Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:16](=[O:25])[NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[CH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)#[N:2].[Na+].Cl>O.CO>[C:1]([C:3]([C:16](=[O:25])[NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1)#[N:2]
Reactant: N#CC(=Cc1ccc(OCC(=O)[O-])cc1)C(=O)NCc1cccnc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC(=Cc1ccc(OCC(=O)O)cc1)C(=O)NCc1cccnc1
Reaction time: 8 h

Procedure:
The filtrate and the remainder of the solid from Example 82 were dissolved in water (100 ml)/methanol (100 ml), and neutralized with 20 ml of 0.1 mol/l hydrochloric acid. Methanol was evaporated and impurities were removed by extraction with ethyl acetate. The aqueous layer was filtered to remove insoluble components, concentrated to about 50 ml, and then allowed to stand overnight. The precipitated solid was filtered, washed with a small amount of acetone, and then dried by heating under reduced pressure to give the compound of interest (102 mg, 19%) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:4].[OH:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:12][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Reactant: Cc1cccc(NC(=O)CCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)COc2ccc(C(=O)Oc3ccccc3)cc2)c1

Procedure:
To a solution of 2-chloro-N-m-tolyl-acetamide (580 mg, 3.16 mmol) and phenyl 4-hydroxybenzoate (677 mg, 3.16 mmol) in acetone (20 mL) was added potassium carbonate (502 mg, 3.63 mmol) and potassium iodide (26 mg, 0.16 mmol) and the mixture was heated to reflux overnight. The mixture was concentrated under vacuum, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent to provide the desired product. MS (DCI-NH3): m/z 379 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C@@H:13]([C:22]([O:24]C)=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C@@H:13]([C:22]([OH:24])=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(N)c2ccccc12)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
To a solution of methyl 3-(4-amino-1-naphthyl)-N-(tert-butoxycarbonyl)-L-alaninate (2.4 g, 7.0 mmol) in methanol (10 mL) was added 8M aqueous NaOH (1.5 mL, 12 mmol) and the mixture was stirred at ambient temperature for 45 minutes. The mixture was concentrated under reduced pressure, taken up in water (5 mL) and extracted with diethyl ether (2×10 mL). The aqueous layer was then shaken with ethyl acetate (30 mL) and 1M HCl (13 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined ethyl acetate layers were washed with brine (1×5 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (1.9 g, 83%).
Reaction SMILES: [C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH:28]([NH:32]C(=O)OCC4C=CC=CC=4)[CH2:27]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:11]1)=[O:9].Cl>CO.C(OCC)(=O)C.[Pd]>[NH2:32][CH:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:15][CH:12]3[CH2:13][CH2:14][N:10]([C:8](=[O:9])[CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:11]3)[N:25]=2)[CH2:27]1
Reactant: O=C(NC1CCCN(c2nc(NC3CCN(C(=O)Cc4ccccc4-c4ccccc4)C3)nc3ccccc23)C1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1CCCN(c2nc(NC3CCN(C(=O)Cc4ccccc4-c4ccccc4)C3)nc3ccccc23)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzyl (1-(2-(1-(2-biphenyl-2-ylacetyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperidin-3-yl)carbamate (570 mg) synthesized in the same manner as the method described in Example 1 was dissolved in methanol (6 mL), followed by addition of a solution (0.25 mL) of 4 M HCl in ethyl acetate and 10% Pd—C (100 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 3 days. The catalyst was removed by filtration, then the filtrate was concentrated, made basic with saturated aqueous sodium hydrogencarbonate, and then extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, then the residue was purified by silica gel column chromatography (chloroform/methanol=3:1), and the resulting compound was solidified in hexane to obtain the title compound.
Reaction SMILES: [CH2:1]([NH2:14])[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][NH2:13].[C:15]([OH:19])(=O)[CH2:16][OH:17]>O>[OH:19][CH2:15][C:16]([NH:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][CH2:1][NH:14][C:15](=[O:19])[CH2:16][OH:17])=[O:17]
Reactant: O=C(O)CO
Reactant: NCCCOCCCCOCCCN
Solvent: O
Product: O=C(CO)NCCCOCCCCOCCCNC(=O)CO
Reaction time: 2 h

Procedure:
4,9-Dioxadodecane-1,12-diamine (22.8 g, 0.112 mole) was placed in a 250 ml round bottom flask and glycolic acid (17.0 g, 0.224 mole) added portion-wise with stirring and cooling. The resultant liquid was heated in an oil bath to 185° C. whereupon distillation of water occurred. Heating was continued at 185° to 195° C. for 2 hours after which time distillation of water subsided and the liquid was poured into a crystallization dish. The resultant oil slowly crystallized in the form of large white clusters; yield 35.5 g (99.3%); m.p. 67°-71° C. The solid was recrystallized from cold absolute methanol to give a white, crystalline product; m.p. 74°-77° C.; infrared (Nujol), 1120 cm-1, 1625 cm-1, 3250 cm-1 ; proton nuclear magnetic resonance (CDCl3 /TMS, 100 MHz), δ1.55-1.95 (complex multiplet, 8 protons), δ3.30-3.65 (complex multiplet, 12 protons), δ4.03 (singlet, 4 protons), δ4.98 (broad singlet, 2 protons), δ7.51 (broad triplet, 2 protons).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc(Br)cc2n1Cc1ccccc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2n1Cc1ccccc1

Procedure:
Prepared from 1-benzyl-6-bromo-1,3-dihydro-benzoimidazol-2-one and 3-nitro-phenyl boronic acid in the same fashion as that of Example 5. White solid: mp 202-203° C.; 1H-NMR (DMSO-d6) δ 11.2 (s, 1H), 8.38 (t, 1H, J=1.97 Hz), 8.15 (dd, 1H, J=7.83, 1.97 Hz), 8.80 (d, 1H, J=7.83 Hz), 7.72 (t, 1H, J=7.83 Hz), 7.56 (bs, 1H), 7.43-7.22 (m, 6H), 7.13 (d, 1H, J=7.83 Hz), 5.1 (s, 2H); MS (ES) m/z 344([M−H]−, 100%); Anal. Calc. For C20H15N3O3 0.25 H2O: C, 68.66, H, 4.46, N, 12.01. Found: C, 68.42, H, 4.44, N, 11.77.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH2:74][F:75])([CH2:72][F:73])[O:70][B:69]([OH:76])[C:68]=2[CH:77]=1>CN(C=O)C>[F:75][CH2:74][C:71]1([CH2:72][F:73])[O:70][B:69]([OH:76])[C:68]2[CH:77]=[C:64]([CH2:63][NH:62][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][C:14]([C:11]4[CH2:10][C:9]([C:4]5[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=5)([C:24]([F:27])([F:25])[F:26])[O:13][N:12]=4)=[CH:15][C:16]=3[CH3:23])[CH:65]=[CH:66][C:67]1=2
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(CF)CF
Reaction time: 0.17 h
Yield: 33.2 %

Procedure:
A solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-benzoic acid (100 mg, 0.24 mmol) and DIPEA (124 mg, 0.88 mmol) in DMF (5 mL) was stirred at rt for 5 min and then HATU (183 mg, 0.48 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (126 mg, 0.44 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by prep-TLC to provide the final title product (50 mg, 33%). 1H NMR (400 MHz, CDCl3): δ 7.47 (m, 9H), 4.61 (m, 6H), 4.07 (d, 1H), 3.78 (d, 1H), 2.41 (s, 3H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[S:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])[CH:21]=[CH:22][CH:23]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][S:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[O:30])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: O=C(O)c1ncsc1-c1cccc(Cl)c1
Product: CC(F)(F)c1ccc(Cn2cc(NC(=O)c3ncsc3-c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-chloro-phenyl)-thiazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=449.00.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@H:15](O)[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>C1COCC1>[F:27][C@@H:15]1[CH2:16][CH2:17][C@:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:11][CH2:12][C@@H:13]2[CH2:14]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@H](O)C[C@H]2CS1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@@H](F)C[C@H]2CS1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
tert-Butyl (±)-[(4aR*,6S*,8aS*)-8a-(2-fluorophenyl)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 63-(4) (1.5 g) was dissolved in THF. Then, perfluorobutanesulfonyl fluoride (1.36 mL, specific gravity: 1.682 g/cm3), a triethylamine-trihydrofluoric acid complex (1.23 mL, specific gravity: 0.989 g/cm3) and triethylamine (3.15 mL, specific gravity: 0.73 g/cm3) were sequentially added at room temperature. After completion of the addition, the mixture was stirred for 16 hours. The mixture was heated to 50° C. and further stirred for 24 hours. Perfluorobutanesulfonyl fluoride (0.68 mL), a triethylamine-trihydrofluoric acid complex (0.62 mL) and triethylamine (1.58 mL) were further sequentially added to the mixture, followed by further stirring with heating under reflux for eight hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography to obtain the title compound (106 mg).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH2:19]([NH:26][C:27](=[O:33])[CH:28]([CH3:32])[C:29](O)=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:27](=[O:33])[CH:28]([CH3:32])[C:29]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1ccccc1
Product: CC(C(=O)NCc1ccccc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=428.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-benzyl-2-methyl-malonamic acid.
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])P(=O)(OC(C)C)OC(C)C.C([Li])CCC.[Si:27]([O:34][CH2:35][CH2:36][CH:37]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CCCCCCC>[Si:27]([O:34][CH2:35][CH2:36]/[CH:37]=[CH:1]/[P:12](=[O:21])([O:13][CH:14]([CH3:15])[CH3:16])[O:17][CH:18]([CH3:19])[CH3:20])([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Agent: [Li]CCCC
Solvent: CCCCCCC
Product: CC(C)OP(=O)(/C=C/CCO[Si](C)(C)C(C)(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.6 %

Procedure:
To a solution of tetraisopropyl methylenebisphosphonate (2.50 g, 7.26 mmol) in n-heptane (50 ml) was added n-butyllithium (2.70 ml of 2.7M solution in n-hexanes; 7.29 mmol) and the mixture stirred at room temperature under dry nitrogen for 15 min. To the solution was added crude 3-(t-butyldimethylsilyloxy) propanal (approx. 5.85 mmol) and the mixture heated under reflux for 0.5 hr then stirred at room temperature for 64 hr. The mixture was filtered then the solvent removed. The residue was purified by column chromatography on silica gel eluting with dichloromethane-ethyl acetate (9:1, 4:1) to afford diisopropyl (E)-4-(t-butyldimethylsilyloxy)but-1-enylphosphonate as a colourless oil (1.10 g, 43%); νmax (film) 2940, 1625, 1460, 1380, 1250, 1105, 980 and 830 cm-1 ; δH (CDCl3) 0.03 (6H, s, SiCH3), 0.90 (9H, s, C(CH3)3), 1.32 (12H, dd, J 3 Hz and 6 Hz, CH(CH3)2), 2.43 (2H, m, CH2), 3.72 (2H, t, J 7 Hz, CH2O ), 4.65 (2H, m, CH(CH3)2), 5.72 (1H, dd, J 17 Hz and 20 Hz, PCH=CH), 6.75 (1H, ddt, J 7 Hz, 17 Hz and 20 Hz, PCH=CH); FABMS(thioglycerol) 351 (MH+) (Found: C, 54.76; H, 10.05%. C16H35O4PSI requires C, 54.84; H, 10.07%).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:11]([O:13][CH3:14])=[O:12].[CH2:22]=O>C(Cl)Cl>[S:2]1[C:3]2[CH2:7][CH2:8][N:9]([CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:11]([O:13][CH3:14])=[O:12])[CH2:22][C:4]=2[CH:5]=[CH:6]1
Reactant: C=O
Reactant: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Reaction time: 2 h

Procedure:
35 g of the hydrochloride of racemic methyl alpha-(2-thienylethylamino)(2-chlorophenyl)acetate are suspended in 150 ml of a 30% (w/w) aqueous solution of formaldehyde. The mixture is kept at 50° C. for 2 hours and then poured, at about 20° C., into 200 ml of methylene chloride. The organic phase is concentrated and the residual oil is dissolved in 120 ml of isopropyl ether in which the hydrochloride is prepared as before; 29.5 g are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH:12]=[CH2:13])=[N:9][CH:10]=1)=[O:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cnc(Cl)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ncc(C(=O)OC)cn1
Temperature: 110 °C
Reaction time: 10 h
Yield: 44.8 %

Procedure:
To a solution of methyl-2-chloropyrimidine-5-carboxylate (2.084 g, 12.08 mmol) and tributyl(vinyl)tin (3.635 g, 11.46 mmol) in toluene (15 ml) was added triphenylphosphine (94.9 mg, 0.362 mmol) followed by tetrakis(triphenylphosphine) palladium(0) (418.5 mg, 0.362 mmol). The mixture was stirred at 110° C. for 10 h under anhydrous argon. After evaporation of solvent, the residue was purified by flash chromatography (hexanes-ethyl acetate=4:1, then 1:1) to give the title compound (0.842 g) as a white solid. Mass spectrum (ESI) 166.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.26 (s, 2H), 6.95-7.01 (m, 1H), 6.82 (dd, 1H, J=1.4, 17.2 Hz), 5.92 (dd, 1H, J=1.4, 10.5 Hz), 4.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:34]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:38]([CH:34]4[CH2:37][CH2:36][CH2:35]4)=[O:39])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)C4CCC4)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12

Procedure:
Prepared according to procedure P1.4 in Example 1A using rac-(1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol and cyclobutancarbonyl chloride.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=1)[O:18][CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][C:5]1[N:6]=[C:2]([S:1][CH2:14][C:15]2[CH:34]=[CH:33][CH:32]=[C:17]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])[CH:16]=2)[S:3][C:4]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: COC(=O)Cc1sc(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1sc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A mixture of methyl (2-mercapto-4-methylthiazol-5-yl)acetate (385 mg), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (600 mg), potassium carbonate (400 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [4-methyl-2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]thiazol-5-yl]acetate (665 mg, yield 72%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3 volume ratio).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:44])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([F:43])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:36])([F:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:44])=[CH:17][C:18]=4[F:43])=[N:42][C:27]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)ncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCNCC4)cc3F)ncc21
Yield: 94.5 %

Procedure:
A solution of 0.067 g (0.109 mmole) 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-229) in 3 mL of dichloromethane was stirred with 3 mL of trifluoroacetic acid for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.0533 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-piperidin-4-yl-benzamide (I-230) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 5-bromo-2-nitrophenol (10.4 g, 47.7 mmol), benzyl bromide (9.8 g, 57.2 mmol) and potassium carbonate (9.9 g, 71.5 mmol) was taken up in acetone (50 mL) and heated to reflux for 5 h. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (9:1 hexanes/ethyl acetate) to give 2-(benzyloxy)-4-bromo-1-nitrobenzene (14.19 g, 97%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, J=8.4 Hz, 1H), 7.32-7.48 (m, 5H), 7.30 (d, J=1.8 Hz, 1H), 7.19 (dd, J=8.7, 1.8 Hz, 1H), 5.23 (s, 2H).
Reaction SMILES: C[O:2][C:3]1[C:4]([C:21]#[C:22][C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:5][CH:6]=[C:7]([O:19][CH3:20])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.F[B-](F)(F)F.[IH2+:34].N1C=CC=CC=1.N1C=CC=CC=1>C1COCC1>[I:34][C:21]1[C:4]2=[N:5][CH:6]=[C:7]([O:19][CH3:20])[C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:3]2[O:2][C:22]=1[C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1
Reactant: [IH2+]
Reactant: COc1ccc(COc2c(OC)cnc(C#Cc3cnn(C)c3)c2OC)cc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(COc2c(OC)cnc3c(I)c(-c4cnn(C)c4)oc23)cc1
Yield: 63 %

Procedure:
To a stirred solution of 3,5-dimethoxy-4-(4-methoxy-benzyloxy)-2-(1-methyl-1H-pyrazol-4-ylethynyl)pyridine (80 mg, 0.21 mmol) in dry THF (2 ml) was added bispyridine iodonium tetrafluoroborate (94 mg, 0.25 mmol) and the reaction was refluxed for 0.5 hours. After cooling, the reaction was quenched with 10% Na2S2O3 (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated onto silica-gel under reduced pressure. The solid residue was purified by flash chromatography (silica-gel, eluted with EtOAc:hexanes, 3:2) to give the product as a white solid (65 mg, 63%). 1H—NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 8.16 (s, 1H), 8.15 (s, 1H), 7.38 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.60 (s, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.77 (s, 3H).