Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1)[NH2:15]
Reactant: NN
Reactant: Clc1cccc(-c2ccccn2)n1
Solvent: c1ccncc1
Product: NNc1cccc(-c2ccccn2)n1

Procedure:
A mixture of 4.0 g of 6'-chloro-2,2'-bipyridine and 10 ml of anhydrous hydrazine in 50 ml of dry pyridine was refluxed for 48 hours. Additional hydrazine (10 ml) was added and the solution was refluxed for an additional 72 hours while 5 ml portions of hydrazine were added at 18 hour intervals. The volatiles were removed under vacuum, the residue dissolved in ether, dried over sodium sulfate and concentrated to a solid. This solid was recrystallized from ether-heptane, giving 3.0 g of 6'-hydrazino-2,2'-bipyridine as white crystals, mp 69°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[S:11]([Cl:14])(=[O:13])=[O:12].ClC1C(OC)=C([S:24]([Cl:27])(=[O:26])=[O:25])C(OC)=CC=1>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[S:11]([Cl:14])(=[O:13])=[O:12].[S:24]([Cl:27])([Cl:14])(=[O:26])=[O:25]
Reactant: COc1ccc(Cl)c(OC)c1S(=O)(=O)Cl
Agent: COc1cccc(OC)c1S(=O)(=O)Cl
Product: O=S(=O)(Cl)Cl

Procedure:
Using the procedure described above, a mixture of 2,6-dimethoxybenzenesulfonyl chloride and 3-chloro-2,6-dimethoxybenzenesulfonyl chloride, which results from ring chlorination of the 2,6-dimethoxybenzenesulfonyl chloride by sulfuryl chloride, was prepared from 1,3-dimethoxybenzene.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1.[BH4-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:24]([OH:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Temperature: 60 °C
Yield: 11 %

Procedure:
The product from Example 136C (46 mg, 0.12 mmol) in ethanol (2 mL) and tetrahydrofuran (0.5 mL) was treated with sodium borohydride. The mixture was concentrated and passed through a short column of silica with a gradient of 2 to 10% MeOH/CH2Cl2. The resulting residue rinsed with ether, dissolved into methanol (1 mL), treated with 0.1 M aqueous hydrochloric acid (0.2 mL) heated at 60° C. for three hours, treated with more 0.1 M aqueous hydrochloric acid (0.05 mL), heated at 60° C. for one hour, concentrated, and chromatographed through a short column of silica with a gradient of 2 to 10% 2 M NH3 in MeOH/CH2Cl2 to provide the title compound as a white powder (11% yield). 1HNMR (300 MHz, CD3OD) δ 1.17 (d, 3H), 1.4-1.54 (m, 1H), 1.49 (d, 3H), 1.73-1.86 (m, 2H), 1.95-2.08 (m, 1H), 2.24-2.36 (m, 1H), 2.43-2.60 (m, 2H), 2.93-3.14 (m, 2H), 3.19-3.33 (m, 2H), 4.89 (q, 1H), 6.59 (s, 1H), 7.32 (ddd, 1H), 7.39 (dd, 1H), 7.45-7.47 (m, 2H), 7.49 (ddd, 1H), 7.62 (m, 1H), 7.71 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[N+:19]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:19][C:10]1[C:11]2[N:15]=[C:14]([CH3:16])[NH:13][C:12]=2[CH:17]=[CH:18][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)nc3c2[N+](=O)[O-])c(Cl)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)nc3c2N)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an N2 atmosphere, methyl 2-(3-chloro-4-(2-methyl-4-nitro-1H-benzo[d]imidazol-5-yloxy)phenyl)acetate (0.226 g, 0.601 mmol) was dissolved in ethyl acetate and tin chloride dihydrate (0.543 g, 2.41 mmol) was added. The reaction was allowed to stir at room temperature for 16 h. The reaction was diluted with ethyl acetate and washed with a 10% NaHCO3 (aq) solution. The aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (Na2SO4), filtered, and concentrated in vacuo, and the title compound isolated. LC-MS ESI (pos.) m/z: 346.0 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C1(N=C=NC2CCCCC2)CCCCC1.[F:41][C:42]([F:50])([F:49])[S:43]([CH2:45][C:46](O)=[O:47])=[O:44]>C1C=CC=CC=1>[F:41][C:42]([F:50])([F:49])[S:43]([CH2:45][C:46]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:47])=[O:44]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CS(=O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)CS(=O)C(F)(F)F)[C@H]2SC1
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution of 1.54 g (0.004 mol) of 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, t-butyl ester and 0.825 g (0.004 mol) of dicyclohexylcarbodiimide in 50 ml of benzene was added 0.704 g (0.004 mol) of trifluoromethylsulfinylacetic acid. The reaction mixture was stirred at 25° for 2 hr., then it was filtered and adsorbed onto 4 g of silica gel. Chromatography on 100 g of silica gel with 50:50 benzene-ethyl acetate gave 1.55 g (69 percent) of 7-trifluoromethylsulfinylacetamido-3-(1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, t-butyl ester as a white foam. The ester was dissolved in 9 ml of trifluoroacetic acid and stirred at 25° for 5 minutes, then added dropwise to 200 ml of ether. The precipitate was collected, dissolved in 5 percent sodium bicarbonate and the solution was diluted to 150 ml. After extraction with ethyl acetate the aqueous phase was acidified to pH 1.5 and extracted thrice more with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated to 35 ml, to which residue (the free acid) was added a solution of 1.5 g of 30 percent sodium 2-ethylhexanoate in isopropanol followed by 200 ml of ether. The precipitated salt was collected, reprecipitated from methanol-ether and dried in vacuo to give 0.680 g of product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2.C(=O)([O-])[O-].[K+].[K+].[C:27]([NH:34][CH2:35]CBr)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[I-].[Na+]>C1OCCOCCOCCOCCOCCOC1.CN(C)C=O.CC(C)=O>[C:30]([O:29][C:27](=[O:28])[NH:34][CH2:35][CH2:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNCCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To 3.23 g (12.04 mmol) of desipramine free base was added 80 ml of dry acetone, 3.6 g of anhydrous potassium carbonate, 3.0 g (13.45 mmol) of 2-(BOC-amino) ethyl bromide, 3 ml of anhydrous dimethylformamide, 15 mg of 18-crown-6 and 500 mg of sodium iodide. The mixture was allowed to reflux 18 hours under argon atmosphere. The reaction mixture was cooled to room temperature and filtered. The residue was washed with 10 ml of acetone. The filtrate was concentrated and the residue was purified by silica gel column chromatography using 4% methanol in ethyl acetate to give 4.8 g (11.7 mmol, 96%) of 23 as a thick oil.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[NH2:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O>CO>[CH2:19]([O:18][C:16]1[CH:17]=[C:9]2[C:10]([C:11](=[O:13])[N:3]=[C:1]([CH3:2])[NH:8]2)=[CH:14][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCN(CC)CC
Reactant: Nc1cc(OCc2ccccc2)ccc1C(=O)O
Solvent: CO
Product: Cc1nc(=O)c2ccc(OCc3ccccc3)cc2[nH]1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 0.695 g (5.62 mmol) of ethyl acetoamidate hydrochloride in MeOH (16 ml) were added under stirring at RT 0.82 ml (5.86 mmol) of triethyl amine and 5 minutes later 1.14 g (4.69 mmol) of 2-amino-4-benzyloxy-benzoic acid. The reaction mixture was heated at reflux for 5 h, cooled to RT, the precipitate that had formed was filtered off by suction and dried in a high vacuum to give 0.9 g (69.4%) of the desired 7-benzyloxy-2-methyl-1H-quinazolin-4-one as an white solid. ISP mass spectrum, m/e: 267.3 (M+1 calculated for C16H14N2O2: 267).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCCNCC1)=O)(C)(C)C.N1(CC2C=CC([C@@H]3OC4=NC=CC=C4OC3)=CC=2)CCNCC1>>[N:11]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH2:6][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCCNCC1
Agent: c1cnc2c(c1)OC[C@H](c1ccc(CN3CCNCC3)cc1)O2
Product: c1cnc2c(c1)OC[C@H](c1ccc(CN3CCCNCC3)cc1)O2

Procedure:
The title product FF is prepared from compound ft-1 (prepared from Intermediate C and [1,4]diazepane-1-carboxylic acid tert-butyl ester according to General Method N) according to the procedure described for the synthesis of Intermediate S.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([CH3:37])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]C4C=CC=CC=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])[CH3:2]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:37])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(CCc4ccccc4)cc3)oc2C)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(CC)cc3)oc2C)cc1

Procedure:
2-Methyl-2-(4-{2-[5-methyl-2-(4-phenethylphenyl)oxazol-4-yl]ethoxy}phenoxy)-propionic acid ethyl ester Rf=0.38 in 1:4 EtOAc:hexanes; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 2H), 7.24-7.16 (m, 7H), 6.82-6.74 (m, 4H), 4.22-4.16 (m, 4H), 2.95-2.86 (m, 6H), 2.31 (s, 3H), 1.50 (s, 6H), 1.24-1.20 (m, 6H); MS (EI) 536.2 (M+Na)+, 514.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[NH:10]1[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:10]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: C1CCC2NCCCC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reaction time: 8 h

Procedure:
5-Bromo-thiophene-3-carboxylic acid (0.44 g, 2.18 mmol) was dissolved in acetonitrile (3 mL) and decahydroquinoline (a 3:2 mixture of cis- to trans-isomers; 2 mL) then HATU (2.18 mmol) was added. The reaction mixture was stirred overnight, and then the solvent evaporated and the residue purified by flash chromatography on silica eluting with 0-50% ethyl acetate in cyclohexane. The fractions containing the desired cis-product were concentrated under vacuum to give the title compound (0.63 g) as a colourless gum. LCMS m/z 330.36 [M+H]+ R.T.=4.09 min. (Analytical Method 5).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:19]4=[N:20][CH:21]=[CH:22][CH:23]=[C:18]4[N:17]([CH2:24][CH3:25])[N:16]=3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:26]B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH2:24]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:26])=[CH:7][N:6]=3)=[CH:10][CH:11]=2)=[N:16]1)[CH3:25]
Reactant: CCn1nc(-c2ccc(Oc3ccc(Cl)cn3)cc2)c2ncccc21
Reactant: CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: COCCOC
Solvent: O
Product: CCn1nc(-c2ccc(Oc3ccc(C)cn3)cc2)c2ncccc21
Yield: 20.1 %

Procedure:
A mixture of 3-[4-(5-chloropyridin-2-yloxy)phenyl]-1-ethyl-1H-pyrazolo[4,3-b]pyridine (58 mg), methylboronic acid (59.4 mg), Pd(dppf)2Cl2 (18 mg) and Cs2CO3 (766 mg) in DME/H2O (4 mL, 3/1) was exposed to microwave irradiation at 140° C. for 1 h, and then Pd(OAc)2 (3.7 mg), Xphos (15.7 mg) and Cs2CO3 (107 mg) were added. The mixture was exposed to microwave irradiation at 140° C. for 1 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (H2O in CH3CN containing 10 mM NH4HCO3). Crystallization from AcOEt/hexane gave title compound (11 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@H:35]([CH2:38][CH3:39])[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]([CH2:36][OH:37])[CH2:38][CH3:39])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC[C@H](CO)NS(=O)(=O)c1ccccc1Br
Product: CC[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (R)-2-bromo-N-(1-hydroxybutan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C20H21FN4O3S, 416.13; m/z found, 417.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.32 (m, 2H), 8.16-8.12 (m, 1H), 7.96 (m, 1H), 7.68-7.63 (m, 1H), 7.60-7.55 (m, 1H), 7.40-7.30 (m, 3H), 3.43-3.35 (m, 1H), 3.33 (d, J=5.9, 1H), 3.12-3.05 (m, 1H), 1.60-1.48 (m, 1H), 1.42-1.28 (m, 1H), 0.79 (t, J=7.4, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:18][CH2:19][C:20]#[CH:21])[C:15]([OH:17])=O)=[CH:10][CH:9]=1.[C:22]([Si:26]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH2:40])=[CH:30][C:29]=1[O:41][CH3:42])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl.CN(C)C=O>[C:22]([Si:26]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH:40][C:15](=[O:17])[CH:14]([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)[O:18][CH2:19][C:20]#[CH:21])=[CH:30][C:29]=1[O:41][CH3:42])([CH3:25])([CH3:23])[CH3:24]
Reactant: C#CCOC(C(=O)O)c1ccc(Cl)cc1
Reactant: COc1cc(-c2ccccc2N)ccc1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#CCOC(C(=O)Nc1ccccc1-c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(OC)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (4.3 g, 33 mmol) is added to a solution of (4-chlorophenyl-prop-2-ynyloxy-acetic acid (6.8 g, 30 mmol) in a mixture of 150 ml of dichloromethane and few drops of N,N-dimethylformamide. The reaction mixture is stirred for 4 hours at room temperature and then added to a solution of 4′-(tert-butyl-diphenyl-silanyloxy)-3′-methoxy-biphenyl-2-ylamine (13.8 g, 30 mmol) and triethylamine (4.6 g, 45 mmol) in 150 ml of dichloromethane. The resulting mixture is stirred for 16 hours at room temperature under a nitrogen atmosphere. Subsequently, the mixture is diluted with chloroform and extracted with water. The combined organic layer is dried over sodium sulfate and evaporated and the remaining crude product is subjected to flash-chromatography (ethyl acetate/hexane 3;7) yielding N-[4′-(tert-butyl-diphenyl-silanyloxy)-3′-methoxy-biphenyl-2-yl]-2-(4-chlorophenyl)-2-prop-2-ynyloxy-acetamide as an orange oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]([C:19]([OH:21])=[O:20])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][C@@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1

Procedure:
Saponification of the cis dimethyl ester 13 (0.502 g, 1.56 mmol) gave 0.44 g (96%) of the desired cis dicarboxylate as colorless prisms: mp 175°-176° C; [α]26D +30° (c 1.10, CH3OH); Spectra were identical in all respects to those of the enantiomer N-(benzyloxycarbonyl)-cis-4-carboxy-L-proline. Anal. Calcd for C14H15NO6 ; C, 57.34; H, 5.16; N, 4.78. Found: C, 57.43; H, 5.18; C, 4.68.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:37]([CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:38]([OH:40])=O)[CH:32]=[CH:33][C:34]=1[S:35][CH3:36].C(N(CC)C(C)C)(C)C.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:37]([CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:38]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:40])[CH:32]=[CH:33][C:34]=1[S:35][CH3:36]
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.8 %

Procedure:
A solution of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.62 g, 1.41 mmol) and 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (0.29 g, 0.95 mmol) in methylene chloride (10 mL) was treated with N,N-diisopropylethylamine (500 μL, 2.87 mmol) and 2-aminothiazole (140 mg, 1.27 mmol). The mixture was stirred under nitrogen at 25° C. for 14 h. The reaction mixture was then washed with a 6N aqueous hydrochloric acid solution (1×15 mL) and washed with a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (0.26 g, 71%) as a white solid: EI-HRMS m/e calcd for C18H21ClN2OS2 (M+) 380.0783, found 380.0792.
Reaction SMILES: C(O[C:4]([C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[O:16][CH:17]([F:19])[F:18])=[O:5])C.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[F:15][C:11]1[C:10]([O:16][CH:17]([F:18])[F:19])=[C:9]2[C:14]([C:4]([OH:5])=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[N:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=CNc1cccc(F)c1OC(F)F)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(OC(F)F)c(F)ccc2c1O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A mixture of 10.0 g (0.029 mole) of N-(2,2-diethoxycarbonylvinyl)-3-fluoro-2-difluoromethoxyaniline obtained as described above and 70 ml of diphenyl ether was refluxed by heating for 30 minutes. The mixture was cooled to room temperature, and n-hexane was added thereto. Crystals precipitated were collected by filtration and dried to obtain 5.25 g of ethyl 7-fluoro-8-difluoromethoxy-4-hydroxyquinoline-3-carboxylate as white powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH:9]=[CH2:10].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+].Cl>C1(C)C=CC=CC=1>[CH2:8]([C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:12]1)[CH:9]=[CH2:10]
Reactant: CCOC(=O)CBr
Reactant: C=CCC1(C(=O)OCC)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1(C(=O)OCC)CCN(CC(=O)OCC)CC1
Temperature: 80 °C

Procedure:
The crude TFA salt of ethyl 4-allyl-isonipecotate and ethyl bromoacetate (23.5 g, 141 mmol) were dissolved in toluene. To this solution was added anhydrous K2CO3 (70.7 g, 512 mmol), and the resulting suspension was warmed to 80° C. for 15 minutes. The reaction mixture was cooled down, and adjusted at pH=8.0 with dil.HCl. The resulting solution was worked-up by an ordinal procedure (extraction with ethyl acetate, washing with brine, drying over Na2SO4, concentration by evaporation) to provide 37.4 g of crude ethyl 4-allyl-N-ethoxycarbonylmethyl-isonipecotate, 56.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:10]1[O:12][CH2:11]1)Cl.[OH-].[Na+]>CN(C)C=O>[OH:12][CH:10]([CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OC(CNc1ccccc1)CNc1ccccc1
Temperature: 110 °C
Yield: 6.3 %

Procedure:
A mixture of 0.25 ml (2.74 mmol) of aniline, 0.107 ml (1.37 mmol) of epichlorohydrin, and 60.4 mg (1.51 mmol) of sodium hydroxide in 2 ml of dimethylformamide was heated at 110° C. for 20 h. The solvent was removed in vacuo and the residue was purified by flash chromatography using 5% ethyl acetate in chloroform to give 21 mg (6%) of the desired compound (Rf 0.63, 40% ethyl acetate in chloroform). 1H NMR (CDCl3) δ3.21 (dd, J=13, 8 Hz, 2H), 3.37 (dd, J=13, 4 Hz, 2H), 4.13 (m, 1H), 6.65-6.8 (m, 6H), 7.15-7.3 (m, 6H). Mass spectrum (M+H)+ =243.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([CH3:24])=[N:19]2)(=O)=O>>[CH3:24][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[CH:23][C:14]=2[N:6]2[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]2)[N:19]=1
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cccc2n1
Reactant: C[C@H]1CNCCN1
Product: Cc1ccc2c(N3CCN[C@@H](C)C3)cccc2n1
Yield: 27 %

Procedure:
The title compound was prepared in 27% yield using a similar procedure to Example 127 starting from (2S)-2-methylpiperazine and 2-methyl-5-quinolinyl trifluoromethanesulfonate (D1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25][C:24]=4[CH:31]=3)[N:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C(C1C=CC(NC2C(F)=CN=C(NC3C=CC4OC(C(OC)=O)=CC=4C=3)N=2)=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][C:24]=4[CH:31]=3)[N:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)CC(C(=O)O)O4)ncc2F)cc1
Agent: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(C(C)(C)C)cc4)n3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(Nc2nc(Nc3ccc4oc(C(=O)O)cc4c3)ncc2F)cc1

Procedure:
In a manner similar to the preparation of N4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine, LiOH treatment with N4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine gave N4-(4-tert-butylphenyl)-N2-(2-carboxybenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 9.3 (bd, 2H), 8.25 (s, 1H), 8.10 (s, 1H), 7.65-7.30 (m, 5H), 1.25 (s, 9H); 19F NMR (CD3OD): −21844; LCMS: ret. time: 23.32 min.; purity: 100%; MS (m/e): 421 (MH+).