Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:6]([O:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[Si:6]([O:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C1CCNC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CN2CCCC2)c1F
Yield: 90.9 %

Procedure:
Pyrrolidine (6.8 mL, 82 mmol) was added to a solution of intermediate 32, 3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorobenzaldehyde (16.7 g, 66 mmol) in dichloromethane (200 mL). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (17.4 g, 82 mmol) was added in portions under stirring. The reaction mixture was intensively stirred for 12 h at RT. Water (100 mL) was added. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×100 mL). The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo to give the title compound (19 g, 94%, 60 mmol). 1H NMR data (DMSO-d6): 6.92-7.03 (m, 2H, H—Ar), 6.83-6.91 (m, 1H, H—Ar), 3.58 (d, 2H, J=1.7 Hz, Ar—CH2); 2.38-2.46 (m, 4H), 1.63-1.70 (m, 4H) 0.97 (s, 9H, t-Bu), 0.16 (s, 6H, 2CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:23]/[S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
(Ref: Angew. Chem. Int. Ed., 48:914-917 (2009)). To a stirred suspension of 3-chloro-2-fluorobenzaldehyde (1.308 g, 8.25 mmol) and Cs2CO3 (4.03 g, 12.38 mmol) in DCM (10 mL) was added a solution of (R)-2-methylpropane-2-sulfinamide (1 g, 8.25 mmol) in DCM (50 mL) dropwise for 10 min. The solution was then stirred for 2 h at rt. LC/MS indicated that the reaction was complete. The reaction mixture was then diluted with EtOAc (50 mL) and washed with brine (20 mL×3). The organic layers were dried over Na2SO4 and concentrated in vacuo to give (R,E)-N-(3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (2.3 g, 107%) as a clear oil. MS (ESI) m/z: 262.1 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][N:13]1[CH2:19][CH:18]2[CH2:20][CH2:21][CH:15]([CH2:16][CH2:17]2)[CH2:14]1.[NH2-].[Na+].O>C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH2:11][CH2:12][N:13]2[CH2:19][CH:18]3[CH2:20][CH2:21][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(CCN1CC2CCC(CC2)C1)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 20 parts of α-phenylacetonitrile in 300 parts by volume of toluene is added 94 parts of 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane dissolved in 500 parts by volume of toluene. The mixture is heated with stirring to about 80° C. and then 17 parts of sodium amide is added slowly over a period of 30 minutes. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether, the ether extract dried over calcium sulfate and distilled to afford 2-phenyl-4-(3-azabicyclo[3.2.2]non-3-yl)butyronitrile.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O>CS(C)=O>[S:1]([C:6]1[CH:7]=[C:8]([C:10]2[C:11]([C:15]([F:16])([F:17])[F:18])=[N:12][NH:13][CH:14]=2)[CH:9]=[CH:2][C:3]=1[C:4]#[N:5])[C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:16])([F:18])[F:17])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Sc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C#N
Temperature: 25 °C
Yield: 46.4 %

Procedure:
3.0 g (11.1 mmol) of 2-mercapto-4-(3-trifluoromethylpyrazolyl)benzonitrile in 5 ml of dimethyl sulfoxide was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and poured into 50 ml of water, and the organic matters were extracted with 20 ml of ethyl acetate twice. The ethyl acetate layers were combined, then washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue afforded 1.3 g of 1,1′-thiodi-[2-cyano-5-(3-trifluoromethylpyrazolyl)benzene] (yield 42.4%) as a yellow solid, which was used in Example 2 (3) as the starting material.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[CH:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:14]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH2:16][CH3:17])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:33])[C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@@:14]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH2:16][CH3:17])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(CC)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](CC)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-ethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound. LC-MS: 621.2 [(M+H)+]
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:12][CH2:11][NH:10][S:9]1(=[O:14])=[O:13].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>CN(C)C=O>[CH3:7][N:8]1[S:9](=[O:14])(=[O:13])[N:10]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:11][CH2:12]1
Reactant: CN1CCNS1(=O)=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a stirred suspension of anhydrous potassium carbonate (14.49 g, 104.8 mmol) in anhydrous dimethylformamide (80 ml) was added dropwise over 4 minutes a solution of 2-methyl-1,2,5-thiadiazolidine-1,1-dioxide (14 g, 102.8 mmol) in anhydrous dimethylformamide (40 ml), under nitrogen. After 5 minutes, solid 4-nitrobenzyl bromide (22.43 g, 103.8 mmol) was added in one portion and stirring was continued at room temperature for 5 hours. Water (200 ml) was added and products were extracted into ethyl acetate (3×150 ml). The combined organic phases were washed with brine (1×50 ml), dried (Na2SO4) and concentrated. The crude residue was crystallized from ethyl acetate-hexane (70:30) to give 18.31 g (67%) of the title compound as pale yellow crystals. Purification of the mother liquors by flash chromatography (silica gel, hexane-ethyl acetate, 30:70) afforded a further 5.1 g (18.2%) of required product; mp 105°-107° C.; δH (250 MHz, CDCl3) 8.22 (2H, d, J=8.7 Hz, Ar--H), 7.57 (2H, d, J=8.7 Hz, Ar--H), 4.32 (2H, s, Ar--CH2 --), 3.36--3.21 (4H, m, N--CH2CH2 --N), 2.80 (3H, s, --NMe); m/z (CI) 270 (M+ -1).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:8][C@@H:7]([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][C:12]([Cl:33])=[N:13][C:14]=3[NH:18][CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:6]([OH:34])[C@@H:5]1[OH:35].[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37]>C1COCC1>[Cl:33][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[C@@H:7]2[CH2:8][C@H:4]([NH:3][C:41]([CH2:40][O:39][C:36](=[O:38])[CH3:37])=[O:42])[C@@H:5]([OH:35])[C@H:6]2[OH:34])=[C:14]([NH:18][CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol dihydrochloride (Intermediate JJ3) (250 mg, 0.46 mmol) in dry THF (10 ml) is treated with TEA (0.188 g, 1.86 mmol) followed by acetoxyacetylchloride (0.064 g, 0.46 mmol) and then stirred at room temperature for 30 minutes. The solvent is removed in vacuo and the solvent is partitioned between DCM and 0.1M HCl. The organic portion is separated and washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.C[NH:18][C:19](=[NH:21])S.[OH-].[Na+].O>CO>[C:19]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[NH:18])[NH2:21]
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CNC(=N)S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N=C(N)NNC(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 96 h
Yield: 104.7 %

Procedure:
The synthesis was carried out according to the method of Example 1-(1). 4-Chlorobenzoic acid hydrazide (34.8 g), methylisothiourea sulfate (115.4 g), sodium hydroxide (17.1 g), water (440 ml) and methanol (700 ml) were used as reagents. The mixture was stirred for 4 days at 60° C. to give 45.4 g of a pale-brown solid which was a mixture of a hydrazide compound and the objective compound.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=O.[CH3:11][Li].O>CCOCC>[CH3:10][C:2]([CH3:1])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](=[O:5])[CH3:11]
Reactant: [Li]C
Reactant: CCCCC(C)(C)C(=O)O
Solvent: CCOCC
Solvent: O
Product: CCCCC(C)(C)C(C)=O

Procedure:
A solution of 14.4 g (100 mmol) of 2,2-dimethylhexanoic acid (XXIX) in 100 ml of dry ether was stirred a 0° C. under argon as 130 ml (237 mol) of a solution of methyllithium (1.82 M) in ether was added dropwise. The resultant mixture was stirred with ice-bath cooling for 1 hour and then without cooling overnight. It was then poured into a vigorously stirred 500 ml portion of water in a large beaker. The phases were separated and the aqueous phase was back-extracted twice with ether. The combined extract was dried (MgSO4) and evaporated in vacuo. The residue was distilled at 20 mm to yield 12.7 g of XXX as a colorless oil, bp 125°-130°; Rf (CHCl3) 0.54; nmr 0.9 (3, broad t, J=6.0 Hz), 1.12 (6, s), 1.0-1.8 (6, m) and 2.14 (3, s); ir (film) 8.85, 7.45, 6.80, 5.85, 3.50, 3.41 and 3.38μ.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11](NC(C2C=CC=CC=2)CO)=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:24]>O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11]([OH:12])=[O:24])=[CH:6][CH:7]=1
Reactant: O=C(NC(CO)c1ccccc1)[C@@H]1C[C@@H]1c1ccc(O)cc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@@H]1c1ccc(O)cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 22 mL of dioxan. To the stirred solvent were added (1R,2S)-2-(4-hydroxyphenyl)-N-(2-hydroxy-1-phenylethyl)cyclopropanecarboxamide (0.75 g, 2.52 mmol) and 3N sulfuric acid (22 mL). The reaction mixture was heated at 100° C. for 7 h. The reaction mixture was poured into ice and extracted with ethyl acetate (25 mL). The organic layer was washed with brine solution (25 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow oil (0.51 g, yield: 100%). 1H NMR (300 MHz, DMSO-d6): δ 12.20 (s, 1H), 9.25 (s, 1H), 6.93-6.96 (d, 2H), 6.64-6.67 (d, 2H), 2.24-2.31 (m, 1H), 1.63-1.68 (m, 1H), 1.31-1.37 (m, 1H), 1.20-1.26 (m, 1H).
Reaction SMILES: [C:1]1([CH:7](O)[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.FC(F)(F)S([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])(=O)=O>ClCCl>[Si:25]([O:24][CH2:9][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C#CC(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Phenyl-2-propyn-1-ol (7 g) was dissolved in dichloromethane at 0° C. under nitrogen. 2,6-Lutidine (6.17 ml) was added to the solution followed by dropwise addition of tert-butyldimethylsilyl trifluoromethane sulfonate (12.16 ml); the resulting solution was stirred overnight at room temperature. The dichloromethane was washed with water (2×), brine and dried (MgSO4) and solvent removed in vacuo. The residue was purified on flash silica using 100% petrol moving to 5% ethyl acetate/petrol, to afford the title compound as a yellow oil (10.31 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=[N:3]1.O.[NH2:21][NH2:22]>CO>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=[N:3]1
Reactant: COC(=O)c1ccc(C(=O)NCc2ccnn2C)s1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1nccc1CNC(=O)c1ccc(C(=O)NN)s1
Yield: 49 %

Procedure:
Methyl 5-(1-methyl-1H-pyrazol-5-ylmethylcarbamoyl)thiophene-2-carboxylate (0.25 g, 0.90 mmol) in methanol (2.5 mL) was stirred with hydrazine monohydrate (0.17 mL, 3.6 mmol) at 70° C. for 3.5 hours. The precipitated solid was recovered by filtration, washed with chloroform and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid (1-methyl-1H-pyrazol-5-ylmethyl)amide (yield 49%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][C:53]=1[CH3:65]>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=2)=[CH:54][C:53]=1[CH3:65]
Reactant: COc1ccc(-c2cccc(N)c2)cc1C
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 79.1 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 78% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [SH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:8][C:7](=[O:9])[CH2:6][C:3]1([CH2:2][SH:1])[CH2:5][CH2:4]1)[CH3:16]
Reactant: CCO
Reactant: O=C(O)CC1(CS)CC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1(CS)CC1
Temperature: 20.5 °C
Reaction time: 3 h

Procedure:
To a 3 L flask, a solution of 1-(mercaptomethyl)cyclopropaneacetic acid (204.5 g) in ethanol (1000 ml) was charged. 96% sulfuric acid (22.73 g) was added, and the reaction mixture was stirred for 3 h at 19-22° C. The reaction mixture was concentrated to ¼ of its volume at 50° C. under reduced pressure, and the residue was partitioned between water (1000 ml) and ethyl acetate (200 ml). The organic phase was separated, washed with 10% NaHCO3 (400 ml), and dried for 2 h over anhydrous sodium sulfate. The mixture was filtered and evaporated at 50° C., under reduced pressure, to afford 197.9 g of the crude 1-(mercaptomethyl)cyclopropaneacetic acid ethyl ester, as a slightly colored liquid with a strong, unpleasant odor.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH:31]1([C:36](Cl)=O)[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:8][C:7]1[C:2]2[N:1]=[C:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:23][C:3]=2[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[C:5]([F:9])[CH:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(N)c2O)c1=O
Reactant: O=C(Cl)C1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(C4CCCC4)oc23)c1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
0.48 g of 3-[3-amino-4-chloro-6-fluoro-2-hydroxyphenyl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (from intermediate 7) was initially charged with 0.14 g of triethylamine in 30 ml of absolute xylene, and the mixture was, at 0° C., admixed dropwise with 0.18 g of cyclopentanecarbonyl chloride. After 10 minutes, the mixture was warmed to 20° C., 0.1 g of pyridinium p-toluenesulfonate was added and the mixture was heated at reflux for six hours. After cooling, the xylene phase was washed three times with 30 ml of water each time, dried over sodium sulfate and freed from the solvent under reduced pressure. The crude product was purified by medium pressure liquid chromatography (MPLC); mobile phase: cyclohexane/ethyl acetate (9:1). Yield: 0.27 g;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[S:12][C:13]([C:21]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:4][N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCOCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:3][CH:4]=2)=[O:9])[S:12][C:13]=1[C:21]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22]
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(N2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 40585.8 %

Procedure:
Compound 502 (100 mg, 0.239 mmol) was suspended in 1,4-dioxane (1 mL), and morpholine (0.063 mL, 0.72 mmol) was added thereto, followed by stirring overnight at 100° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was reslurried with ethanol to afford the entitled Compound 503 (109 mg, 97 mmol) as a pale brown solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH2:36][CH:37]([Cl:39])[Cl:38])[CH:31]([NH:40][C:41](=[O:71])[C:42](=[N:68][O:69][CH3:70])[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[S:46][CH:47]=1)[C:30]2=[O:72])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[CH2:36][CH:37]([Cl:39])[Cl:38])[CH:31]([NH:40][C:41](=[O:71])[C:42](=[N:68][O:69][CH3:70])[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[S:46][CH:47]=1)[C:30]2=[O:72])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(Cl)Cl)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(Cl)Cl)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A solution of meta-chloroperbenzoic acid (85% pure) (0.05 g) in methylene chloride (1 cc) is added all at once to a solution, cooled to -10° C., of product (8b) (0.2 g) in methylene chloride (5 cc). After 30 minutes at -10° C., the reaction mixture is diluted with ethyl acetate (20 cc) and washed with a saturated solution of sodium bicarbonate (2×10 cc) and a saturated solution of sodium chloride (2×10 cc). After the mixture has been dried over sodium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., crude syn isomer of 2-benzhydryloxycarbonyl-3-(2,2-dichloroethyl)-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (product 8) (0.15 g) is obtained in the form of a hard orange foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>ClCCl>[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: COC[C@@H]1CCCN1
Solvent: ClCCl
Product: COC[C@@H]1CCCN1C(=O)c1cnoc1-c1ccc(C)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added (2S)-2-(methoxymethyl)pyrrolidine (5.7 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C17H20N2O3: 300.1474, found 300.1481.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1([CH3:34])[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[CH:30][C:31]([NH2:33])=[CH:32][C:23]1=2.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:33][C:31]2[CH:30]=[CH:29][C:24]3[NH:25][CH2:26][CH2:27][CH2:28][C:22]([CH3:34])([CH3:21])[C:23]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCCNc2ccc(N)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CC1(C)CCCNc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Yield: 17.2 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (112 mg, 0.330 mmol), 5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (76 mg, 0.399 mmol), 4 N HCl in dioxane (99 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 24 hours. Concentrated under reduced pressure and purified with normal phase chromatography to yield a brown solid, N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (28 mg, 17%). LCMS: m/z=493.30 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.25 (m, 2H), 7.06 (br s, 1H), 6.68 (d, 1H, J=8.1 Hz), 5.76 (br s, 1H), 5.42 (m, 1H), 3.82 (m, 1H), 3.75 (m, 2H), 3.53 (m, 2H), 3.21 (m, 1H), 3.03 (m, 2H), 2.78 (s, 3H), 2.16 (m, 2H), 1.88 (m, 2H), 1.79 (m, 2H), 1.64 (m, 2H), 1.40 (m, 6H), 1.33 (m, 4H).