Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([N:32]4[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]4)[C@@H:29]([OH:39])[C@H:28]3[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:19]=2)=[O:17])[CH2:11][CH2:10]1.FC(F)(F)C(O)=O.C(NC(=O)NCCCNC(C1N=C2C(N=CN2[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O)C.[CH3:113][N:114]([CH3:118])[C:115](Cl)=[O:116]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:113][N:114]([CH3:118])[C:115](=[O:116])[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([N:32]4[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]4)[CH:29]([OH:39])[CH:28]3[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:19]=2)=[O:17])[CH2:11][CH2:10]1
Reactant: CN(C)C(=O)Cl
Reactant: NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)CC1
Agent: CCNC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)C(O)C4O)c3n2)CC1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (4-amino-cyclohexyl)-amide trifluoroacetate (Example 83, first step a) using a procedure analogous to that of 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid [3-(3-ethyl-ureido)-propyl]-amide trifluoroacetate (Example 87) replacing ethyl isocyanate with dimethylcarbamic chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[Br:18][C:15]1[C:14]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:13][C:12]([Cl:11])=[N:17][CH:16]=1
Reactant: c1ccsc1
Reactant: Clc1ncc(Br)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ncc(Br)c(-c2cccs2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of thiophene (3.3 g, 39 mmol) in THF (100 mL) was cooled to −78° C. n-Butyllithium (2.5 M in hexane, 24 mL, 59 mmol) was added and the mixture stirred at −78° C. for 1 h. 2-Chloro-5-bromopyrimidine (7.5 g, 39 mmol) was added and the mixture stirred at −78° C. for 1 h. DDQ (17.7 g, 78 mmol) was added with stirring, followed by the addition of methanol (5 mL). The mixture stirred for 1 h and was then warmed to 0° C. and then to RT. The reaction mixture was poured into 0.5 M sodium ascorbate (aq) solution (100 mL), and allowed to stir for 1 h. The mixture was treated with saturated aqueous potassium carbonate solution (50 mL), and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via column chromatography on silica gel (eluting with 100% dichloromethane) to afford 5-bromo-2-chloro-4-(thiophen-2-yl)pyrimidine as a yellow solid. MS m/z=276 [M+H]+. Calc'd for C8H4BrClN2S: 275.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CNC2)=NC=1CC.[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:64][CH3:65])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][N:48](C(OCC3C=CC=CC=3)=O)[CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]>>[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:64][CH3:65])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][NH:48][CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl (3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 1.15, 1.22–1.34, 2.45, 2.71, 2.89, 3.06, 3.22, 3.41, 3.51, 3.65, 3.85, 4.51, 5.32, 6.88, 7.02, 7.24; IR (liq.) 2971 (s), 2935, 2496 (w), 2446, 2402 (w), 2261 (w), 2072 (w), 1605, 1566 (s), 1483 (s), 1441, 1395, 1287 (s), 1230 (s), 1045 (s) cm−1 HRMS (ESI) calcd for C21H29N4O2Cl+H1 405.2057. found 405.2044.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH2:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:3]1.O=C1N(C2C=CC(C3CCN(C(=O)COC(=O)C)CC=3)=C(F)C=2)C[C@H](CNC(=O)C)O1>>[OH:21][CH2:20][C:19]([N:16]1[CH2:17][CH:18]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([N:6]3[CH2:5][C@H:4]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:3][C:2]3=[O:1])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1)=[O:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)COC(C)=O)CC3)cc2)C(=O)O1
Agent: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)COC(C)=O)CC3)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)CO)CC3)cc2)C(=O)O1

Procedure:
Following the general procedure of EXAMPLE 40, and making non-critical variations but substituting (S)-(-)-N-[[2-oxo-3-[4-[1-(acetoxy)acetyl]-3,6-dihydro-2H-pyridin-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 59) for (S)-(-)-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,6-dihydro-2H-pyridin-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide, the title compound is obtained, HRMS (FAB) calcd for C19H23N3O5 +H: 374.1716. Found: 374.1713.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:14]([C:32](=[O:34])[NH2:33])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][N:45]([C:48](=[O:50])[CH3:49])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1>O1CCOCC1>[C:48]([N:45]1[CH2:44][CH2:43][N:42]([C:39]2[CH:40]=[CH:41][C:36]([NH:35][C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:23][CH2:24]4)[C:14]([C:32](=[O:34])[NH2:33])=[CH:13][N:12]=3)=[CH:37][CH:38]=2)[CH2:47][CH2:46]1)(=[O:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc(On3nnc4ccccc43)ncc2C(N)=O)CC1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(C(=O)OC(C)(C)C)CC4)n3)cc2)CC1
Reaction time: 3 h
Yield: 43.4 %

Procedure:
A mixture of tert-butyl 4-((2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (0.205 g, 0.438 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.192 g, 0.877 mmol) and pTsOH monohydrate (0.166 g, 0.874 mmol) in dioxane (4 mL) was stirred at 100 C. for 3 h. The mixture was then purified by HPLC to give tert-butyl 4-((2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (0.105 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH3:32])(=[O:41])=[O:40])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1ccccc1S(=O)(=O)NC(=O)NCCc1ccc(-n2nc(C)c(-c3ccccc3)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2-methylbenzenesulfonamide: 1H-NMR (CDCl3) δ 7.93 (1H, d, J=8.3 Hz), 7.50-7.21 (12H, m), 6.29 (1H, br.s), 3.49-3.43 (2H, m), 2.81 (2H, t, J=6.5 Hz), 2.62 (3H, s), 2.33 (3H, s), 2.24 (3H, s).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Br)[C:29]#[CH:30]>C1(C)C=CC=CC=1>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:30][C:29]#[CH:28])[C:8]1=[O:21]
Reactant: C#CCBr
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Solvent: Cc1ccccc1
Product: C#CCn1c(=O)n(O)c(=O)c2oc3ccccc3c21

Procedure:
Following general procedure B2 and D1, 3-(2,4-dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with an 80% solution of propargyl bromide in toluene and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 3.49 (t, J=2 Hz, 1H); 5.15 (d, J=2 Hz, 2H); 7.53 (dd, J=8 Hz, 1H); 7.70 (dd, J=8 Hz, 1H); 7.85 (d, J=8 Hz, 1H); 8.19 (d, J=8 Hz, 1H); Ret. time=1.86 min., m/z=257.0.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])(C)(C)C.Cl.[CH3:34][O:35][C:36]([NH:38][CH:39]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)C(O)=O)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.CCOC(C)=O>[CH3:34][O:35][C:36](=[O:37])[NH:38][CH:39]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:6](=[O:7])[N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([B:24]3[O:25][C:26]([CH3:32])([CH3:31])[C:27]([CH3:30])([CH3:29])[O:28]3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 66.1 %

Procedure:
2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (530 mg, 1.21 mmol) was dissolved in DCM (4 mL) and treated with HCl (4M in dioxane, 1 mL, 4 mmol). The reaction mixture was stirred at RT for 19 h then the solid was filtered off and rinsed with DCM. After being thoroughly dried (461 mg, 92%), a portion of this solid (200 mg, 0.485 mmol) was combined with Methoxycarbonylamino-phenyl-acetic acid (122 mg, 0.582 mmol) and HATU (221 mg, 0.582 mmol) were suspended in DCM (5 mL) and K3PO4 (309 mg, 1.455 mmol) was added. After stirring 24 h, the reaction mixture was diluted with EtOAc and washed with 1M LiOH and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (75% to 100% EtOAc) to provide the title compound (204 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[C:4]([C:9]2[C:10]3[C:11](=[N:17][N:18](COCC[Si](C)(C)C)[CH:19]=3)[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:37]([O-])=O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[O:28][C:3]1[C:2]2[N:1]=[N:37][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[N:18][NH:17][C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1
Reactant: Cn1cc(-c2ccc(N)c(N)c2Oc2ccc(F)cc2F)c2cn(COCC[Si](C)(C)C)nc2c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(-c2ccc3[nH]nnc3c2Oc2ccc(F)cc2F)c2cn[nH]c2c1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (103 mg, 0.200 mmol) in acetic acid (0.40 mL) was treated with water (1.0 mL) followed by sodium nitrite (69.0 mg, 1.00 mmol) and stirred at 20° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate (2×) and brine, dried with magnesium sulfate, filtered, and concentrated to give the SEM-protected intermediate which was used without further purification. The crude intermediate was diluted with methylene chloride (4.00 mL) and trifluoroacetic acid (4.00 mL) and stirred at 40° C. for 3 h. The reaction mixture was concentrated, diluted with acetonitrile, adjusted to pH 7 with 1 M NaOH, and purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (16 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ 14.05 (br s, 1H), 7.86-7.72 (m, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.31-7.22 (m, 1H), 6.85-6.73 (m, 2H), 3.53 (s, 3H); LCMS calculated for C19H13F2N6O2 (M+H)+: m/z=395.1. found: 395.1.
Reaction SMILES: C([Si]([C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1)(CC)CC)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:9]([C:10]1[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1)#[CH:8]
Reactant: CC[Si](C#Cc1ccc(C(=O)OC)nc1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 6.1 %

Procedure:
To a solution of methyl 5-((triethylsilyl)ethynyl)picolinate (1.68 g, 6.05 mmol) in THF (12.11 ml) was added TBAF, 1.0M in THF (6.68 ml, 6.68 mmol, Sigma Aldrich). The reaction was allowed to stir for 6 hours at RT. The reaction was concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through silica gel column eluting with a gradient of 10% to 100% EtOAc in hexane followed by 1% AcOH in EtOAc, to afford 5-ethynylpicolinic acid (0.05 g, 0.37 mmol, 6.10% yield).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.I[CH3:10].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([CH3:10])[CH2:4]1
Reactant: CI
Reactant: O=C1NCC(CCl)O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CC(CCl)OC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-(Chloromethyl)-1,3-oxazolidin-2-one (500 mg, 3.69 mmol) and iodomethane (0.27 mL, 4.43 mmol) were dissolved in DMF (5 mL) and the resulting solution was cooled to 0° C. Sodium hydride (60%, 177 mg, 4.43 mmol) was added followed by additional DMF (2 mL). The reaction was warmed to room temperature and stirred for 4 hours. Additional iodomethane (0.14 mL, 2.22 mmol) and sodium hydride (60%, 88 mg, 2.2 mmol) were then added and the reaction mixture stirred at room temperature for two hours. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (12 to 100% EtOAc/hexanes) to afford racemic 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one as a yellow liquid. 1H NMR (500 MHz, CDCl3) δ 4.82-4.60 (m, 1H), 3.81-3.55 (m, 3H), 3.48-3.44 (m, 1H), 2.90 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=O)[C@@H:14]([NH:16]C(=O)OC(C)(C)C)[CH3:15])[CH2:3][CH2:2]1>CC(O)=O>[CH:1]1([N:4]2[C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[N:12]=[C:13]2[C@@H:14]([NH2:16])[CH3:15])[CH2:3][CH2:2]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(F)c1NC1CC1
Solvent: CC(=O)O
Product: C[C@H](N)c1nc2cccc(F)c2n1C1CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A stirred solution of (S)-tert-butyl 1-(2-(cyclopropylamino)-3-fluorophenylamino)-1-oxopropan-2-ylcarbamate (651.7 mg, 1.932 mmol) in AcOH (20 mL) was heated at 60° C. for 30 min, after being concentrated under reduced pressure, the residue was subjected to 4 M HCl in 1,4-Dioxane (20 mL). The resultant mixture was stirred at rt for 40 min. The mixture was concentrated under reduced pressure and dissolved in water (5 mL) and then basified with 1 N NaOH to pH 9.5. The mixture was concentrated under reduced pressure and triturated with MeOH-CDM (1:1). The crude product was purified by column chromatography on a silica gel column using DCM-MeOH—NH4OH (9:1:0.05) as eluent to give (S)-1-(1-cyclopropyl-7-fluoro-1H-benzo[d]imidazol-2-yl)ethanamine: LC-MS (ESI) m/z 220.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:9](S(C)(=O)=O)=[N:10][C:4]=2[CH:3]=1.[Si:23]([O:30][C@H:31]1[C@H:35]2[O:36][CH2:37][C@@H:38]([OH:39])[C@H:34]2[O:33][CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N12CCCC=C1CCCCN2>CN(C=O)C>[Si:23]([O:30][C@H:31]1[C@H:35]2[O:36][CH2:37][C@@H:38]([O:39][C:9]3[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=4[N:10]=3)[C@H:34]2[O:33][CH2:32]1)([C:26]([CH3:29])([CH3:27])[CH3:28])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)ncc21
Agent: C1=C2CCCCNN2CCC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)ncc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring solution of 6-chloro-2-(methylsulfonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine (100 mgs, 0.276 mmol) and (3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (72.0 mg, 0.276 mmol) in anhydrous DMF (2.3 mL) was added diazabicyclo[5.4.0]undec-7-ene (DBU, 0.06 mL, 0.42 mmol). The reaction was stirred under N2 at RT for 20 h, then evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 24 g silica RediSep Rf® Gold column and employing a 0-90% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C24H40ClN3O5Si2 541.22 observed m/e: 542.08 (M+H)+ (Rt 1.74/2.0 min)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13](O)=[O:14])=[C:11]([CH3:16])[O:10][N:9]=1.S(Cl)(Cl)=O.[CH3:21][NH:22][CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:22]([CH3:23])[CH3:21])=[O:14])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: CNC
Solvent: O=S(Cl)Cl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)N(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To 3-(2-chlorophenyl)-5-methylisoxazol-4-carboxylic acid (25 mg, 0.10 mmol) was added thionyl chloride (1 mL) and the neat solution allowed to stir 60° C. After 30 min, excess thionyl chloride was evaporated and dimethyl amine (40 μL, 0.08 mmol, 2M in tetrahydrofuran) was added and allowed to stir overnight at ambient temperature. The residue was purified using reversed phase HPLC to afford the title compound (5 mg). HRMS (ESI, pos. ion) m/z calcd for C13H13ClN2O2: 264.0666, found 264.0669.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].Cl.[CH3:13][C:14]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Yield: 99.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 69 and using 4-bromo-3-chlorobenzoic acid (989 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (956 mg) described in Preparation Example 64, the title compound (1.7 g) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH3:18])[C:10]2[CH2:19][CH2:20][O:21][C:22]([CH2:25][C:26](O)=[O:27])([CH2:23][CH3:24])[C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH3:18])[C:10]2[CH2:19][CH2:20][O:21][C:22]([CH2:25][CH2:26][OH:27])([CH2:23][CH3:24])[C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cccc2c3c(n(Cc4ccccc4)c12)C(CC)(CC(=O)O)OCC3
Solvent: C1CCOC1
Product: CCc1cccc2c3c(n(Cc4ccccc4)c12)C(CC)(CCO)OCC3
Temperature: 90 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a solution of (9-benzyl-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.45 g, 1.2 mmol) in tetrahydrofuran at room temperature was added 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran and it was stirred at 90° C. for 4 hours. The mixture was quenched with 5% HCl solution and stirred at room temperature for 20 minutes. It was extracted with ethyl acetate and washed with saturated sodium bicarbonate. The extracts were dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.321 g (74%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 7.17 (m, 3H), 6.94 (d, 1H), 6.84 (m, 2H), 6.70 (t, 1H), 6.56 (d, 1H), 3.87 (m, 1H), 3.79 (m, 1H), 3.68 (dt, 1H), 3.64 (br, 1H), 3.41 (td, 1H), 2.93 (q, 2H), 2.43 (q, 2H), 2.04 (m, 1H), 1.93 (dt, 1H), 1.86 (m, 1H), 1.77 (m, 1H), 1.49 (m, 1H), 1.38 (m, 1H), 1.17 (t, 3H), 0.70 (t, 3H)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CC[CH2:14][CH2:13]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:9])[CH:13]=[CH2:14])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C1CCOC1
Product: C=CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
p-Nitrobenzaldehyde (1 g, 6.6 mMoles) and 30 ml of dry tetrahydrofuran (THF) was stirred at 0° C. in a septum sealed flask equipped with a pressure equalizing funnel. After purging with dry nitrogen, 7 ml of 1M vinyl magnesium bromide in THF was added dropwise under a nitrogen atmosphere. After addition of the Grignard reagent, the reaction was allowed to stir at room temperature for 30 min. The bulk of the THF was removed under vacuum and the reaction was quenched by pouring it into a slurry containing 200 ml of water, crushed ice and 100 ml of ether. The final pH of the slurry was adjusted to near neutral by dropwise addition of 2M sulfuric acid. The product was extracted with ether and the pooled extracts were washed twice with 30 ml of water and twice with 30 ml of saturated NaCl. Ether was removed under vacuum yielding a dense yellow oil which was chromatographed on preparative silica TLC plates using toluene: acetonitrile 10:1 (v/v) as running solvent. Elution of the product from silica with methanol yielded 700 mg of semi-crystalline 1-(4'-nitrophenyl)-2-propen-1-ol. Recrystallization from toluene and then ethanol gave needles of pure product. IR: (chloroform) (cm-1) --OH, 3600, 1040; intermolecular --OH, --C=CH2, 3020, 2870, 985, 935 aromatic, 1607, 858; --NO2, 1510, 1350, 872. NMR: δ(p.p.m.) ([2H]chloroform), 2.2 (1H, broad s, --OH, D2O exchangeable), 5.26 (1H, d, J2,3 cis 10.6 Hz, J3,3 gem 1 Hz, --C=CH2), 5.32 (1H, broad m, --CH=C), 5.42 (1H, d, J2,3 trans 17.2 Hz, J3,3 gem 1 Hz --C=CH2), 6.0 (1H, m, C--CH=C), 7.4 (2H, d, J 9 Hz, aromatic), 8.21 (2H, d, J 9 Hz, aromatic). UVmax 272 nm, ε =10,500M-1 cm-1.; Mp.=55° C.