Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]2([CH2:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[CH:13]=3)[O:8]2)[CH2:4][O:3]1.C[Si]([N:31]=[C:32]=[N:33][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:21]([C:20]1[CH:19]=[C:18]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][C:5]([CH2:6][OH:7])([CH2:4][OH:3])[CH2:16]/[C:15]/3=[N:33]\[C:32]#[N:31])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC1(C)OCC2(CO1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(CO)(CO)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
To a solution of 3-(2′,2′-dimethyl-4-oxospiro[chroman-2,5′-[1,3]dioxane]-6-yl)benzonitrile (155 mg, 0.44 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.88 mL, 0.88 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (181 mg, 217 μL 0.97 mmol) dropwise. The resulting mixture was stirred for another 20 h after the addition. The reaction mixture was poured into ice-water (25 g), stirred for 30 min and filtered through a pad of Celite. The separated aqueous phase of the filtrate was extracted with DCM once. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give yellowish gel like solid (E)-N-(6-(3-cyanophenyl)-2,2-bis(hydroxymethyl)chroman-4-ylidene)cyanamide (160 mg), which was used in the next step without further purification. MS ESI +ve m/z 374 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N)CCC>[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]#[C:26][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][CH:6]=[CH:5]4)[CH2:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C#CCCN1CC=C(c2ccccc2)CC1
Solvent: CCCCN
Product: C(#Cc1ccc2[nH]ccc2c1)CCN1CC=C(c2ccccc2)CC1

Procedure:
A solution of 5-bromoindole (0.5 g, 0.0025 mol) and the acetylene prepared in Example 9, Step (a) in 15 mL of N-butylamine is degassed by bubbling in dry nitrogen for 15 minutes, and 0.06 g, (5.0×10-5 mol) of tetrakis (triphenylphosphine)palladium(O) is added. The flask is flushed with nitrogen and the mixture is headed at reflux for 18 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 25 mL of dichloromethane and the combined organic layers are washed with 25 mL of water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound containing 0.3 mol of water; mp 173°-174° C.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14]Br.[CH3:17][O:18][C:19](=[O:28])[C@@H:20]([NH2:27])[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.C(#N)C>O>[CH3:17][O:18][C:19](=[O:28])[C@@H:20]([N:27]1[CH2:14][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][C:6]=2[C:10]([F:11])([F:12])[F:13])[C:3]1=[O:16])[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)[C@@H](N)CC1CCCC1
Reactant: COC(=O)c1cccc(C(F)(F)F)c1CBr
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 82 °C
Yield: 81.2 %

Procedure:
A mixture of 2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (695 mg, 2.34 mmol), (S)-2-amino-3-cyclopentyl-propionic acid methyl ester (400 mg, 2.34 mmol), triethylamine (358 μL, 2.57 mmol), and acetonitrile (20 mL) was heated at 82° C. for 7 h. The crude reaction mixture was treated with water (5 mL) and then concentrated in vacuo to remove the acetonitrile. The remaining solution was then diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL), the combined organics were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The residue was then purified via automated flash chromatography (12 g silica gel column, 10-40% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (675 mg, 81%) as a clear colorless oil: [α]25D=−16.0°, (c=0.15, methylene chloride); HR-ES(+) m/e calcd for C18H20NO3F3 [M+H]+ 356.1468, observed 356.1466; 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.02 (t, J=8.00 Hz, 2H), 7.71-7.89 (m, 1H), 4.92 (dd, J=4.08, 10.41 Hz, 1H), 4.69 (s, 2H), 3.66 (s, 3H), 0.94-2.21 (m, 11H).
Reaction SMILES: [C:1]1([CH3:7])C=CC=CC=1.C([Sn](CCCC)(CCCC)/C=C/[Sn](CCCC)(CCCC)CCCC)CCC.Br[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43](=[O:51])[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48].[Br:52]Br>C(Cl)(Cl)(Cl)Cl.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>[Br:52]/[CH:1]=[CH:7]/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43](=[O:51])[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48]
Reactant: Cc1ccccc1
Reactant: COC(=O)CCCC(=O)c1ccccc1Br
Reactant: BrBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCCC(=O)c1ccccc1/C=C/Br
Temperature: 120 °C

Procedure:
To 10 ml of toluene was added 6.0g (9.9 mmol) of trans-1,2-bis(tri-n-butylstannyl)ethylene, which was prepared according to the procedure of Corey, et al., J. Org. Chem., 40, 3788 (1975), and 0.5 g (1.8 mmol) of the product of Example 3. To the solution was then added 0.040 g (0.035 mmol) of 2 mole% tetrakis(triphenylphosphine)palladium(0) and the solution was degassed with argon. The reaction mixture was heated under argon for 1 hour at 120 ° C. (oil bath). Thereafter, the reaction mixture was cooled to -20° C. To the reaction mixture was added dropwise with stirring, a solution of 1.5 ml (29.1 mmol) of Br2 in 30 ml of CCl4 until thin layer chromatography of the reaction mixture indicated that all of the product of Example 3 was consumed. The volatile components were removed in vacuo. The residue was flash chromatographed on a silica gel column. Sequential elution with hexane, 5% diethyl ether in hexane, and 10% diethyl ether in hexane produced 0.48 g of the titled product. The product was triturated with cold hexane to give a white solid, m.p. 52°-55° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:15]=2[C:16]([OH:18])=O)=[C:11]([CH3:29])[CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C:55]1[CH:67]=[CH:66][C:58]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:57][CH:56]=1>CN(C=O)C>[F:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:15]=2[C:16]([NH:54][C:55]2[CH:67]=[CH:66][C:58]([C:59]([O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:60])=[CH:57][CH:56]=2)=[O:18])=[C:11]([CH3:29])[CH:10]=1
Reactant: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
Triethylamine (177.4 ml, 1.27 mmol) was added to a solution of 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoic acid (100 mg, 0.32 mmol), HATU (121 mg, 0.32 mmol) and tert-butyl 4-aminobenzoate (61.49 mg, 0.32 mmol) in DMF (1 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered and purified by reverse phase LC-MS using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield tert-butyl 4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)benzoate (43.8 mg, 28%). ESI-MS m/z calc. 489.16, found 490.3 (M+1)+; Retention time: 2.46 minutes (3 minutes run).
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]([OH:12])=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH:14]1[C:27](=[O:28])[N:16]2[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH2:21][O:22][CH3:23])[CH2:19][S:20][C@H:15]12>>[C:1]1([S:7]([CH2:9][C:10]([NH:13][CH:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH2:21][O:22][CH3:23])[CH2:19][S:20][C@H:15]23)=[O:12])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CS(=O)c1ccccc1
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)c3ccccc3)[C@H]2SC1

Procedure:
368 mg. of phenylsulfinylacetic acid and 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 320 mg. of 7-(phenylsulfinylacetamido)-3-methoxymethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:8][NH:9][C:10]2[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=[CH:26][N:27]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:38](=[O:40])[CH3:39])(=O)C>N1C=CC=CC=1>[C:16]([O:17][C@@H:16]1[C@H:18]([O:19][C:18](=[O:19])[CH3:20])[C@@H:20]([CH2:21][O:22][C:38](=[O:40])[CH3:39])[O:23][C@H:15]1[N:14]1[C:24]2[N:25]=[CH:26][N:27]=[C:10]([NH:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]=2[N:12]=[CH:13]1)(=[O:17])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
N6 -(2,2-Diphenylethyl)adenosine (4.6 g, 0.01 mole) and acetic anhydride (2.9 mL, 306 mol%) are mixed in pyridine at room temperature under nitrogen for 20 hours, and the reaction is evaporated in vacuo. The residue is dissolved in chloroform, washed twice with aqueous ice-cold 5% sodium carbonate, and the organic layer is dried (MgSO4) and evaporated in vacuo. Chromatography over silica gel eluting with 5/1 chloroform/methanol affords the title compound after evaporation in vacuo of appropriate fractions; mp 75°-80° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.CN(CCN(C)C)C.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: CN(C)CCN(C)C
Solvent: CO
Solvent: O
Product: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a mixture of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (90 mg, 0.32 mmol) containing [Cu(OH).TMEDA]2Cl2 (14.95 mg, 0.032 mmol) in dry methanol (5 mL) was added phenylboronic acid (81.0 mg, 0.64 mmol) under an air atmosphere and the resulting mixture stirred at room temperature overnight. After this time, the resulting mixture was diluted with water and extracted with ethyl acetate. The organic extracts were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=9:1 to 3:2) afforded the title compound (48 mg, 42%) which was obtained as a white solid. MS: m/e 356.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:19]1([NH:25][C:16]([C@H:10]2[O:11][CH2:12][C@@H:13]([CH2:14][CH3:15])[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@@H]1CO[C@H](C(=O)NC2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.250 g, 0.964 mmol) in CH2Cl2 (10 mL) were added cyclohexylamine (0.096 g, 0.964 mmol), HOAt (0.131 g, 0.964 mmol) and EDC (0.222 g, 1.157 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was washed with H2O (2×) and the organics were dried over Na2SO4 and concentrated to afford the title compound (0.296 g) as a brown oil. LC-MS (ES) m/z=241 [M+H-Boc]+.
Reaction SMILES: [NH4+:1].[OH-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
25 ml of 25% NH4OH were added dropwise while cooling in an ice bath to a solution of 7.3 g of p-methoxybenzenesulfonyl chloride in 50 ml of tetrahydrofuran. Subsequently, the reaction mixture was stirred vigorously for 30 minutes at 70° C. (bath temperature). Thereafter, the tetrahydrofuran was distilled. The residue was extracted with ethyl acetate. There was obtained p-methoxybenzenesulfonamide which was converted into the potassium salt as described in Example 50.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]([S:15]([OH:18])(=[O:17])=[O:16])[CH2:11][C:12]([OH:14])=[O:13])=[O:7])(C)(C)C.Cl.O1CCOCC1.C1(=O)[O:31][C:29](=[O:30])[CH:28]=[CH:27]1>CC(N(C)C)=O>[C:12]([CH2:11][CH:10]([S:15]([OH:18])(=[O:16])=[O:17])[CH2:9][NH:8][C:6](=[O:7])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30])([OH:14])=[O:13]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)OC(=O)NCC(CC(=O)O)S(=O)(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: O=C(O)/C=C\C(=O)NCC(CC(=O)O)S(=O)(=O)O
Reaction time: 8 h
Yield: 82.8 %

Procedure:
4-(Tert-butoxycarbonylamino)-3-sulfobutanoic acid (321 mg, 1.13 mmol) was stirred in the mixture of HCl (conc)/Dioxane (1:4, 15 ml) for 30 min, evaporated and coevaporated with EtOH/Toluene (1:1, 4×20 ml) to dryness. To the dryness material was added maleic anhydride (121 mg, 1.23 mmol) and DMA (20 ml) and the mixture was stirred overnight, evaporated and run through C-18 column eluted with water and crystallized with EtOH/Hexane to afford 263 mg (83%) of the title compound. ESI MS 279.8 (M−H). The NMR data are the same through the route with 4-azido-3-sulfobutanoic acid.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([C:32]3([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]3)[CH:29]=[CH:30][CH:31]=2)O1.C(=O)([O-])[O-].[K+].[K+].CO[CH2:52][CH2:53]OC>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>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:32]4[N:35]=[C:36]([C:26]5[CH:27]=[C:28]([C:32]6([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH2:33][CH2:34]6)[CH:29]=[CH:30][CH:31]=5)[C:52]([CH3:53])=[CH:27][CH:28]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: NC(=O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: COCCOC
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
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+]
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C2(NC(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl cyclopropanecarboxamide (110 mg, 0.300 mmol) was dissolved in 3 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. tert-Butyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropylcarbamate (50% pure, 280 mg, 0.390 mmol), 0.4 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 17 mg, 0.015 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The organic layer was evaporated to dryness and the residue was purified on silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield tert-butyl 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropylcarbamate. This material was then dissolved in 3 mL of dichloromethane containing 1 mL of trifluoroacetic acid (TFA) and was allowed to stir for 15 min at room temperature. The mixture was evaporated to dryness, dissolved in a minimum of N,N-dimethylformamide, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield N-(6-(3-(1-aminocyclopropyl)phenyl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 463.2, found; 464.0 (M+1)+Retention time 1.39 minutes.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:17]=[CH:16][C:10]([CH2:11][O:12][CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][CH2:13][CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][CH:17]=1
Reactant: OCCOCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCOCc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of methanesulfonyl chloride (980 μL, 12.6 mmol) in dry DCM (10 mL) was slowly added to a cooled (0° C.) solution of 2-(4-chloro-benzyloxy)-ethanol (2.14 g, 11.46 mmol) and diisopropyethylamine (2.0 mL, 23 mmol) in dry DCM (10 mL). The reaction mixture was allowed to warm to RT overnight. Water was added and the organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography over silica using a gradient of 0-20% diethyl ether/cyclohexane to afford the pure product.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@H:7]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([CH2:15][CH2:16][O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH2:10]1)(=[O:5])[CH3:4].[OH-:38].[Na+].OO>C(O)C.O.C1COCC1>[C:3]([O:6][C@H:7]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][O:17][CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]([OH:38])[CH2:10]1)(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@@H](CN1CC=C(CCOC(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Reactant: [OH-]
Agent: OO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](CN1CCC(CCOC(c2ccccc2)c2ccccc2)C(O)C1)c1ccc(F)cc1

Procedure:
With reference to FIG. 8, general procedure II was used. The quantities of the chemicals in order of addition are as follows: NaBH4 (0.029 g, 0.762 mmol), THF (10 ml), BF3-ether complex (0.1 ml, 0.81 mmol), (R)-2-(4-(2-(benzhydryloxy)ethyl)-5,6-dihydropyridin-1(2H)-yl)-1-(4-fluorophenyl)ethyl acetate 7c (0.180 g, 0.38 mmol), water (0.3 ml), ethanol (0.4 ml), 3N NaOH (0.3 ml) and 30% H2O2 (0.2 ml, 1.9 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5](O)=[O:6].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([Cl:13])=[O:6]
Reactant: COC(F)(F)C(F)(F)C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: COC(F)(F)C(F)(F)C(=O)Cl
Yield: 95.1 %

Procedure:
A mixture of 47.4 g 3-methoxytetrafluoropropionic acid and 67.3 g phosphorous pentachloride was heated and the contents distilled to obtain a pale yellow liquid boiling to 102°. Redistillation of this liquid yielded 49.8 g (95.2%) 3-methoxytetrafluoropropionyl chloride, b.p. 84°-86°.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[S:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14].O.[OH-].[Li+]>C1COCC1.CO.O>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([S:11][C:12](=[O:16])[N:13]([CH3:14])[CH3:15])=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(Br)ccc1SC(=O)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Sc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2-dimethylcarbamoylsulfanyl-benzoic acid methyl ester (10.0 g, 31.42 mmol) and lithium hydroxide hydrate (1.98 g, 47.14 mmol) in (1/1/1) THF/MeOH/H2O (70 mL total volume) was stirred at room temperature for 4 h. The reaction mixture was concentrated to remove most organic solvents. The residue was diluted with water (500 mL) and extracted with EtOAc (100 mL), which is discarded. The aqueous layer was acidified to pH 3-4 using 1 N HCl and extracted with EtOAc (2×400 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to provide crude 5-bromo-2-dimethylcarbamoylsulfanyl-benzoic acid which was used directly and without further purification.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[H-].[Na+].[Cl:15][C:16]1[C:21]2[C:22](=[O:40])[N:23]3[CH2:39][CH2:38][CH2:37][C@H:24]3[C:25]3[N:26]([CH:27]=[N:28][C:29]=3[C:30](N3C=CN=C3)=[O:31])[C:20]=2[CH:19]=[CH:18][CH:17]=1>O>[Cl:15][C:16]1[C:21]2[C:22](=[O:40])[N:23]3[CH2:39][CH2:38][CH2:37][C@H:24]3[C:25]3[N:26]([CH:27]=[N:28][C:29]=3[C:30]([O:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:31])[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 601 mg (6 mmol) of cyclohexanol, 10 ml of dimethylformamide and 288 mg (6 mmol) of sodium hydride (55 percent oil dispersion) is stirred at room temperature for 0.5 hour, the solution obtained is treated with 2.20 g (6 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole, the mixture is stirred at room temperature for a further 0.5 hour and then poured into about 70 ml of water. The precipitated material is filtered off under suction, washed with water and dried. By recrystallization from ethyl acetate there is obtained cyclohexyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 166°-167°.