Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCCC1.[F:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:10][C:9]=1[NH:28][C:29](=O)[O:30]C(C)=C.Cl.[F:36][C:37]([F:45])([F:44])[C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41]>C1COCC1.CCOC(C)=O>[F:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:10][C:9]=1[NH:28][C:29]([NH:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[C:37]([F:45])([F:44])[F:36])=[O:30]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(C)cc1F
Reactant: CC(C)(CCN)C(F)(F)F
Agent: CN1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C(F)(F)F)c(F)cc3C)c(C)nc2n1
Temperature: 65 °C
Yield: 75.1 %

Procedure:
Add 1-methylpyrrolidine (1.214 mL, 11.54 mmol) in a mixture of prop-1-en-2-yl (2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (0.92 g, 2.31 mmol) and 4,4,4-trifluoro-3,3-dimethylbutan-1-amine hydrochloride (0.487 g, 2.54 mmol) in THF (23 mL) and heat at 65° C. for 4 h. Cool the mixture to RT, dilute with EtOAc, wash with brine (2×), dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (0-50% EtOAc/Hexanes) to afford the title compound (860 mg, 75% yield). MS (m/z): 496.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:5]([Cl:24])=[CH:4][N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1>C(Cl)Cl.CO>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])=[N:7][C:2]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([CH2:32][N:29]3[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]3)=[CH:39][CH:38]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=S(=O)(c1cc(O)ccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccc(O)cc4S(=O)(=O)N4CCCC4)n3)cc2)CC1
Yield: 27 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 4-((2,5-dichloropyrimidin-4-yl)amino)-3-(pyrrolidin-1-ylsulfonyl)phenol and 4-((4-methylpiperazin-1-yl)methyl)aniline in 27% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.87 (d, 1H, J=8.4 Hz), 7.67 (s, 1H), 7.44 (d, 2H, J=8.1 Hz), 7.26 (1H), 7.23 (d, 2H, J=8.4 Hz), 7.10 (d, 1H, J=8.8 Hz), 3.53 (s, 2H), 3.33 (m, 4H), 2.63 (bs, 8H), 2.43 (s, 3H), 1.83 (m, 4H); MS (ESI): 558.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[ClH:36].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:36].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:34])[F:35])=[CH:20][CH:21]=5)=[CH:30][CH:29]=4)=[O:32])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:25]([C:30]2[N:31]=[N:32][N:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:34]=2)[CH:26]=[CH:27][CH:28]=[O:29])=[CH:20][CH:19]=1>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:25]([C:30]2[N:31]=[N:32][N:33]([C:35]([CH3:38])([CH3:36])[CH3:37])[N:34]=2)[CH:26]=[CH:27][CH:28]([OH:29])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)n1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)(C)C)n1
Temperature: 78 °C
Reaction time: 0.08 h

Procedure:
A solution of the dianion of ethyl acetoacetate (400 μL, 3.1 mmoles) in 8 mL of dry tetrahydrofuran was generated as described in Example 10 using 130 mg (3.2 mmoles) of NaH (60% in mineral oil) and 2.5M n-BuLi in hexanes (1.27 mL, 3.2 mmoles) at 0° C. under argon. The orange dianion solution, after being chilled to 31 78° C., was transferred via a cannula into a tetrahydrofuran (12 mL) solution at -78° C. containing 5,5-bis(4-fluorophenyl)-4-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-2,4-pentadienal (0.96 g, 2.4 mmoles). The reaction mixture was stirred at -78° C. for five minutes. Analytical TLC eluted once with 50% (v/v) EtOAc in hexanes showed the major product spot at Rf =0.35. The reaction mixture was diluted with 20 ml of 1N HCl and the organic material was extracted with EtOAc (20 mL×2). The organic layers were combined, dried over MgSO4, evaporated under reduced pressure, and dried under high vacuum (0.001 mmHg) at ambient temperature overnight (16 hours) to give the title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[F:32][C:33]([F:44])([F:43])[O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:40][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][C:33]([F:43])([F:44])[F:32])=[CH:36][CH:37]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(trifluoromethoxy)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=620.94 (M+H+); retention time=1.04 minutes.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][C:32]1[O:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:35]1[O:36][C:32]([CH3:31])=[CH:33][CH:34]=1)[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: Cc1ccc(B(O)O)o1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccc(C)o2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 5-methyl-2-furylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C20H20NO4 (M+H): 338.1382. Found 338.1387
Reaction SMILES: CN([CH:4]=[N:5][C:6]([C:8]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=O)C.[CH3:29][NH:30][NH2:31].C(O)(=O)C.ClCCl>O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:29][N:30]1[C:6]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[CH:16][CH:15]=3)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[N:5][CH:4]=[N:31]1
Reactant: CN(C)C=NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Cn1ncnc1C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 100 °C
Yield: 19.9 %

Procedure:
N-[(dimethylamino)methylene]-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide (0.34 g, 0.88 mmol), methyl hydrazine (0.116 mL, 2.19 mmol) and acetic acid (1 mL) were combined and heated at 100° C. for 2 hours. The reaction mixture was diluted with water (10 mL), solid sodium carbonate was added until the mixture was pH9. Dichloromethane (2×50 mL) was used to extract. The combined organics were dried over sodium sulphate, filtered and concentrated in vacuo to provide a yellow oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 90:10:1) to produce the title compound (0.065 g, 20%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.83-1.93 (m, 4H), 2.05-2.16 (m, 2H), 2.30 (m, 2H), 2.48 (m, 2H), 2.60-2.85 (m, 6H), 3.37 (s, 3H), 3.80 (m, 2H), 3.90 (m, 2H), 4.0 (t, 2H), 6.85 (d, 2H), 7.07 (d, 2H), 7.88 (s, 1H). HRMS ESI+ m/z 371.2434 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCCCCN1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(CCCCCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C

Procedure:
A 262 mg portion of methyl 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]hexanoate was dissolved in 3 ml of methanol and 3 ml of THF, mixed with 2 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred for 7Hours. The reaction solution was washed with diethyl ether, and 1 M hydrochloric acid was added to the water layer until it became pH 3. After its extraction with diethyl ether, the organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]hexanoic acid as a crude product. The thus obtained crude product was dissolved in 3.0 ml of 4 M hydrogen chloride/1,4-dioxane solution at room temperature, and the reaction solution was concentrated under a reduced pressure. THF and diethyl ether were added to the thus obtained residue, and the resulting precipitate was collected by filtration and dried under a reduced pressure to obtain 123 mg of 6-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]hexanoic acid dihydrochloride as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.S(Cl)([Cl:15])(=O)=O>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=[N:7][CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Fc1ccc2cnccc2c1
Product: Fc1ccc2cncc(Cl)c2c1
Temperature: 25 °C

Procedure:
A solution of 1.5 g 6-fluoro-isoquinoline (5) in 4.5 ml sulfuryl chloride was heated to 60° C. in a microwave reactor (CEM Discovery) for 8 h. After cooling to room temperature the mixture was poured on ice and extracted three times with CHCl3. After drying over Na2SO4 the solvent was distilled off and the crude product was purified by flash chromatography to yield 930 mg of 9. Rt=1.37 min (Method #1). Detected mass: 182.0 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([OH:40])[CH:34]=1.[C:41]([C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50]O)=[CH:45][CH:44]=1)#[N:42]>C(Cl)Cl.CCOCC>[Cl:32][C:33]1[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([O:40][CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([C:41]#[N:42])=[CH:44][CH:45]=2)[CH:34]=1
Reactant: Oc1cc(O)cc(Cl)c1
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1ccc(CCOc2cc(O)cc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
Triphenylphoshine (32 g; 122 mmol) and diethylazodicarboxylate (19.2 mL; 122 mmol) were dissolved in CH2Cl2 (150 mL). Chloro-3,5-dihydroxybenzene (9.1 g; 63 mmol; from step (i) above) and 2-(4-cyanophenyl)ethanol (9.04 g; 61 mmol) were added and the solution was stirred at room temperature overnight. The mixture was diluted with Et2O and filtered through Celite. The solvent was removed in vacuo. Purification, first by flash chromatography (SiO2; CH2Cl2:MeOH), then by preparative HPLC (60% CH3CN:0.1 M NH4OAc/aq), afforded 3.55 g (21%) of the sub-title compound.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=C)[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2[CH:13]=C)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:41]([NH2:44])([CH3:43])[CH3:42]>C1COCC1.ClCCCl>[CH:41]([NH:44][C:26]1[N:25]=[C:24]([O:23][CH:21]2[CH2:22][CH:18]3[CH:19]([C:31](=[O:32])[N:33]([CH3:34])[CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:13][CH:11]4[C:10]([C:8]([NH:7][S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:6])=[O:5])=[O:9])([NH:15][C:16]3=[O:17])[CH2:12]4)[CH2:20]2)[CH:29]=[CH:28][N:27]=1)([CH3:43])[CH3:42]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)Nc1nccc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)n1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
Compound 10f (30 mg, 0.05 mmol) and isopropylamine (excess) in THF (10 ml) was heated in a microwave oven at 110° C. for 30 min and then left at ambient temperature for 16 hrs. The solvent was stripped of and the residue was redissolved in DCE (15 ml) and degassed with nitrogen. Hoyeda-Grubbs II catalyst (7 mg) was added and the mixture was heated in a microwave oven at 150° C. for 10 min. The mixture was concentrated to dryness and purified by prep. HPLC-MS-UV which gave the pure title compound (3.1 mg), (M+H)+=589.2.
Reaction SMILES: CI.[CH2:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][C:12]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=3[CH:10]([C:20]3[C:21](=[S:27])[NH:22][C:23](=[O:26])[NH:24][CH:25]=3)[C:8]=2[N:9]=1)[CH3:4].[C:28](=O)(O)[O-].[Na+]>C(O)C.O>[CH2:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][C:12]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=3[CH:10]([C:20]3[C:21]([S:27][CH3:28])=[N:22][C:23](=[O:26])[NH:24][CH:25]=3)[C:8]=2[N:9]=1)[CH3:4]
Reactant: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=S
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCO
Product: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)nc1SC

Procedure:
Methyl iodide (0.044 ml) was added to a stirred solution of the product from example 31 step (v) (0.250 g) and sodium bicarbonate (0.057 g) in ethanol (5 ml) and water (3 ml). After 3 h the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by trituration with ethyl acetate and isohexane.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:7])(O)[CH2:4][CH3:5].Cl[Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].[O:19]1CCCC1>>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:19][CH2:5][CH2:4][CH2:3][OH:7])([CH3:12])[CH3:11]
Reactant: C1CCOC1
Reactant: CCC(O)O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)[Si](OCCCO)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 2.68 g, 0.067 mol) in tetrahydrofuran (112 mL) at 0° C. under an atmosphere of nitrogen was added n-propandiol (5 g, 0.067 mol) in tetrahydrofuran (36 mL), and the mixture was stirred for 15 min at the same temperature, warmed up to room temperature and stirred for 30 min. After cooling to 0° C., chlorotriisopropylsilane (18.2 mL, 0.067 mol) was added dropwise to reaction mixture and the mixture was stirred with gradual warming to ambient temperature over 2 h. After re-cooling to 0° C., the reaction mixture was quenched by addition of water (30 mL) and the mixture was diluted with water, extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 2 to 15% tetrahydrofuran in hexanes gradient) to yield the title compound (25, 14.6 g, 0.063 mol, 94%) as colorless oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:21]>CO.C(O)(C)C>[ClH:21].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCOCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COC(=O)[C@H](CN)N1CCOCC1
Temperature: 40 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
A solution of 1.4 g (5 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-morpholin-4-ylpropanoate in 20 ml of methanol and 10 ml of a solution of hydrochloric acid having a 5-6N concentration in isopropanol is stirred at 40° C. for 20 h and then evaporated to dryness. 1.3 g (96%) of methyl(S)-3-amino-2-morpholin-4-ylpropanoate hydrochloride are obtained in the form of a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[C:9]([CH3:14])[C:8]=1[CH3:15].[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:14][C:9]1[C:8]([CH3:15])=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:12]=[CH:11][N:10]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCOc1cc[n+]([O-])c(C)c1C
Product: COCCCOc1ccnc(COC(C)=O)c1C

Procedure:
20 ml of acetic anhydride was added to 760 mg (3.6 mmol) of 4-(3-methoxypropoxy)-2,3-dimethyl-pyridine N-oxide to carry out the reaction at 90° C. for one hour. The reaction mixture was distilled to remove the acetic anhydride, followed by the addition of a saturated aqueous solution of sodium hydrogen-carbonate. The obtained mixture was extracted with chloroform. The extract was concentrated to obtain 700 mg of 2-acetoxymethyl-4-(3-methoxypropoxy)-3-methylpyridine as a brown oil. 500 mg of sodium hydroxide and 15 cc of ethanol were added to the 2-acetoxymethyl-4-(3-methoxypropoxy)-3-methylpyridine prepared above. The obtained mixture was stirred at 50° C. for one hour. After the completion of the reaction, the reaction mixture was distilled to remove the ethanol, followed by the addition of water. The obtained mixture was extracted with chloroform. The obtained chloroform layer was concentrated to obtain 450 mg of 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine as a brown oil.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@@H](N5CCC[C@H]5C)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 17A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (d, J=8.29 Hz, 1H) 7.76 (d, J=1.84 Hz, 1H) 7.45 (d, J=7.67 Hz, 1H) 7.38 (dd, J=8.44, 1.69 Hz, 1H) 7.06 (d, J=7.36 Hz, 1H) 3.57-3.70 (m, 1H) 3.14-3.29 (m, 1H) 2.99-3.13 (m, 1H) 2.73-2.85 (m, 1H) 2.59 (s, 3H) 2.49 (s, 3H) 2.28-2.67 (m, 5H) 1.91-2.01 (m, 1H) 1.77-1.88 (m, 1H) 1.59-1.73 (m, 1H) 1.43-1.53 (m, 1H) 1.15 (s, 3H). MS: (M+H)+=378.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH2:20]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:16]([Cl:15])[CH:17]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CO
Product: N#CNC(=NCc1ccc(Cl)c(Cl)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Isopropyl N cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3,4-dichlorobenzylamine (0.51 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.42 g, 1.4 mmol, yield: 52%) as colorless crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C@@:13]2([CH2:25][C:26]#[N:27])[CH2:15][C@H:14]2[CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:7]1([C@@:13]2([CH2:25][CH2:26][NH2:27])[CH2:15][C@H:14]2[CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To 18.13 mL 1M lithium aluminum hydride (18.13 mmol) in diethyl ether at 0° C. was added ((1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl)cyclopropyl)acetonitrile (5.2 g, 18.13 mmol), accessed via the method of Preparation 22B, dissolved in 20 mL diethyl ether. After complete addition, the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was diluted with 400 mL diethyl ether and quenched with successive addition of 0.6 mL water, 0.6 mL 15% NaOH, and 3.0 mL water. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give the title product (5.1 g, 18.13 mmol 100%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.14 (m, 10H), 4.29-4.16 (m, 2H), 3.04-2.99 (m, 1H), 2.91-2.86 (m, 1H), 2.39-2.27 (m, 2H), 1.88-1.83 (m, 1H), 1.28-1.19 (m, 2H), 0.84-0.81 (m, 1H), 0.73-0.71 (m, 1H).