Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:31]4[CH:30]=[N:29][N:28]([CH2:27][C:26]([OH:43])([CH3:42])[CH3:25])[CH:32]=4)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following Example 267, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted to give 401. MS: (ESI+)=471.2
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[C:29]([F:30])=[CH:28][C:27]([S:31]([NH2:34])(=[O:33])=[O:32])=[C:26]([F:35])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[F:30][C:29]1[CH:28]=[C:27]([S:31]([NH2:34])(=[O:32])=[O:33])[C:26]([F:35])=[CH:25][C:24]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cc(F)c(Br)cc1F
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cc(F)c(S(N)(=O)=O)cc2F)cc1)[C@H](O)CCc1cccnc1
Temperature: 80 °C
Yield: 36.9 %

Procedure:
Prepared according to the method described in Example 12) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.2 g, Example 33), 4-bromo-2,5-difluorobenzenesulfonamide (0.19 g, Example 37a)), ethanol (3 ml), 2M aqueous sodium carbonate (0.7 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 80° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a foam (0.11 g).
Reaction SMILES: [OH-].[Li+].Cl.C[O:5][C:6](=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C@H:15]([NH:17][C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH3:16])[CH:9]=1.Cl>CO>[C:20]1([C@H:18]([NH:17][C@H:15]([CH3:16])[CH2:14][C:10]2[CH:9]=[C:8]([CH2:7][C:6]([OH:26])=[O:5])[CH:13]=[CH:12][CH:11]=2)[CH3:19])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)Cc1cccc(C[C@@H](C)N[C@H](C)c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](Cc1cccc(CC(=O)O)c1)N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
Lithium hydroxide solution (1M in water, 90 mL, 90 mmol) was added to a solution of methyl[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hydrochloride (preparation 26), (13.5 g, 43.5 mmol) in methanol (200 mL) and the mixture was stirred at room temperature for 18 hours. 1M Hydrochloric acid (90 mL) was then added to the reaction mixture and the methanol removed in vacuo. The resulting precipitate was filtered off and washed with water (20 mL) and a mixture of ethanol/diethyl ether, 20:80, to afford the title compound as a solid in 91% yield, 11.8 g 1H NMR (400 MHz, CD3OD) δ: 7.52-7.45 (5H, m), 7.22-7.18 (2H, m), 7.19 (1H, s), 6.92 (1H, d), 4.56-4.48 (1H, q), 3.46 (2H, s), 3.26-3.13 (2H, m), 2.66-2.62 (1H, m), 1.62 (3H, d), 1.16 (3H, d) ppm; LRMS ESI m/z 298 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]3[NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]2[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]2[N:11]=1
Reactant: Cc1cc2[nH]c(=O)cc(-c3ccc(F)cc3)n2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc2nc(Cl)cc(-c3ccc(F)cc3)n2n1
Temperature: 25 °C

Procedure:
7-(4-Fluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (151 mg) is dissolved in POCl3 (10 mL) and pyridine (0.1 mL) and stirred overnight while heating. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (156 mg). 1H NMR (CDCl3, 300 MHz); δ 8.07 (m, 2H), 7.26 (m, 2H), 6.78 (m, 1H), 6.48 (s, 1H), 2.50 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)=[N:7][C:6]=2[CH:15]=1.C(N(CC)CC)C.[C:23](Cl)(Cl)=[S:24]>O1CCCC1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)=[N:7][C:6]=2[CH:15]=1)=[C:23]=[S:24]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2sc(-c3cccs3)nc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc2sc(-c3cccs3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-(2-thienyl)benzothiazole 7.0 g, 0.03 M is dissolved in 400 cc of tetrahydrofuran and 8.4 cc, 0.06 M, of triethylamine. Thiophosgene 2.3 cc, 0.03 M, is added, and the resulting mixture stirred at ambient temperature overnight. The solids which form are filtered, and washed with tetrahydrofuran. The filtrate is concentrated to dryness, and chromatographed on Alumina IV. The product is recrystallized from acetonitrile to yield 5.7 g of colorless needles, 70% of theory, m.p. 147°-149°.
Reaction SMILES: [Na+:1].NCC([O-])=O.[OH-].[Na+].[SH:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[O:12]>O1CCCC1>[Na+:1].[SH:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([NH:19][CH2:20][C:21]([O-:23])=[O:22])=[O:18])=[O:12]
Reactant: O=C(O)CNC(=O)c1cccc(NC(=O)CS)c1
Agent: NCC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])CNC(=O)c1cccc(NC(=O)CS)c1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
Stable Hydrate of N-[3-Mercaptoacetylamino)benzoyl]-glycine Sodium Salt.-- An aqueous solution of 10% sodium hydroxide (65 ml. 0.1625 mole) is slowly added to a suspension of N-[3-(mercaptoacetylamino)benzoyl]glycine (43 g., 0.16 mole) in 230 ml. of tetrahydrofuran with cooling at 10-20° C. The mixture is warmed to about 20-25° C. and filtered from a trace of solid. Diluting the filtrate with 480 ml. of tetrahydrofuran promotes the formation of a suspension which is stirred for 2 hr. and collected. The collected material is washed with tetrahydrofuran and air dried to provide 50 g. (88.3 % yield) of N-[3-(mercaptoacetylamino)benzoyl]glycine sodium salt hydrated with 3.5 moles water, m.p. 68-120° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C1(C)C=CC=CC=1>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1F
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=C1CCC(c2ccc(F)c(F)c2)CC1
Reaction time: 18 h
Yield: 96 %

Procedure:
A mixture of 6.30 g of 8-(3,4-difluorophenyl)-1,4-dioxaspiro[4.5]decane, 60 ml of toluene and 40 ml of formic acid was stirred for 18 hours. The formic acid phase was separated and extracted twice with 30 ml of toluene each time. The combined toluene phase was washed neutral with water, dried over sodium sulphate and concentrated. There were obtained 5.00 g of 4-(3,4-difluorophenyl)cyclohexanone as a colourless oil.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:31]=4)=[O:28])=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:40]#[N:41])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O.C(OCC)(=O)C>[C:40]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:41]
Reactant: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCc5ccccc5)c(C#N)cc34)cc2)c1
Solvent: CCOC(C)=O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(O)c(C#N)cc34)cc2)c1
Temperature: 65 °C
Reaction time: 19 h
Yield: 72 %

Procedure:
After dissolving N-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea (1.43 g, 2.5 mmol) in trifluoroacetic acid (10 ml) and thioanisole (1.17 ml, 10 mmol) under a nitrogen atmosphere, the solution was stirred at 65° C. for 19 hours. The reaction solution was concentrated under reduced pressure, and after adding 5% aqueous sodium bicarbonate (30 ml) and ethyl acetate (50 ml) to the obtained residue and stirring, the precipitated crystals were filtered out, washed with water and ethyl acetate and dried under reduced pressure. The organic layer of the filtrate was separated, washed with saturated brine and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a yellow crystalline residue. This was combined with the previous crystals, suspended in ethyl acetate (40 ml) and subjected to sonication, and then the crystals were filtered out, washed with diethyl ether and dried at 60° C. to obtain the title compound (862 mg, 1.8 mmol, 72.7%) as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1>CCOC(C)=O>[Cl:14][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1nccc(-c2cccnc2Cl)n1
Reactant: NCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1ncccc1-c1ccnc(NCCCN2CCOCC2)n1
Temperature: 80 °C

Procedure:
To 2-chloro-4-(2-chloropyridin-3-yl)pyrimidine (100 mg, 0.44 mmol) and potassium carbonate (122 mg, 0.88 mmol) was added DMSO (1.0 mL) and 3-morpholinopropan-1-amine (77 mg, 0.53 mmol). The resulting mixture was heated for 15 hours at 80° C. The cooled reaction was diluted with EtOAc and extracted with water. The organic layer was dried over sodium sulfate, filtered and concentrated to yield the desired product as a yellow oil. MS m/z=334 [M+M]+. Calc'd for C16H20ClN5O: 333.84.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example A.19) (3.0 g, 8 mmol) and commercially available 3-bromo-benzene-boronic acid (1.954 g, 10 mmol) according to the general procedure IVb. Obtained as an orange oil (3.28 g, 91%). MS (ISP) 446.0 [(M+H)+] and 448.0 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:22])[CH:3]=1>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)cc2F)cc1
Agent: Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2F)cc1
Yield: 91.9 %

Procedure:
In a manner similar to Example 4, Step (b), 4-(4′-chloro-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (1.39 g, 0.00433 mol) was refluxed in 6 M hydrochloric acid to give 1.22 g of 4-(4′-chloro-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid as a light purple solid; mp 127-129° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29](Cl)[CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][NH2:41].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])[CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1
Reactant: COCCCN
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: COCCCNc1cccc([C@@H]2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]2c2ccccc2)c1

Procedure:
The title compound, MS: m/e=565.4 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(3-chloro-phenyl)-4-phenyl-piperidin-1-yl]-methanone, 3-methoxy-propylamine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: C([N:3](CC)[CH:4]=[CH:5][C:6]([C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])=O)C.[NH2:30]N>CO.C(O)(=O)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:17]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:6]2[NH:30][N:3]=[CH:4][CH:5]=2)[CH:9]=1)=[O:18]
Reactant: CCN(C=CC(=O)c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OC)CC
Reactant: NN
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccn[nH]1
Yield: 78.1 %

Procedure:
To a solution of 1-[3-(3-Diethylamino-acryloyl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (1.5 g, 3.72 mmole) in methanol/acetic acid (50 mL/2.0 mL) mixture was added hydrazine (0.82 g, 37.22 mmole). The reaction mixture was refluxed at 55 C for 20 hrs. The methanol/acetic acid was evaporated from the reaction mixture and the solid was triturated with ether/methanol. The solid was filtered and washed with ether. Next, the solid was dried in vacuo to furnish a colorless solid (1.0 g, 76%). LCMS m/z (%)=345 (M+H, 100), 1H NMR (Bruker, 400 MHz, DMSO-d6) δ: 13.0 (bs, 1H), 8.89 (bs, 1H), 8.37 (bs, 1H), 8.09-810 (d, J=6.05 Hz, 1H), 7.74-7.97 (bs, 1H), 7.52-7.64 (bs, 1H), 7.39-7.40 (d, J=5.94 Hz, 1H), 7.27-7.32 (m, 2H), 7.01-7.09 (m, 2H), 6.73 (s, 1H), 3.82 (s, 3H) (major tautomer).
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][N:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](Cl)=[S:6]>CCOCC>[CH3:3][N:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[S:6])[NH:1][NH2:2]
Reactant: CN(C(=S)Cl)c1ccccc1
Reactant: NN
Solvent: CCOCC
Product: CN(C(=S)NN)c1ccccc1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
To a solution of 7.7 g (0.24 mole) anhydrous hydrazine in 200 ml of dry ether, N-methyl-N-phenylthiocarbamyl chloride (20.4 g, 0.11 mole) was added below 5° C. with stirring. The mixture was stirred and allowed to warm to room temperature. The mixture was filtered and the residue resuspended in about 100 ml water and stirred. Filtration gave 8.8 g of the desired product as a whitish powder, m.p. 121°-22°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][N:5]2[CH:15]=[CH:16][N:17]=[C:4]2[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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]>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=2)=[N:3][C:4]2[N:5]([CH:15]=[CH:16][N:17]=2)[CH:6]=1
Reactant: Fc1ccccc1-c1cn2ccnc2nc1Cl
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2F)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
665 mg (2.68 mmol) 7-Chloro-6-(2-fluorophenyl)-imidazo[1,2-a]pyrimidine are given in 9.2 mL dimethoxyethane (not completely dissolved). 442.9 mg (2.95 mmol) 4-formylphenylboronic acid and 5.3 mL Na2CO3 solution (10%) are added. After addition of 98.6 mg (0.12 mmol) 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture is purged 3× with argon and heated to 90° C. for 20 hours. The reaction mixture is cooled down and treated with 30 mL water and 150 mL dichloromethane. After vigorous stirring at rt for 90 minutes the organic phase is separated. The aqueous phase is extracted with dichloromethane (100 mL). The combined organic phases are washed with water (50 mL) and brine (50 mL) and dried (Na2SO4). The solvent is removed and the crude product purified via chromatography (silicagel, dichloromethane/methanol). 404.8 mg (47.5%) of the desired product (contaminated) are obtained.
Reaction SMILES: C(O)(=[O:3])C.[O:5]([CH2:12][C:13]([NH:15][CH:16]1[C:27](=[O:28])[N:18]2[CH:19]([C:24]([OH:26])=[O:25])[C:20]([CH3:23])([CH3:22])[S:21][C@H:17]12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.OO>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[O:5]([CH2:12][C:13]([NH:15][CH:16]1[C:27](=[O:28])[N:18]2[CH:19]([C:24]([OH:26])=[O:25])[C:20]([CH3:23])([CH3:22])[S:21](=[O:3])[C@H:17]12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC1(C)C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Reaction time: 1 h

Procedure:
Acetic acid (10 cc) was added to 6-(2-phenoxyacetamido)-2,2-dimethylpenam-3-carboxylic acid (3.50 g.), and sodium tungstate dihydrate (100 mg.) was further added thereto. To the mixture was added 30% hydrogen peroxide (1.2 cc) while cooling in an ice bath, and the mixture was stirred for 1 hour. Water was added to the mixture and the precipitate was collected by filtration, washed with water and dried to yield crystals (3.24 g.) of 6-(2-phenoxyacetamido)-2,2-dimethylpenam-3-carboxylic acid-1-oxide, m.p. 166°-167° C.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=2)[CH:8]=1)C.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:15]2[C:14]3[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=3)[CH:8]=[C:7]2[CH2:6][C:5]([CH3:27])([CH3:26])[C:4]([OH:28])=[O:3])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(C)(C)Cc1cc2nc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(cc(CC(C)(C)C(=O)O)n2Cc2ccc(Cl)cc2)n1
Temperature: 60 °C

Procedure:
3-[5-Methoxy-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionic acid ethyl ester (0.050 g, 0.12 mmol) was dissolved in THF (0.1 mL), MeOH(0.1 mL), and H2O (0.1 mL). LiOH(0.02 g, 0.50 mmol) was added and the reaction was heated to 60° C. for 2 hours. Once no starting material was seen by LCMS, the reaction was cooled to room temperature and diluted with EtOAc and water. The mixture was neutralized with solid citric acid to ˜pH 5, the aqueous layer was extracted three times with EtOAc, the combined organics were washed twice with water, once with brine, dried over MgSO4, filtered and concentrated to give the desired acid. LCMS (ESI) M+H 373.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1)=[O:7])([O-:3])=[O:2]
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])s1)c1ccccc1[N+](=O)[O-]

Procedure:
By following the procedure of the first part of Example 1, but using 2-nitrobenzoyl chloride (18.5 g), 2-amino-5-nitrothiazole (14.5 g) and pyridine (ca 80 ml), there was obtained 2-nitro-N-(5-nitro-2-thiazolyl)-benzamide, m.pt 248°-250°, after crystallization from 2-methoxyethanol.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:17]=[C:16]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1>C1C=CC=CC=1>[C:33]([CH2:32][CH2:31][C:30]([N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[N:17]=[C:16]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])=[O:36])([OH:35])=[O:34]
Reactant: O=C1CCC(=O)O1
Reactant: O=C(C1CCCN1)N1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Solvent: c1ccccc1
Product: O=C(O)CCC(=O)N1CCCC1C(=O)N1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Yield: 120 %

Procedure:
A solution of 2 g of (-)-N'-[(pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine in 20 ml of anhydrous benzene is added with 0.56 g of succinic anhydride and 0.05 g of N,N-dimethylaminopyridine, then the reaction mixture is refluxed for 2 hours. After that, solvent is evaporated off under reduced pressure, to give 3 g of (-)-N'-[(1-(carboxyethylcarbonyl)pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]3([CH2:14][CH2:13]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]3([CH2:14][CH2:13]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: CI
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CC2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of 2′-chloro-9′-cyclopentyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 131; 15 g, 51.24 mmol) in DMA (1 L) under nitrogen was added methyl iodide 3.51 mL, 56.36 mL). The mixture was cooled in ice/water to 4° C. Sodium hydride (60% mineral oil dispersion; 2.26 g, 56.36 mmol) was added in one portion. A small exotherm to 6° C. was observed. The reaction mixture was stirred on an ice/water bath for 1 hour, the cooling bath was removed and the reaction stirred at room temperature overnight. Solvent was evaporated in vacuo and the residue treated with water. This afforded a solid, which was filtered off and washed with water to give an off white solid, which was crystallised from IPA (100 mL) with hot filtration through fluted paper to remove a small amount insoluble matter. The crystallised material was filtered, washed with chilled IPA, and dried by dessication under high vacuum at room temperature over the weekend to give the title compound as a white crystalline solid (12.78_g, 81%)