Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([C:10](=[O:12])[CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].C(=O)([O-])O.[Na+].[Br:28][CH:29]([CH3:33])[C:30](Br)=[O:31]>C1(C)C=CC=CC=1.O>[C:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[C:2]([NH:1][C:30](=[O:31])[CH:29]([Br:28])[CH3:33])[S:13][C:5]=2[CH2:6]1)(=[O:12])[CH3:11]
Reactant: CC(Br)C(=O)Br
Reactant: CC(=O)N1CCc2c(sc(N)c2C(=O)c2ccccc2Cl)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2c(sc(NC(=O)C(C)Br)c2C(=O)c2ccccc2Cl)C1
Temperature: 60 °C

Procedure:
13.3 g of toluene and 3.66 liters of water were added to 600 g of 2-amino-3-(2-chlorobenzoyl)-6-acetyl-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine, to which 301 g of sodium hydrogencarbonate was further added. While heating to 60° C., 301 ml of 2-bromopropionyl bromide was dropped into the solution. Further, 170 g of sodium hydrogencarbonate and 170 ml of 2-bromopropionyl bromide were added in order to complete the reaction. After cooling down to room temperature, 500 g of sodium hydrogencarbonate was added, after which the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate, followed by combination with the organic phase, washing with water and drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant solid matter was washed with ether to obtain 800 g of the intended product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20]O)[CH:16]=[CH:17][CH:18]=1.[Br:22]Br>C(Cl)Cl>[Br:22][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:14]=1
Reactant: BrBr
Reactant: OCCc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: ClCCl
Product: BrCCc1cccc(OCc2ccc3ccccc3n2)c1
Reaction time: 16 h
Yield: 189.2 %

Procedure:
8.6 g of 2-[3-(quinol-2-ylmethoxy)phenyl]ethanol are dissolved in 200 ml of methylene chloride. There are added 9.8 g of tdphenylphosphine and then, at 10° C., 1.9 g of bromine dissolved in 50 ml of methylene chloride. Stirring is carded out at room temperature for 16 hours. The mixture is concentrated to dryness and the residue is taken up in ether. The mixture is washed with a 10% sodium carbonate solution and dried over sodium sulphate. Concentration to dryness is carded out. The residue is chromatographed on 450 g of silica using methylene chloride as eluant. There are obtained 7.7 g of 1-bromo-2-[3-(quinol-2-yl-methoxy) phenyl]ethane. Yield: 72%.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]([C:12]([O:14]C)=[O:13])=[CH:11][C:6]2=[N:5][C:4]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:3]1=2.O[Li].O.Cl>CO>[O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:6]2=[N:5][C:4]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:3]1=2
Reactant: COC(=O)c1ccn2c(=O)c3c(nc2c1)CCCCCC3
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1ccn2c(=O)c3c(nc2c1)CCCCCC3

Procedure:
A solution of methyl 12-oxo-7,8,9,10,11,12-hexahydro-6H-cycloocta[d]pyrido[1,2-a]-pyrimidine-3-carboxylate (80 mg, 0.28 mmol) and LiOH H2O in MeOH (5 mL) was stirred at room temperature for 0.5 h. The reaction mixture was adjusted to pH around 6 with 1 N HCl and extracted with ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was used for the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[CH2:5][CH2:6][O:7][S:25]([CH3:24])(=[O:27])=[O:26])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(CCO)CCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(CCOS(C)(=O)=O)CCOS(C)(=O)=O)cc1
Temperature: -7.5 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
25 gms (0.1111 moles) of the product obtained from Example 1 and 45 gms (0.4455 moles) of triethylamine with 125 ml of dichloromethane were charged in a reaction vessel and cooled to −5 to −10° C. A solution of Methane sulphonyl chloride (45 gms, 0.3888 moles) in dichloromethane (50 ml) was added slowly at −5 to 10° C. and stirred for about 16 hours at 25-30° C. The resulting mixture was washed with water (25 ml). The collected organic layer was concentrated to obtain the title compound (36 gms).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Si](C(C)C)(C(C)C)[N:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH:23]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:24]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
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: O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Yield: 57.2 %

Procedure:
A mixture of 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (12.9 g, 45.4 mmol) (prepared as in WO 2007/070514, Ex.65) and [1-(triisopropylsilyl)-1H-pyrrol-3-yl]boronic acid (Frontier Scientific) (10.4 g, 38.9 mmol) and sodium carbonate (4.36 g, 41.2 mmol) in 1,2-dimethoxyethane (100 mL) and water (35 mL) was degassed by purging with a stream of nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.25 g, 1.94 mmol) was then added and the reaction was heated to reflux for 9 hours. As the coupling reaction proceeded, the TIPS protecting group was also slowly removed. The solvent was removed by rotary evaporation and the product was purified by flash column chromatography, eluting with a gradient from 10-50% ethyl acetate in hexanes to afford the desired product (7 g, 57%).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:24])[NH:6][C:7]1[CH:13]=[CH:12][C:11]([S:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])=[CH:10][C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([N:29]=[C:30]=[S:31])=[O:28]>O1CCOCC1>[C:1]([NH:4][C:5](=[O:24])[NH:6][C:7]1[CH:13]=[CH:12][C:11]([S:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])=[CH:10][C:8]=1[NH:9][C:30]([NH:29][C:27]([O:26][CH3:25])=[O:28])=[S:31])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N
Reactant: COC(=O)N=C=S
Solvent: C1COCCO1
Product: COC(=O)NC(=S)Nc1cc(S(=O)(=O)Oc2ccccc2)ccc1NC(=O)NC(C)=O
Temperature: 25 °C

Procedure:
17.5 g of 2-(3-acetylureido)-5-phenoxysulfonylaniline and 15 ml of methoxycarbonyl isothiocyanate in 150 ml of dioxane are heated at 80° C. for 5 minutes, and then stirring is continued without heating. After slowly cooling down to room temperature, the dioxane is distilled out under reduced pressure. The residue is dissolved in dimethylformamide, the solution is treated with active charcoal and evaporated and then methanol is added. After cooling down, the precipitate is filtered off with suction and washed with methanol and diisopropyl ether. Melting point 215° C., decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:26][C:25]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:24]=1[F:23]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2Cl)n1Cc1ccc(F)cc1F
Temperature: 80 °C
Yield: 65.7 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 21; 200 mg, 0.62 mmol), tetrabutylammonium iodide (229 mg, 0.62 mmol) and 2,4-difluorobenzyl bromide (320 μL, 2.5 mmol) in dimethylformamide (4 mL) was heated at 80° C. overnight. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated and purified by chromatography, eluting with 60-70% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-1-(2,4-difluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (182 mg, 68%) as an off-white solid. APCI(+)-MS (M+H) 447.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1.[CH2:15]([C@@H:17]1[O:19][CH2:18]1)[Cl:16]>>[Cl:16][CH2:15][C@@H:17]([OH:19])[CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1
Reactant: ClC[C@H]1CO1
Reactant: CCC(CC)COc1cccc(Br)c1
Product: CCC(CC)COc1cccc(C[C@H](O)CCl)c1

Procedure:
Metallation of 1-bromo-3-(2-ethylbutoxy)benzene followed by addition to (R)-(−)-epichlorohydrin gave (S)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol. Yield (1.57 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 7.14 (t, J=7.8 Hz, 1H), 6.78-6.73 (m, 3H), 5.13 (d, J=5.2 Hz, 1H), 3.88-3.83 (m, 1H), 3.80 (d, J=6.0 Hz, 2H), 3.52 (dd, J=10.8, 4.6 Hz, 1H), 3.43 (dd, J=11.0, 5.8 Hz, 1H), 2.74 (dd, J=13.8, 5.0 Hz, 1H), 2.62 (dd, J=13.6, 7.6 Hz, 1H), 1.61-1.55 (m, 1H), 1.47-1.31 (m, 4H), 0.86 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[CH:9].[C:16](=[O:18])=[O:17]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:16]([OH:18])=[O:17]
Reactant: C#Cc1ccc(-c2ccccc2)cc1Br
Reactant: O=C=O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br

Procedure:
Prepared analogously to Example 4.3.a. from 3-bromo-4-ethynylbiphenyl and carbon dioxide. Yield: 2.5 g (89% of theory); C15H9BrO2 (M=301.13); calc.: molecular ion peak (M+H)+: 301/303 (Br); found: molecular ion peak (M+H)+: 301/303 (Br); Rf value: 0.3 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:39])([F:38])[CH2:36][OH:37])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:32])[NH:33][CH2:34][C:35]([F:38])([F:39])[CH2:36][O:37][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NCC(F)(F)CO)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCC(F)(F)CNC(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reaction time: 0.03 h
Yield: 42.7 %

Procedure:
(S)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(2,2-difluoro-3-hydroxypropyl)urea (12 mg, 0.027 mmol), prepared as described in Procedures 3, 5, 6, 7 and 8, in THF (0.5 mL) was added NaH (4 mg, 60% in mineral oil, 0.1 mmol). After 2 min, tert-butyl 2-bromoacetate (6 mg, 0.04 mmol) was added. The reaction mixture was stirred for 15 min, filtered and concentrated in vacuo. The residue was purified by preparative HPLC Shimadzu-Phenomenex Luna C18 column, 21.2×100 mm eluting with 10-90% CH3CN (90% in H2O, 0.1% TFA) gradient over 15 min with flow rate 20 mL/min and UV detection at 220 nm to give (S)-tert-butyl 2-(3-(3-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)-2,2-difluoropropoxy)acetate as a white solid (8 mg, 43% yield). LCMS RT=4.12 min, [M+H] 694.35 (LCMS Method 1) NMR: 500 MHz 1H (CDCl3) 8.25 ppm, 1H, m; 7.67 ppm, 1H, m; 7.50 ppm, 1H, m; 7.17 ppm, 1H, d; 7.06 ppm, 6H, m; 6.89 ppm, 1H, m; 6.61 ppm, 2H, m; 5.87 ppm, 1H, t; 4.35 ppm, 1H, d; 4.07 ppm, 1H, d; 3.95 ppm, 1H, d; 3.88 ppm, 1H, m; 3.74 ppm, 2H, m; 3.55 ppm, 2H, m; 1.42 ppm, 9H, m.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]([CH2:31][CH2:32][OH:33])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]([CH2:31][CH:32]=[O:33])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[CH2:34][C:35]([CH3:36])([CH3:38])[CH3:37]
Reactant: CCOC(=O)CC(CCO)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)CC(CC=O)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
To a solution of ethyl 3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)-5-hydroxypentanoate (330 mg) and triethylamine (0.89 mL) in DMSO (5 mL) was added sulfur trioxide pyridine complex (410 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added, at room temperature, 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product (350 mg) of the title compound as a pale-orange oil. This compound was used for the next step without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:32][C:33]1[N:34]=[CH:35][C:36]2[N:41]=[C:40]([C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH3:50])[CH:43]=3)[O:39][C:37]=2[N:38]=1.O[CH:52]1[CH2:55][CH:54]([C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])[CH2:53]1>O1CCCC1.C(N(CC)CC)C>[Cl:32][C:33]1[N:34]=[CH:35][C:36]2[N:41]=[C:40]([C:42]3[CH:43]=[C:44]([CH3:50])[C:45]([O:49][CH:52]4[CH2:55][CH:54]([C:56]([O:58][CH2:59][C:60]5[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=5)=[O:57])[CH2:53]4)=[C:46]([CH3:48])[CH:47]=3)[O:39][C:37]=2[N:38]=1
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1O
Reactant: O=C(OCc1ccccc1)C1CC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
At 0° C., 1.14 g of triphenylphosphine and 0.69 ml of diethyl azodicarboxylate were initially charged in 30 ml of tetrahydrofuran, and the mixture was stirred for 15 min. 1.00 g of 4-(5-chlorooxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenol, 0.61 ml of triethylamine and 0.90 g of benzyl 3-hydroxycyclobutanecarboxylate were then added, and the reaction was stirred under argon, initially at room temperature for 6 h. Another 1.14 g of triphenylphosphine and 0.69 ml of diethyl azodicarboxylate were then added, and the reaction was stirred for 12 h. After another addition of 1.14 g of triphenylphosphine and 0.69 ml of diethyl azodicarboxylate and 2 further hours of reaction time at room temperature, the reaction was concentrated and the resulting residue was purified by flash chromatography (silica gel, heptane/ethyl acetate). This gave 1.45 g (86%) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:12]([Cl:16])(=O)(=[O:14])[OH:13]>>[N:7]1([C:1]2[CH:6]=[C:5]([S:12]([Cl:16])(=[O:14])=[O:13])[CH:4]=[CH:3][CH:2]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: c1ccc(N2CCCC2)cc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cccc(N2CCCC2)c1
Temperature: 60 °C
Yield: 7 %

Procedure:
1-phenylpyrrolidine (4.3 g, 29.25 mmol) was added dropwise to sulfurochloridic acid (20 mL) at 0° C. and the resulting solution was then maintained at 60° C. overnight. The reaction mixture was then quenched by adding 200 mL of ice/salt. The resulting solution was extracted with ethyl acetate (3×100 mL), and the organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography using a 1:500 ethyl acetate/petroleum ether solvent system. The collected fractions were combined and concentrated to give 0.5 g (7%) of 3-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.36 (m, 1H), 7.24 (d, 1H), 7.07 (s, 1H), 6.82 (d, 1H), 3.34 (t, 4H), 2.05 (t, 4H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29]C(=O)OC(C)(C)C)=[CH:28][C:22]=2[S:21](=[O:38])(=[O:37])[N:20]=1.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[N:20][S:21](=[O:38])(=[O:37])[C:22]=2[CH:28]=1
Reactant: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 99 %

Procedure:
A solution of Example 40G (3.24, 6.00 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (2.86 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.42 (m, 1H) 0.74 (m, 7H) 1.32 (m, 1H) 1.58 (m, 3H) 2.15 (m, 2H) 7.07 (m, 2H) 7.51 (m, 2H) 7.77 (m, 2H) 8.16 (m, 1H) 13.57 (m, 1H). MS (ESI−) m/z 438 (M−H)−.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:33])[NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:36][CH2:37][CH2:38][OH:39]>CCCCCC.C(OCC)(=O)C>[OH:39][CH2:38][CH2:37][NH:36][C:5]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:33]
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)NCCO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 59%. Melting point: 152-155° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1([F:29])[CH2:24][CH:23]1[C:25]([NH:27][NH2:28])=[O:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:28][NH:27][C:25]([CH:23]1[CH2:24][C:22]1([F:29])[F:21])=[O:26])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)C1CC1(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2,2-difluorocyclopropanecarbohydrazide 267 (0.184 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 268 (0.36 g, quant. yield) as a white foam.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]([CH2:31][CH2:32][C:33](=O)[C:34]([O:36][CH3:37])=[O:35])([NH:24]S(C(C)(C)C)=O)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:48][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]3([NH:24][CH:33]([C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)C(=O)CC[C@@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CC[C@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Methyl 4-[(2R,4R)-1-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-4-{[(1,1-dimethylethyl)sulfinyl]amino}-2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-2-oxobutanoate (Intermediate 6, 62 mg, 0.086 mmol) in DCM (1 mL) was added TFA (4 mL, 51.9 mmol) and the reaction mixture was stirred at 25° C. for 6 hrs. Triethylsilane (1 mL, 6.26 mmol, Aldrich) was added to the reaction mixture and it was stirred for 1 hr. The reaction mixture was left still overnight and the day after it was poured very carefully in a NaHCO3 saturated solution to be neutralised and DCM was added. The two phases were separated, the aqueous layer was extracted with DCM (3×) and the combined organic phases were dried and evaporated to dryness. The crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc) to give the two diastereoisomers:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])N1CCOCC1
Temperature: 80 °C
Yield: 81.2 %

Procedure:
To a slurry of 215.1 g of 2.4-dinitrobenzoic acid in 1000 ml of toluene was added with stirring 196.2 g of morpholine. Next 76.5 g of phosphorus oxychloride was added dropwise at such a rate to maintain the reaction temperature below 90° C. The mixture was refluxed for 5 hrs, cooled to 80° C., and slowly poured into 1000 ml of aqueous 5% NaHCO3 solution with stirring. The precipitate was filtered, washed with water and dried to yield 231.7 g of N-(2,4-dinitrobenzoyl)morpholine, mp 159°-161° C.