Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[NH:10][C:9]1=[O:13])=[O:6])[CH3:3].C([Li])CCC.[CH2:20]([O:22][P:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26])[CH3:21].[Cl-].[Na+]>O1CCCC1>[CH3:12][C@@H:11]1[N:10]([P:23](=[O:27])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])[C:9](=[O:13])[C@H:8]1[NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:14])[CH3:3])=[O:6]
Reactant: CCOP(=O)(Cl)OCC
Reactant: C[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
(3S-trans)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-4-methyl-2-azetidinone (4.6 g) was dissolved in 75 ml of dry tetrahydrofuran and cooled to -78° C. in a dry ice-acetone bath under a nitrogen atmosphere, and was treated with 1.56 M n-butyl lithium (14.8 ml, 1 equivalent). The mixture was stirred for 30 minutes at -78° C. and then diethylphosphorochloridate (3.97 g) was added and stirring continued for 1 hour. The mixture was poured into saturated sodium chloride solution (60 ml) and extracted with ethyl acetate (three 40 ml portions). The extracts were combined and dried over anhydrous Na2SO4 and the solvent removed in vacuo. The residue was chromatographed on 125 g of silica gel eluted with ethyl acetate. Removal of solvent in vacuo followed by trituration with ether and drying yielding 4.72 g of the title compound, melting point 101°-103.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.[CH:26]1([CH:29]=[O:30])[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=[C:10]2[CH:9]1[CH:29]([CH:26]1[CH2:28][CH2:27]1)[OH:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1
Reactant: O=CC1CC1
Agent: [Li]C(C)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1C(O)C1CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.86 g (6.38 mmol) of 7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (Ex. 2, Step A) in 20 mL of toluene at −78° C. was added 5.88 mL (7.65 mmol, 1.3 M solution in cyclohexane) of sec-butyllithium. The reaction mixture was stirred at −78° C. for 20 min, then 0.524 mL (7.01 mmol) of cyclopropanecarboxaldehyde was added dropwise. The reaction mixture was stirred at −78° C. for 10 min. The −78° C. bath was removed and the mixture was allowed to stir at ambient temperature for 1 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with three portions of ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated to give 2.24 g of crude material. Purification by flash chromatography (silica gel, 7 to 10% ethyl acetate/hexane) gave the title compound as a mixture of 4 diastereomers. LC/MS 363 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[N:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[N:30]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3cccc(Cl)n3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R1=Me) and 6-chloro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:29][O:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])[C:8]([NH:10][CH:11]2[CH2:14][N:13]([C:15]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][N:23]([NH2:26])[C:22]3=[O:27])(=[O:20])=[O:19])=[O:16])[C:12]2=[O:28])=[O:9])[N:6]=1.C[O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49]C)[N:45]=[C:44]1[C:51]([O:53][C:54](=[O:55])[C:43]1=[CH:42]2)=[O:52]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:29][O:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])[C:8]([NH:10][CH:11]2[CH2:14][N:13]([C:15]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][N:23]([NH:26][C:51]([C:44]4[C:43]([C:54]([OH:55])=[O:53])=[CH:42][C:41]5[C:46](=[CH:47][C:48]([OH:49])=[C:39]([OH:38])[CH:40]=5)[N:45]=4)=[O:52])[C:22]3=[O:27])(=[O:19])=[O:20])=[O:16])[C:12]2=[O:28])=[O:9])[N:6]=1
Reactant: COc1cc2cc3c(nc2cc1OC)C(=O)OC3=O
Reactant: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2CCN(N)C2=O)C1=O)c1csc(N)n1)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3nc4cc(O)c(O)cc4cc3C(=O)O)C2=O)C1=O)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a solution of 0.47 g (0.75 mmol) of 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-amino-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt in 10 ml of dimethylformamide was added 0.26 g (0.86 mmol) of 6,7-dimethoxy-2,3-quinoline-dicarboxylic anhydride, and the mixture was stirred overnight at room temperature. After the dimethylformamide was distilled off in vacuo, the residue was dissolved in water and the pH adjusted to 6.5 with 1N potassium hydroxide. Freeze drying yielded 0.76 g of crude product which was purified by column chromatography on XAD resin under mplc conditions with water as eluent to give 0.12 g of 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(3-carboxy-6,7-dihydroxy-2-quinolinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, tripotassium salt, melting point 240°-280° C., dec., and 0.21 g of a mixture of 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[ (3-carboxy-6,7-dihydroxy-2-quinolinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, tripotassium salt and 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(2-carboxy-6,7-dihydroxy-3-quinolinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, tripotassium salt in a ratio of ca. 2:1.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH:16]=O)=[CH:9]2.[O-]S([O-])(=O)=O.[Mg+2]>C(O)C.C(Cl)Cl>[Br:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH:16]=[N:2][CH3:1])=[CH:9]2
Reactant: COc1ccc2cc(C=O)ccc2c1Br
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCO
Product: CN=Cc1ccc2c(Br)c(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methylamine (2.35 mL of an 8.03 M solution in ethanol, 18.8 mmol) in 5 mL of methylene chloride was added under nitrogen dropwise over 5 minutes to a mixture of 5-bromo-6-methoxy-naphthalene-2-carbaldehyde (1.00 g, 3.77 mmol), prepared in the previous step, and 3 g of anhydrous MgSO4 in 20 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 21 h (overnight). The reaction was filtered and the filtrate concentrated under reduced pressure to give (5-bromo-6-methoxy-naphthalen-2-ylmethylene)-methyl-amine (1.05 g, 100%) as a light tan solid, mp 105-107° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=2[CH3:12])[N:5]=[CH:4][CH:3]=1.[CH3:17][N:18](C)C=O>O>[C:17]([C:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=2[CH3:12])[N:5]=[CH:4][CH:3]=1)#[N:18]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(Br)ccnc12
Reactant: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)c2c(C#N)ccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-5,8-dimethyl-6-nitroquinoline (3.87 g, 13.77 mmol), cuprous cyanide (3.67 g, 41.31 mmol) and dimethylformamide (70 mL) is stirred at room temperature for 30 minutes and then heated to 155° C. and stirred at this temperature for 1 hour. Water is added, and the reaction mixture is filtered. The precipitate is washed with water and methylene chloride. The filtrate is extracted with methylene chloride (3×125 mL), and the combined organic layers are dried (sodium sulfate) and evaporated. Purification by chromatography through a short column consisting of layers of sand/flash silica gel/sand, using chloroform as eluent, provides 4-cyano-5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]Br.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].CO>O>[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][NH:26][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Nc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1
Reactant: CCCCN
Agent: Br
Solvent: O
Solvent: CO
Product: CCCCNCc1cc(N)c(Cc2ccccc2)c(S(N)(=O)=O)c1
Reaction time: 24 h

Procedure:
A mixture of 3-amino-4-benzyl-5-sulfamylbenzyl bromide hydrobromide (1.1 g; prepared as described in Example 61), n-butylamine (5.0 ml) and methanol (10 ml) is stirred at 22°-25° C. for 24 hours. The resulting solution is then diluted with water (20 ml) to precipitate crude (3-amino-4-benzyl-5-sulfamylbenzyl)-n-butylamine. After filtration and recrystallization from aqueous ethanol it is obtained with a melting point of 141°-143° C.
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:25]([CH2:27][NH2:28])O>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[CH2:2]([C:1]1[O:24][CH2:25][CH2:27][N:28]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NCCO
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCCCCCC=CCCCCCCCCCCCC1=NCCO1

Procedure:
Following the procedure of Example 10, erucic acid was reacted with ethanolamine in the presence of titanium tetrabutylate as catalyst to form 2-(12-heneicosenyl)-2-oxazoline. The quantities used were as follows:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:11][C:12]1[CH:13]=[C:14]2[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:25](O)=[O:26])=[O:22])[NH:18][C:15]2=[CH:16][N:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C@H:24]([NH:23][C:21]([C:19]2[NH:18][C:15]3=[CH:16][N:17]=[C:12]([Cl:11])[CH:13]=[C:14]3[CH:20]=2)=[O:22])[C:25](=[O:26])[N:6]2[CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:4][CH2:5]2)=[CH:34][CH:33]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
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: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(C(F)(F)F)CC1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 4-trifluoromethyl piperidine (17 mg, 0.11 mmol) was added a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 40 mg, 0.11 mmol) in DMF (400 μL) followed by a solution of HATU (50 mg, 0.13 mmol) in DMF (400 μL) and finally a solution of DIPEA (23 μL, 0.13 mmol) in DMF (200 μL). The resulting mixture was stirred at rt for 96 h then solvent was removed in vacuo. The crude material was purified by crystallisation from THF/petroleum ether to give the title compound as a yellow powder. (ES+)=497.23 [M+H]+; RT=3.50 min.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][CH3:14])=[O:12])[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>CN(C)C=O>[NH2:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][CH3:14])=[O:12])[N:10]=2)[N:7]=1
Reactant: CNC(=O)c1cn2nc(I)ccc2n1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cn2nc(Oc3cccc(N)c3)ccc2n1
Yield: 35.7 %

Procedure:
Using 6-iodo-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (0.30 g, 0.99 mmol), N,N-dimethylformamide (3.0 mL), potassium carbonate (275 mg, 1.99 mmol) and 3-aminophenol (163 mg, 1.49 mmol) as starting materials and in the same manner as in Example 91, the title compound (0.10 g, 36%) was obtained as a dark brown powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:28]2[C:32]([OH:33])=[C:31](C(OCC)=O)[CH:30]=[N:29]2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1.[OH-].[Na+].CCO.Cl>O>[F:1][C:2]1[CH:3]=[C:4]([N:28]2[C:32]([OH:33])=[CH:31][CH:30]=[N:29]2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1
Reactant: CCOC(=O)c1cnn(-c2ccc(-n3cc(OC)c(=O)c(-c4ccnn4-c4ccccc4)n3)c(F)c2)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cn(-c2ccc(-n3nccc3O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
A mixture of ethyl 1-{3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl}-5-hydroxy-1H-pyrazole-4-carboxylate (1.41 g, 2.73 mmol), 4 M NaOH (40 mL), and EtOH (40 mL) was refluxed for 4 h. After cooling to room temperature, conc. HCl (20 mL) was added slowly. The mixture was stirred for 30 min at room temperature and then refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/THF (2/1) and recrystallized from THF/MeOH to give the title compound (387 mg, 32% yield) as a pale yellow solid: mp 221-229° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 3.78 (3H, s), 5.57 (1H, d, J=1.5 Hz), 6.99 (1H, d, J=1.9 Hz), 7.14 (1H, t, J=9.0 Hz), 7.31-7.51 (6H, m), 7.64-7.68 (1H, m), 7.79-7.84 (2H, m), 8.52 (1H, d, J=1.9 Hz), 12.17 (1H, brs). LC-MS (ESI) m/z 445 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: Brc1cnc2ccnn2c1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: c1ccc(-c2nn3c(c2-c2cnc4ccnn4c2)CCC3)nc1
Yield: 26.2 %

Procedure:
To a microwave tube, add 6-bromo-pyrazolo[1,5-a]pyrimidine (0.175 g, 0.884 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (0.25 g, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol), 2M aqueous potassium carbonate (0.5 mL, 1.0 mmol) and dimethylsulfoxide (1.5 mL). Irradiate the reaction in a microwave reactor set at 110° C., 50 Watts, 10 min with external cooling. Dilute the reaction mixture with diethyl ether (250 mL) and extract the product into 0.1M aqueous hydrochloric acid (450 mL). Make the aqueous solution basic by adding 5M aqueous sodium hydroxide (25 mL) and extract with dichloromethane (300 mL). Filter the organic layer and concentrate under reduced pressure. Recrystallize the resulting solid from ethyl acetate, filter, rinse with ethyl acetate, and dry at 100° C. under vacuum to obtain 70 mg (26%) of the title compound as a tan solid. MS (electrospray, m/z) 302.9 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].Cl.[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])[C:23]([CH3:31])=[CH:22][C:21]=3[F:32])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:33][CH3:34]>C(Cl)Cl.N1C=CC=CC=1>[F:32][C:21]1[CH:22]=[C:23]([CH3:31])[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([NH:8][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[C:10]([O:33][CH3:34])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COCC(=O)Cl
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(N)c(OC)cc23)c(F)cc1C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)Nc1cc2ncnc(Nc3cc(OC(=O)OC)c(C)cc3F)c2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
Methoxyacetyl chloride (62 μl, 0.68 mmol) was added dropwise to a solution of 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (215 mg, 0.52 mmol) in methylene chloride (5 ml) and pyridine (l.5 ml) at 0° C. and the mixture stirred for 2 hours at 0° C. Further methoxyacetyl chloride (14 μl, 0.15 mmol) was added and the mixture stirred for 20 minutes at 0° C. The reaction mixture was partitioned between ethyl acetate and water and the aqueous layer adjusted to pH9 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60138/2) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-methoxyacetamidoquinazoline (1 75 mg, 75%) as a white solid.
Reaction SMILES: N1C(C)=CC=CC=1C.[Si:9]([O:16]S(C(F)(F)F)(=O)=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([F:36])[CH2:33][C@@H:32]1[C@@H:37](O)[C@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:39]([N:41]1[C@@H:45]([CH:46]([CH3:48])[CH3:47])[CH2:44][O:43][C:42]1=[O:49])=[O:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl>ClCCl>[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([F:36])[CH2:33][C@@H:32]1[C@@H:37]([O:16][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])[C@H:38]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:39]([N:41]1[C@@H:45]([CH:46]([CH3:47])[CH3:48])[CH2:44][O:43][C:42]1=[O:49])=[O:40])=[O:30])([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](Cc1ccccc1)[C@H](O)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](Cc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Add 2,6-lutidine (5.3 mL, 54 mmol) and tert-butyl-dimethylsilyl-trifluoromethylsulfonate (1.62 mL, 7.08 mL) to a solution of 2-(R)-[2-(S)-benzyl-1-(S)-hydroxy-3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)-3-oxopropyl]-4-(R)-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (2.585 g, 5.4 mmol) in dichloromethane (40 mL) at −78° C. Stir 3 h, warm to room temperature, stir 5 min and cool in an ice bath. Add 1 N HCl (100 mL), wash with 1 N HCl (2×100 mL), saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a white foam (2.779 g, 87%).
Reaction SMILES: [CH2:1]([CH:9]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:10][O:11][C:12]1[C:13]2[C:21]([CH:22]=[C:23]3[CH:27]=[CH:26][S:25][C:24]=13)=[C:20]([O:28][CH2:29][CH:30]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16]1[S:17][CH:18]=[CH:19][C:15]=1[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[CH3:64][Sn:65](Cl)([CH3:67])[CH3:66].O>C1COCC1>[CH3:64][Sn:65]([CH3:67])([CH3:66])[C:26]1[S:25][C:24]2[C:12]([O:11][CH2:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[C:13]3[C:21](=[CH:22][C:23]=2[CH:27]=1)[C:20]([O:28][CH2:29][CH:30]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:16]1[S:17][C:18]([Sn:65]([CH3:67])([CH3:66])[CH3:64])=[CH:19][C:15]1=[CH:14]3
Reactant: CCCCCCCCCCC(CCCCCCCC)COc1c2cc3ccsc3c(OCC(CCCCCCCC)CCCCCCCCCC)c2cc2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCC(CCCCCCCC)COc1c2cc3cc([Sn](C)(C)C)sc3c(OCC(CCCCCCCC)CCCCCCCCCC)c2cc2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Compound (4a) (0.350 g, 0.420 mmol) was solubilized in anhydrous THF (17 mL) and cooled at −78° C. under N2. n-Butyllithium (0.42 mL, 2.5M) was then added and the stirring was continued for 30 minutes at this temperature and then 30 minutes at room temperature. The reaction mixture was cooled to −78° C. again before adding trimethylstannyl chloride (1.1 mL, 1.0 M). The reaction was warmed up to room temperature and stirred overnight. The reaction was stopped by adding water, and the mixture was extracted with diethyl ether, dried over MgSO4, filtered, and concentrated in vacuo. The crude monomer was solubilized in 5 mL of THF and then dropped in methanol (200 mL). The product was allowed to precipitate in the freezer overnight before filtering and washing with cold methanol to afford a yellow fluffy powder as the title compound (0.420 g, 86%). 1H NMR (500 MHz, CDCl3, 298 K): 8.43 (s, 2H); 7.51 (s, 2H); 4.29 (d, J=5.4 Hz, 4H); 2.00 (quintet, J=6.0 Hz, 2H); 1.74 (m, 4H); 1.45 (m, 60H); 0.88 (m, 12H); 0.47 (s, 18H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): 149.22; 142.73; 141.25; 132.62; 130.19; 124.51; 109.71; 75.50; 39.37; 31.99; 31.97; 31.42; 30.23; 29.83; 29.82; 29.78; 29.75; 29.47; 29.42; 27.08; 22.74; 14.19; 14.18; 8.40 ppm. HRMS (ESI-TOF-MS): m/z calcd for C60H104O2S2Sn2 1158.5516. found 1158.5543.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCO>[Br:1][C:2]1[S:3][C:4]([CH2:7][NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:5][N:6]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: Nc1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ncc(CNc2nccs2)s1
Yield: 51.1 %

Procedure:
A solution of 2-bromothiazole-5-carbaldehyde (150 mg, 0.78 mmol) and 2-amino-thiazole (78 mg, 0.78 mmol) in toluene (7 mL) and 3 Å molecules sieves were stirred at reflux overnight. The strong yellow solution of the corresponding imine was then poured over NaBH4 (147 mg, 3.9 mmol) in hot EtOH (50 mL). The colorless solution was filtered, concentrated and purified by column chromatography (30% AcOEt/PE) yielding N-((2-bromothiazol-5-yl)methyl)thiazol-2-amine (110 mg, 51%) as a solid.