Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:41][C:42]([F:53])([F:52])[O:43][C:44]1[CH:51]=[CH:50][C:47](C=O)=[CH:46][CH:45]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:47]4[CH:46]=[CH:45][C:44]([O:43][C:42]([F:41])([F:52])[F:53])=[CH:51][CH:50]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(COc2ccc(N3CCN(Cc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.1 %

Procedure:
Tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 148 (4.22 g, 9.60 mmol) was dissolved in methylene chloride (10 ml). To the solution, trifluoroacetic acid (30 ml) was added followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (10 ml) and triethylamine (10 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in dichloroethane. To the solution, 4-trifluoromethoxybenzaldehyde (1.64 ml, 11.5 mmol) and sodium triacetoxyborohydride (3.05 g, 14.4 mmol) were added with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, a saturated sodium hydrogencarbonate solution and methylene chloride were added, and the solution was stirred and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and then crystallized from methylene chloride-ethyl acetate to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (3.23 g, yield 63%) as a light yellow powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:18])C.O.[OH-].[Na+]>CCOCC>[OH:18][CH:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCCCCCCC(O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Lithium aluminum hydride (114 mg, 3.00 mmol) was added to diethyl ether (3 mL) at 0° C. A solution of ethyl-7-(2-naphthoyl)-heptanoate 49 g (312 mg, 1.00 mmol) in ether (2 mL) was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for 1 hour, then at room temperature for 1 hour. Deionized water was added slowly dropwise (5 mL) followed by 2N NaOH (5 mL). The mixture was filtered through a short pad of Celite, washing with ether. The organic layer was separated and dried (MgSO4). The solvents were removed in vacuo to give the title compound 70 (247 mg, 91%). 1H NMR (400 MHz, DMSO-d6): δ 7.83 (m, 4H), 7.45 (m, 3H), 5.22 (m, 1H), 4.64 (m, 1H), 4.28 (m, 1H), 3.35 (m, 2H), 1.68 (m, 2H), 1.37 (m, 2H), 1.22 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH3:16][C:17]([CH3:19])=O>C(O)(=O)C>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:17]2([CH3:19])[CH3:16])([O-:15])=[O:14]
Reactant: CC(C)=O
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: CC1(C)Nc2ccccc2-c2c([N+](=O)[O-])cnn21

Procedure:
A mixture of 20.4 g (0.1 mole) of 5-(o-aminophenyl)-4-nitropyrazole, 300 ml of acetone and 0.3 ml of acetic acid is heated under reflux for 1 hour. After evaporation, 24.0 g (98.5%) of 1-nitro-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 193°-195° C.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:34])([F:33])[C:6]1[CH:7]=[C:8]([NH:12][C:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25]4[CH:30]=[C:29]([CH:31]=[O:32])[N:28]=[CH:27][N:26]=4)=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)=[O:14])[CH:9]=[CH:10][CH:11]=1>C1COCC1>[F:34][C:5]([F:33])([F:4])[C:6]1[CH:7]=[C:8]([NH:12][C:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25]4[CH:30]=[C:29]([CH:31]([OH:32])[CH3:1])[N:28]=[CH:27][N:26]=4)=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reaction time: 3 h

Procedure:
Methylmagnesium bromide solution (3 M in ether, 20 mL) is added to a solution of 5-(6-formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (5.0 g 11.7 mmol) in THF (400 mL) at 0° C. The mixture is stirred at that temperature for 3 h before the reaction is then quenched with saturated aqueous NH4Cl. The product is extracted with EtOAc (3×40 mL) and the combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is purified semi-prep HPLC (C18; 30-100% I/H2O with 0.1% TFA) to give the title compound as a racemate. MS (ESI) m/z 441.1 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.62 (s, 1 H), 8.36 (d, J=8.84 Hz, 1 H), 8.06 (s, 1 H), 7.95 (d, J=3.79 Hz, 1 H), 7.90 (d, J=8.08 Hz, 1 H), 7.58 (t, J=7.83 Hz, 1 H), 7.43 (d, J=2.27 Hz, 2 H), 7.12 (dd, J=8.97, 2.40 Hz, 1 H), 7.09 (s, 1 H), 6.75 (d, J=3.79 Hz, 1 H), 4.75 (d, J=6.57 Hz, 1 H), 1.45 (d, J=6.57 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[O:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[BH4-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH2:27][OH:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1CO

Procedure:
A solution of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.071 g; 0.25 mmol) in THF (20 mL) and methanol (5 mL) was stirred at ambient temperature as an excess of NaBH4 (0.071 g; 1.88 mmol) was added. After one hour the solvents were evaporated and the residue was taken up into dichloromethane and washed with water. The dichloromethane phase was dried over MgSO4, filtered, and evaporated. The resultant residue was crystallized from ethyl acetate and hexane to obtain the title product as a white solid, mp 170-172° C.; MS (ES) m/z 406.1; [M−H]−
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:31])[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccccc1)c1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Combine 2-(3-bromophenyl)-1,3-dioxolane (10.0 ml, 66.0 mmol) and tetrahydrofuran (100 ml) and cool to about −78° C. Add dropwise a solution of n-butyllithium, 1.6 M solution in hexane (44.0 ml, 66.0 mmol). After 10 min, add a solution of benzaldehyde (7.6 ml, 66.0 mmol) in tetrahydrofuran (50 ml) via cannula. After 1 hour, warm to room temperature. After 18 hours, quench into water and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 7:3 hexane:EtOAc to give the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:21])[CH2:16][NH:17][CH2:18][CH2:19][NH2:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([N:24]=[C:25](SC)SC)#[N:23]>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:21])[CH2:16][N:17]3[CH2:18][CH2:19][NH:20][C:25]3=[N:24][C:22]#[N:23])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(C)CNCCN)cc1OC1CCCC1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: COc1ccc(C(C)CN2CCNC2=NC#N)cc1OC1CCCC1
Yield: 12.9 %

Procedure:
A mixture of intermediate 22 (0.0068 mol) and dimethyl cyanocarbonimidodithioate (0.0068 mol) in ethanol (20 ml) was stirred and refluxed for 2 days. The solvent was evaporated and the residue was first purified by short open column chromatography over silica gel (eluent: CH2Cl2, CH2Cl2 /CH3OH 96/4 and 90/10), then twice by HPLC (1 eluent: CH2Cl2 /CH3OH 90/10 and 2. Eluent: CH2Cl2 /CH3OH 96/4). The pure fractions were collected and the solvent was evaporated, yielding 0.3 g (13%) of (±)-[1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-2-imidazolidinylidene] cyanamide (compound 1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:8][C:9]2[CH:14]=[C:13]([N:15]=[C:16]=[S:17])[C:12]([F:18])=[CH:11][C:10]=2[Cl:19])[CH2:7][CH2:6]1)=[O:4].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1>C(O)C>[CH3:1][O:2][C:3]([C:5]1([S:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]3)=[S:17])[C:12]([F:18])=[CH:11][C:10]=2[Cl:19])[CH2:6][CH2:7]1)=[O:4]
Reactant: C1CCNNC1
Reactant: COC(=O)C1(Sc2cc(N=C=S)c(F)cc2Cl)CC1
Solvent: CCO
Product: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CC1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
While stirring at room temperature, a solution of 6.3 g of 1-(2-chloro-4-fluoro-5-isothiocyanato-phenylthio)-cyclopropanecarboxylic acid methyl ester in 30 ml of ethanol is added dropwise to a solution of 2.2 g of hexahydropyridazine in 30 ml of ethanol. After stirring for 30 minutes at room temperature, the reaction mixture is concentrated by evaporation in vacuo, yielding 7.9 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclopropanecarboxylic acid methyl ester having a melting point of from +156° to +157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH:69]2[CH2:74][CH2:73][CH2:72][CH2:71][NH:70]2)[CH:64]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:70]1[CH2:71][CH2:72][CH2:73][CH2:74][CH:69]1[C:65]1[CH:64]=[N:63][CH:68]=[CH:67][CH:66]=1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: c1cncc(C2CCCCN2)c1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3c3cccnc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(pyridin-3-yl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[N:24][C:23]=3[CH2:34][CH:35](OC)OC)=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1)=O)(C)(C)C.Cl>CCO>[ClH:33].[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:35]=[CH:34][C:23]4[N:24]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=5)[S:26][C:22]=4[C:20]3=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CC(OC)OC)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Temperature: 0 °C
Yield: 194.1 %

Procedure:
Mix 3-(4-{[2-(4-chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (208 g, 344 mmol) in EtOH (2.2 L) and treat with concentrated HCl (208 mL). Heat the mixture to reflux for one hour and then cool to 0° C. Collect the solid by filtration and rinse with ice-cold Et2O (4×500 mL). Dry the solid under vacuum at 55° C. for 2 days to give 159 g (97%) of the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.37 (s, 2H), 8.15 (m, 2H), 7.75 (d, 1H, J=7.6), 7.66 (m, 2H), 7.22 (d, 1H, J=7.5), 7.05 (d, 1H, J=7.3), 7.01 (dd, 1H, J=2.5, 8.7), 6.92 (d, 1H, J=8.6), 5.09 (m, 1H), 4.45 (m, 2H), 4.04 (m, 2H), 3.82 (s, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)=[O:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:35][O-:36].[Na+].C1(C)C=CC=CC=1>ClCCl>[N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12]([O:36][CH3:35])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)=[O:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[O-]
Reactant: N#Cc1ccc(C(=O)c2ccc3nc(Cl)c(Cc4ccc(-n5cncn5)cc4)c(Cl)c3c2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2ccc(C(=O)c3ccc(C#N)cc3)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
A heterogeneous mixture containing 4-(3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-2,4-dichloroquinoline-6-carbonyl)benzonitrile (583 mg, 1.20 mmol, Intermediate 16: step d), sodium methoxide (780 mg, 14.4 mmol), and toluene (17 mL) was heated to 110° C. After 45 minutes, the flask was allowed to cool to 23° C. Dichloromethane (100 mL) was added to the flask and then the mixture was filtered through Celite®, rinsing with dichloromethane. Silica gel (5 g) was added to the filtrate and the solvent was removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a column of silica gel for flash chromatography purification. Elution with hexanes initially, grading to 80% ethyl acetate-hexanes afforded the title compound as a white solid.
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[O:12]=[C:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].IC>CC(C)=O>[O:12]=[C:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:2])=[O:19]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)CCCCC(=O)O
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CCCCC(C)=O
Reaction time: 1 h
Yield: 97.8 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (3.4 mL, 22.86 mmol) was added to a solution of 6-oxoheptanoic acid 23 (1.1 g, 7.63 mmol) in acetone (15 mL) at 23° C. After stirring for 15 min iodomethane (2.4 mL, 38.3 mmol) was added. The reaction was stirred for 1 h and then the solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 7:3 hex/EtOAc) to provide 1.18 g (95%) of the methyl ester 24 (see scheme 4).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[O:10][C:9](=[O:20])[CH:8]=2)[N:6]=1.C1COCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+].O>>[OH:18][CH2:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[CH:8][C:9](=[O:20])[O:10]2)=[CH:15][CH:14]=1
Reactant: Cc1nc(-c2cc(=O)oc3cc(C(=O)O)ccc23)cs1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(=O)oc3cc(CO)ccc23)cs1
Temperature: 0 °C

Procedure:
To a solution of 4-(2-methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carboxylic acid (250 mg, 0.87 mmol) in THF (10 mL) triethylamine (0.31 mL, 2.18 mmol) was added. The mixture was stirred until it became a clear solution. The reaction was then cooled to 0° C. and isobutylchloroformate was added dropwise (230 uL, 1.74 mmol). After 1 hour stirring at 0° C. a solution of sodium borohydride in water (132 mg, 3.48 mmol in 3.5 mL) was added slowly and the mixture was stirred for another hour. The reaction mixture was quenched with a saturated ammonium chloride solution and the product was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 8.26 (d, 1H), 8.07 (s, 1H), 7.42 (s, 1H), 7.35 (d, 1H), 6.64 (s, 1H), 4.80 (d, 2H), 4.56 (t, 1H), 2.85 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.N1C=CN=C1.[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35]>C(Cl)Cl>[Si:37]([O:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[CH2:21])=[CH:18][CH:19]=2)[CH3:13])[CH2:7][CH2:6]1)([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=Cc1ccc([C@H](C)N2CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c3ccccc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 0.137 mmol) and imidazole (11.2 mg 0.165 mmol) in CH2Cl2 (10 mL) was added a solution of TBSCl (24.6 mg, 0.164 mmol) in CH2Cl2 (15 mL) dropwise at 0° C. The mixture was stirred overnight at rt. The mixture was filtered, and the solvent was evaporated to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (40 mg, 60%). 1H NMR (CDCl3): 0.02 (s, 6H), 0.87 (m, 9H), 1.23 (m, 1H), 1.52 (d, 3H), 1.62 (m, 1H), 1.98 (m, 2H), 2.14-2.38 (m, 3H), 2.97 (m, 1H), 3.58 (m, 2H), 5.28 (m, 1H), 5.71 (m, 1H), 6.68 (m, 1H), 6.88 (m, 1H), 7.16 (m, 1H), 7.22-7.38 (m, 7H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.Cl.[F:38][CH:39]([F:46])[N:40]1[CH:44]=[CH:43][C:42]([NH2:45])=[N:41]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([NH:45][C:42]3[CH:43]=[CH:44][N:40]([CH:39]([F:46])[F:38])[N:41]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ccn(C(F)F)n1
Reactant: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccn(C(F)F)n1)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.088 mL, 0.66 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (171 mg, 0.44 mmol) in DCM (10 mL) and the reaction was stirred at RT for 30 minutes. After this time 1-(difluoromethyl)pyrazol-3-amine hydrochloride (75 mg, 0.44 mmol) and DIPEA (0.154 mL, 0.89 mmol) were added sequentially. The resulting solution was stirred at RT for 16 hours after which time the solvent was removed in vacuo and ethyl acetate (20 mL) and water (20 mL) were added. The aqueous phase was extracted with ethyl acetate (2×20 mL), washed with a saturated solution of sodium hydrogen carbonate (20 mL), and brine (20 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography on silica, eluting with 50-100% ethyl acetate in isohexane, to give the desired product as a white solid (132 mg). 1H NMR δ (CDCl3): 2.40-2.12 (m, 4H), 4.03-3.89 (m, 4H), 4.25 (t, 2H), 4.71 (t, 2H), 5.01-4.96 (m, 1H), 6.76 (t, 1H), 7.03 (t, 1H), 7.08 (d, 1H), 7.11 (s, 1H), 7.22 (s, 1H), 7.38 (dd, 1H), 7.75 (d, 1H), 8.13 (d, 1H), 8.33 (d, 1H), 8.50 (s, 1H); 19F NMR δ (CDCl3): −93.84; m/z 500 (M+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:42])[C@@H:10]([NH:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([Cl:40])[C:33]=1[CH3:41])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si](C(C)(C)C)(C)C)=[C:18]([F:30])[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:40][C:34]1[C:33]([CH3:41])=[C:32]([NH:31][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:30])[CH:17]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:42])[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)c(F)c3)o2)[C@H](C)O)ccc(C#N)c1Cl

Procedure:
4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(tert-butyldimethylsilyloxy)-3-fluoro-phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (130 mg, 0.21 mmol) using tetrabutylammonium fluoride (1.0 M solution in THF, 0.62 mL, 0.62 mmol) in a procedure analogous to that used for the preparation of example 7. After column chromatography (50% EtOAc/hexanes) the title compound was isolated as a white solid (743 mg, 88%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.49 (m, 2H), 7.16 (m, 1H), 6.89 (d, J=8.6 Hz, 1H), 5.67 (d, J=8.6 Hz, 1H), 5.08 (dd, J=3.7, 8.4 Hz, 1H), 4.61 (m, 1H), 2.98 (br s, 1H), 2.40 (s, 3H), 1.40 (d, J=6.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[NH:7][CH2:6][CH2:5]2.C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:12][CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][NH:7]1
Reactant: CC1NCCc2cc(Br)ccc21
Reactant: C[Sn](C)(C)c1ccccn1
Product: CC1NCCc2cc(-c3ccccn3)ccc21

Procedure:
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with 2-trimethylstannyl-pyridine to provide the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[CH2:4][CH2:5][C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:6](=[O:8])[CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:10])=[O:9])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: CN(C)C(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CCC(=O)N(C)C)nc12

Procedure:
From N,N-dimethylsuccinamic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+21.9° (c=1.04, CHCl3), ES-MS m/e (%): 394 (M+H+, 100).