Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Br:23])[C:21]=1[OH:22])[CH:17]=O.C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[CH:17][C:16]3[CH:15]=[C:14]([Br:13])[C:21]([OH:22])=[C:20]([Br:23])[CH:19]=3)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc2c(c1)NC(=O)C2=Cc1cc(Br)c(O)c(Br)c1
Reaction time: 1.5 h
Yield: 65.7 %

Procedure:
6-cyano-1,3-dihydro-indol-2-one (46.3 mg, 0.29 mmol) and 3,5-dibromo-4-hydroxybenzaldehyde (80 mg, 0.39 mmol) and p-toluenesulfonic acid monohydrate (1 mg, 0.005 mmol) were treated with toluene (30 mL) and the reaction refluxed with stirring with a Dean-Stark water trap attached for 1.5 h. During this time an orange solid deposited, which, on cooling, was filtered off, washed with toluene and dried in vacuo at 125° C. for 3 days to give 80 mg of 6-cyano-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one; 1H-NMR (DMSO-d6): δ11.05 (bs, 1H), 8.86 (s, 2H), 7.97 (s, 1H), 7.85 (d, J=7.9 Hz, 1 H), 7.50 (d, J=7.9 Hz, 1 H), 7.20 (s, 1H). Mass spectrum (negative ion electrospray): m/z=417 (M−1, 48%), 419 (M−1, 100%), 421 (M−1, 48%).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:4]=1[NH:5][C:6]2=O.P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[C:18]3[C:13]([C:12](=[O:19])[C:4]=2[N:5]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2-c2c1[nH]c(=O)c1ccccc21
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-c2c1nc(Cl)c1ccccc21
Yield: 78.7 %

Procedure:
A mixture of 6H-indeno[2,1-c]isoquinoline-5,7-dion obtained in reference example 16 (26.6 g, 108 mmol) and phosphorous oxychloride (300 ml) was refluxed with heat in the presence of 1 ml of N,N-dimethylformamide for 2 hours. The reaction mixture was distilled to dryness. To the residue was added ice water to obtain a crystal precipitated by filtration. The crystal obtained was washed with water and recrystallized from toluene to give 22.5 g (yield 78.7%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCC(NCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C1CCC(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 4-benzylamino-cyclohexanecarboxylic acid tert-butyl ester (630 mg, 2.180 mmol) in DMF (20 mL) is added t-butyl bromoacetate (1 mL, 6.856 mmol) and Cs2CO3 (1.0 g, 3.069 mmol). The mixture stirs for 2 h. Then H2O (50 mL) is added the mixture is extracted with EtOAc (2×100 mL), dried with sodium sulfate and concentrated. The resulting solid is purified by flash chromatography (gradient elution: 0-20% EtOAc/Hep) which affords 300 mg of 4-(benzyl-tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.24 (m, 5 H), 1.38 (m, 18 H), 1.86 (m, 4 H), 2.09 (m, 1 H), 3.14 (m, 2 H), 3.71 (m, 2 H), 7.29 (m, 5 H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1>CCCCCC>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[O:5][CH2:1][CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCCO
Solvent: CCCCCC
Product: C#CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 3-butyn-1-ol (3.0 g, 0.042 mol) and 3,4-dihydropyran (4.20 g, 0.05 mol) in hexane (10 ml) (Bongini et. al., Synthesis, 618, 1979), is added to a suspension of Dowex (1.5 g) in hexane (10 ml) and the mixture is stirred for 1 hr at room temperature. The resin is filtered off and the solvent removed in vacuo. The crude residue is purified by flash chromatography using hexane/ethyl acetate (9:1, v/v) to give 3-butyn-1-yl tetrahydropyranyl ether (6.47 g, 97%) as a colorless liquid: Rf=0.25; Hexane/ethyl acetate (1:1, v/v) IR (film) ν3300 (C≡C--H), 2160 (C≡C); and 1H NMR (CDCl3) δ1.48 (m, 6H), 1.88 (t, J=3 Hz, 1H), 2.35 (m, 2H), 3.60 (m, 4H), 4.56 (br S, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([CH3:25])=[CH:20][CH:19]=2.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH3:25])[CH:22]=3)[NH:17][C:16]=2[CH3:15])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc2[nH]c(C)c(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)c2c1

Procedure:
is obtained as described in Example 10 (a) from 10 g 4-chloro-3-sulfamoylbenzoyl chloride and 7.8 g 2,5-dimethylindole in dichloro-ethane in the presence of 12 g aluminum chloride. M.p. 248°-250° C.
Reaction SMILES: [C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C@H:11](OS(C(F)(F)F)(=O)=O)[C@H:10]([N:21]2[C:25]3[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=3[S:23][C:22]2=[O:32])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].[CH3:33][S-:34].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C@@H:11]([S:34][CH3:33])[C@H:10]([N:21]2[C:25]3[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=3[S:23][C:22]2=[O:32])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: C[S-]
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](OS(=O)(=O)C(F)(F)F)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(OC(C)=O)[C@@H]1C[C@@H](SC)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-[(2S,4S,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]propyl acetate (compound 22d, 420 mg, 0.83 mmol) in DMF (7 mL) was added sodium thiomethoxide (84 mg, 1.2 mmol). After being stirred at room temperature for 2 hours, the resulting solution was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford crude product of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-methylsulfanyl-tetrahydrofuran-2-yl]propyl acetate (compound 22e), which was used in next step without further purification. MS obsd. (ESI−) [(M−H)−]: 399.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:4]1(=[O:6])=[O:5].[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([O-:22])=[CH:20][CH:19]=1)([O-:17])=[O:16].[Na+]>C1COCC1>[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([O:22][CH2:2][N:3]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:4]2(=[O:6])=[O:5])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCl
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2S(=O)(=O)N1COc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 21.3 %

Procedure:
A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) and sodium p-nitrophenoxide (2.55 g, 12.9 mmol) in THF (50 ml) was heated overnight at 50° C. and then refluxed for 45 minutes. The reaction mixture was cooled, poured into a dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with sodium bicarbonate solution and water, dried (Na2SO4), and taken to dryness in vacuo. Chromatography (silica gel; MDC) afforded an oil that was crystallized from hot cyclohexane/ether. The resultant solid was recrystallized from ethanol to afford 0.92 g of 2-(4-nitrophenoxymethyl)-saccharin as white shiny platelets, mp 162°-164° C. 1H nmr (90 MHz, CDCl3, DMSO-d6):5.95 (2H, s). FDMS m/e 334 (M+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=1[Br:25])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CCO.CCOC(C)=O.[Pt]>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Br:25])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of (S)-2-(2-Bromo-6-methyl-4-nitrophenyl)-2-tert-butoxyethyl pivalate (9 g, 0.022 mol) in EtOH (50 mL) and EtOAc (50 mL) was added Pt/C (1.4 g), and the reaction was fitted with a balloon of H2. The reaction mixture was stirred at room temperature for 3 h. TLC showed the reaction was complete. The reaction mixture was filtered over Celite. The filtrate was concentrated in vacuo to give (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (7 g, 82%) as brown oil, which was immediately used for next step without further purification. 1H-NMR: 400 MHz, (CDCl3) δ: 6.70 (s, 1H), 6.40 (s, 1H), 5.38 (app. s, broad, 1H), 4.22 (app. s, broad, 1H), 4.05 (app. s, broad, 1H), 3.60 (app. s, broad, 2H), 2.47 (s, 3H), 1.17 (s, 9H), 1.13 (s, 9H).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:36]=[CH:35][C:24]([O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=2)=[CH:23][CH:22]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:2]1([C:8]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][N:10]([CH2:19][C:21]3[CH:36]=[CH:35][C:24]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)(c4ccccc4)C3)cc2)nc1
Yield: 105.8 %

Procedure:
Using a method similar to Example 345, using 3,3-diphenyl-pyrrolidine hydrochloride salt (0.107 g, 0.412 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.415 mmol), sodium triacetoxyborohydride (0.133 g, 0.628 mmol), and acetic acid (0.035 mL 0.611 mmol) in 1,2-dichloroethane (8.0 mL) provides 0.196 g (106%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C29H28N3O2 450.2182, found 450.2205; 1H NMR (methanol-d4): 8.68 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.4, 8.8 Hz), 7.46 (d, 2H, J=7.3 Hz), 7.35-7.26 (m, 8H), 7.21-7.12 (m, 4H), 7.04 (d, 1H, J=8.8 Hz), 3.75 (s, 2H), 3.38-3.24 (m, 2H), 2.98-2.91 (m, 2H), 2.71-2.64 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[C:27]3=[CH:28][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[O:38][C:15]([NH:16][C@@H:17]([CH:35]([CH3:37])[CH3:36])[C:18](=[O:34])[N:19]5[CH2:29][C@H:22]([O:23][C:24]3=[N:25][CH:26]=1)[CH2:21][C@H:20]5[C:30]([O:32]C)=[O:31])=[N:14][N:13]=4)=[CH:6][CH:5]=2)[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([C:3]1[C:4]2[C:27]3=[CH:28][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[O:38][C:15]([NH:16][C@@H:17]([CH:35]([CH3:37])[CH3:36])[C:18](=[O:34])[N:19]5[CH2:29][C@H:22]([O:23][C:24]3=[N:25][CH:26]=1)[CH2:21][C@H:20]5[C:30]([OH:32])=[O:31])=[N:14][N:13]=4)=[CH:6][CH:5]=2)[CH3:2]
Reactant: CCc1cnc2c3cc(ccc13)CCCCc1nnc(o1)N[C@@H](C(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)OC)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cnc2c3cc(ccc13)CCCCc1nnc(o1)N[C@@H](C(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)O)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (3R,5S,8S)-22-ethyl-8-isopropyl-7-oxo-2,27-dioxa-6,9,11,12,24-pentaazapentacyclo[16.6.2.13,6.110,13.021,25]octacosa-1(24),10,12,18,20,22,25-heptaene-5-carboxylate (from Step 2) in THF/H2O (1/1 v/v) was added LiOH (4 eq). The resulting reaction mixture was stirred at RT for 2 h and then treated with 1N aq. HCl until pH=2 was reached. The aqueous phase was extracted with EtOAc, the organic layer was separated, dried over Na2SO4, filtered and concentrated to give a white solid. MS (ES+) C27H33N5O5 requires: 507. Found: 508 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1)=[O:12]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1ccccc1CC(=O)O
Solvent: O=S(Cl)Cl
Product: COc1ccccc1CC(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 59.4 %

Procedure:
2-Methoxyphenylacetic acid (75 mg, 0.45 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (95 mg, 0.3 mmol) obtained in Example 1, (3), the title compound (83 mg, yield 60%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).
Reaction SMILES: Cl.[C:2]([C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:15]=3[O:16][C@@H:17]3[CH2:21][NH:20][C@H:19]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:18]3)[C:7]=2[C:6]=1[CH3:33])(=[O:4])[NH2:3].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[C:2]([C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:15]=3[O:16][C@@H:17]3[CH2:21][N:20]([S:35]([CH3:34])(=[O:37])=[O:36])[C@H:19]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:18]3)[C:7]=2[C:6]=1[CH3:33])(=[O:4])[NH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CN1
Agent: Cl
Product: CC(=O)OC[C@@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CN1S(C)(=O)=O

Procedure:
Prepared analogously to example 10.2 from acetic acid (2S,4S)-4-[2-(6-carbamoyl-5-methyl-thieno[2,3-d]pyrimidin-4-ylamino)-5-fluoro-phenoxy]-pyrrolidin-2-ylmethyl ester hydrochloride and methanesulfonyl chloride. Methansulfonyl chloride was added at 0° C.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][NH:17][CH3:18])[CH:3]=1.[C:19](=[O:22])([O-])[OH:20].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:18])[C:19](=[O:22])[O:20][C:4]([CH3:16])([CH3:5])[CH3:3])[CH:3]=1
Reactant: CNCc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 73 %

Procedure:
To a solution of 1-[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (4.4 g) in ethyl acetate (60 mL) was added di-tert-butyl bicarbonate (2.8 mL), and the mixture was stirred at room temperature for 14 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless oil (yield 3.4 g, 73%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:25][CH2:26][N:27]([C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[O:8])[CH2:28][CH2:29]2)[N:19]=1
Reactant: O=C(O)c1ccsc1
Reactant: COc1ccnc(N2CCNCC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccnc(N2CCN(C(=O)c3ccsc3)CC2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
To a solution of 1.0 g (7.81 mmol) of 3-thienylcarboxylic acid and 1 mL (7.86 mmol) of triethylamine in 30 mL of CH2Cl2 cooled to 0° C. 0.84 g (7.81 mmol) of ethyl chloroformiate are added. The mixture is maintained at 0° C. for 20 minutes and then 1.5 g (7.81 mmol) of 4-methoxy-2-(1-piperazinyl) pyrimidine dissolved in 10 mL of CH2Cl2 are added to the solution. The temperature is allowed to rise to room temperature and the solution continually stirred for 2 hours and the organic phase is washed with H2O, dried over NaSO4 and the solvent evaporated off under reduced pressure. The resulting oil is treated with ethyl ether to yield a solid which is recrystallised from ethanol/H2O to give 0.8 g (2.63 mmol) of 4-methoxy-2-[4-(3-thienylcarbonyl)-1-piperazinyl]pyrimidine. m.p.=90-92° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:24]=1C(OC)=O>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([C:30]2[CH:29]=[CH:24][C:23]([Cl:22])=[CH:32][C:31]=2[Cl:33])=[O:21])=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
A 5 L round bottom flask equipped with an addition funnel, N2 inlet, thermometer and a mechanical stirrer was charged with 387 mL of 1M sodium bis-trimethylsilylamide in TBF and cooled to −60° C. A solution of 230 g (1.35 mol) of 4-chlorophenylacetic acid in 300 mL of THF was added keeping the temperature below −40° C. After stirring the mixture for 90 min at −70° C., 264 g (1.29 mol) of methyl 2,4-dichlorobenzoate was added over 20 min. The solution was stirred for 40 min at −70° C., the cooling bath was removed and the mixture was allowed to warm to 0° C. Reaction was quenched by pouring into 4 L of 2N HCl and ice and extracted with ether. Each ether layer was washed with saturated NaHCO3, brine, dried with MgSO4 and filtered through a 2″ plug of silica gel. The filtrate was concentrated to ca. 1 lit of a slushy liquid which was diluted with 1 L of hexane and cooled in a refrigerator. The solid formed was filtered, washed with hexane and dried. A second crop was isolated by concentrating the mother liquors. The two crops of crystals were combined.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[N+:12]([C:7]1[CH:6]=[CH:5][N+:4]([O-:9])=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=1)([O-:14])=[O:13]
Reactant: [O-][n+]1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])c(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a stirred solution of 2-trifluoromethyl-pyridine 1-oxide (0.43 g, 2.43 mmol) in concentrated H2SO4 (2 mL) is added 70% HNO3 (1.6 mL) dropwise at 0° C. Reaction mixture is allowed to stir for 2 h at 130° C. After completion of reaction it is quenched with ice (˜200 g) and pH is adjusted 7 with solid K2CO3 (15-20 g) and extracted with EtOAc (3×20 mL). Organic part is washed with water, brine and dried over anhydrous MgSO4. Solution is concentrated under reduced pressure. The residue is purified by column chromatography (silica-gel, 100-200 mesh, eluent; 20% EtOAc in hexane) to afford 4-nitro-2-trifluoromethyl-pyridine 1-oxide (0.1 g, 20%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:48])/[C:13](=[N:27]\[O:28][C:29]3([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:33])[CH2:31][CH2:30]3)/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:49])[N:8]2[S:50]([OH:53])(=[O:52])=[O:51])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:48])/[C:13](=[N:27]\[O:28][C:29]3([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]3)/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:49])[N:8]2[S:50]([OH:53])(=[O:51])=[O:52])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Yield: 46.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (164 mg, 0.214 mmol), DCM (2.14 mL) and TFA (989 μl, 12.8 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (50 mg, 41%) as a white powder. LCMS: Rt=0.29 min, m/z=501.1 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.31 (d, J=9.0 Hz, 1H), 8.59 (s, 1H), 8.09 (s, 1H), 6.83 (s, 1H), 5.26 (dd, J=9.0, 5.5 Hz, 1H), 4.67 (dd, J=14.5, 4.3 Hz, 1H), 4.49-4.39 (m, 1H), 4.33 (ddd, J=7.4, 5.5, 4.3 Hz, 1H), 1.34-1.27 (m, 4H).
Reaction SMILES: [OH:1][C@H:2]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]([C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[O:8]1)=O.B.CSC>C1COCC1>[I:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:5][NH:4][CH2:3][C@H:2]([OH:1])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:15]2
Reactant: O=C(NC[C@H](O)COc1ccccc1)[C@H]1CCc2cc(I)ccc2O1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: O[C@@H](CNC[C@H]1CCc2cc(I)ccc2O1)COc1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution containing (2R)-N-[(2S)-2-hydroxy-3-phenoxypropyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide (Example 79, 9.204 mmol, 1 eq.) in THF (140 mL) at room temperature was slowly added borane-methyl sulfide complex (2 M in THF, 46.07 mmol, 5.0 eq.). After completion of addition, reaction solution was heated to reflux, maintained at that temperature for 2 hours, and then cooled to room temperature. The resulting solution was quenched with EtOH (5 mL) dropwise, then with 2 M HCl (20 mL) slowly. The resulting mixture was heated at reflux for 1 hour and was then allowed to cool to room temperature. This solution was basified with 1 N NaOH and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was dissolved in MeOH and EtOAc and filtered. The filtrate was concentrated and dried in vacuo to afford the product as a white solid in 99% yield. MH+=440.2, retention time (LC-MS)=2.24 min.