(=O)c2ccc(C(C)(C)C)s2)C1
Temperature: 80 °C
Yield: 76 %

Procedure:
To a 10 ml flask were added (4-hydroxyphenyl)boronic acid (60.7 mg, 0.44 mmol), sodium carbonate decahydrate (26.4 mg, 0.44 mmol), methyl (S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate INT-35 (130.0 mg, 0.44 mmol), Pd(dppf)Cl2 (16.09 mg, 0.022 mmol), THF (2.0 mL), CH3CN (2.0 ml) and water (1.0 mL). The solution was degassed using N2 bubbling for 10 min. The reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was dried under reduced pressure to remove the solvent and diluted in DCM (20 mL). The mixture was extracted with DCM (3×10 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. The final compound was purified by column chromatography (50% DCM in hexane) to afford 102.0 mg (76%) of methyl (S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate INT-37 as a solid powder. LCMS-ESI (m/z) calculated for C34H36N4O5S: 612.3. found 613.3 [M+H]+, tR=3.138 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.81 (s, 1H), 9.13 (d, J=1.5 Hz, 2H), 8.77 (dd, J=11.4, 8.1 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 7.73 (d, J=3.8 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 6.99-6.84 (m, 3H), 4.88 (s, 1H), 3.72 (d, J=8.9 Hz, 1H), 3.62 (s, 1H), 3.59 (d, J=6.4 Hz, 1H), 3.50 (ddd, J=18.7, 12.0, 5.8 Hz, 1H), 3.36 (d, J=7.5 Hz, 1H), 3.27-3.16 (m, 1H), 3.18-2.97 (m, 3H), 2.15-1.95 (m, 2H), 1.88 (dd, J=12.5, 7.5 Hz, 1H), 1.32 (s, 9H).