Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:4]1[CH:5]=[C:6]([CH3:17])[C:7]([CH3:16])=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:15])=O)=[CH:9]2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH2:1]([N:3]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:4]1[CH:5]=[C:6]([CH3:17])[C:7]([CH3:16])=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:35])[NH2:15])=[CH:9]2)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN(c1cc(C)c(C)c2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Product: CCN(c1cc(C)c(C)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 40 °C
Reaction time: 5 h
Yield: 76.7 %

Procedure:
A mixture of 7-[ethyl(2-thienylsulfonyl)amino]-4,5-dimethyl-1H-indole-2-carboxamide (0.20 g), Lawesson's reagent (0.22 g) and tetrahydrofuran (10 mL) was stirred at 40° C. for 5 hr. The reaction solution was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography(ethyl acetate:hexane=1:9-ethyl acetate) to give 7-[ethyl(2-thienylsulfonyl)amino]-4,5-dimethyl-1H-indole-2-carbothioamide (0.16 g, yield 77%) as pale-yellow crystals. A mixed solution of the obtained crystals (0.16 g), bromomalonaldehyde (0.13 g) and N,N-dimethylacetamide (8 mL) was stirred at 80° C. for 3 hr. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:3) to give the title compound (85 mg, yield 47%) as pale-yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[Cl:10].[C:11]([CH2:13][C:14](=[O:16])[CH3:15])#[N:12].[Na].CC(C)([O-])C.[Na+].[I-].[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOCCOC.COCCOC>[C:11]([CH:13]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[Cl:10])[C:14](=[O:16])[CH3:15])#[N:12]
Reactant: COc1ccc(Br)c(Cl)c1
Reactant: CC(=O)CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Product: COc1ccc(C(C#N)C(C)=O)c(Cl)c1
Temperature: 25 °C
Yield: 801.9 %

Procedure:
Under argon gas atmosphere, to a solution of 1-bromo-2-chloro-4-methoxybenzene (120 g) in a mixed diglyme (230 mL) and 1,2-dimethoxyethane (90 mL), sodium cyano acetone (62.6 g), sodium t-butoxide (114.6 g) and sodium iodide (81.2 g) were added with stirring at room temperature to obtain a suspension. By another process, under argon gas atmosphere, a mixture of diglyme (40 mL), palladium acetate (426 mg) and triphenylphosphine (1.99 g) was stirred for about 30 minutes at 110° C. to dissolve. This solution was dropped into the above suspension. The mixture was warmed to 110 to 115° C. of internal temperature and stirred for 7 hours. The reaction mixture was cooled, diluted with ethyl acetate (480 mL) and washed with an aqueous solution of sulfuric acid (concentrated sulfuric acid 101 g/water 660 mL). The organic layer was washed with 10% saturated aqueous solution of sodium chloride (360 mL) twice. Activated charcoal (3.6 g) was added to the organic layer. The mixture was stirred for 1 hour and filtered. The filtrate was washed with ethyl acetate (240 mL) to obtain a solution of 1-cyano-1-(2-chloro-4-methoxyphenyl)propan-2-on (971.7 g).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[N:8][C:7]2[NH:6][CH:5]=[N:4][C:3]1=2.C(O[CH:21]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@:23]([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH:38]([F:40])[F:39])[O:22]1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C([O-])(O)=O.[Na+]>CC#N>[C:27]([O:26][C@@H:25]1[C@H:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@:23]([CH2:41][O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([CH:38]([F:39])[F:40])[O:22][C@H:21]1[N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:1])[NH:10][C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])=[N:8][C:7]1=2)(=[O:29])[CH3:28]
Reactant: CC(=O)OC1O[C@@](COCc2ccccc2)(C(F)F)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Reactant: CC(C)C(=O)Nc1nc2[nH]cnc2c(=O)[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of compound N-(6-oxo-6,9-dihydro-1H-purin-2-yl)isobutyramide (0.57 g, 2.58 mmol) in anhydrous CH3CN (50 mL) was added BSA (1.26 mL, 5.17 mmol) portion-wise while maintaining the reaction temperature at 25° C. Then the reaction was stirred at 40° C. for 1 h until a clear solution persisted. Compound 5 (0.6 g, 1.29 mmol) in CH3CN (5 mL) was added into the mixture at 0° C. followed by TMSOTf (0.94 mL, 5.17 mmol). The mixture was stirred at 40° C. for 2 h and then poured into saturated NaHCO3 solution (10 mL) at 0° C., extracted with ethyl acetate, washed with water, brine solution, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude compound was purified by silica gel chromatography [petroleum ether:ethyl acetate (5:1 to 1:1)] to provide the product 21 as a white foam (0.5 g, 60%). LC-MS: (M+H)+=626
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:23][NH:24][CH3:25].C(O)(=O)C>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:24]([CH3:25])[CH3:23])[S:5][CH:6]=1
Reactant: CNC
Reactant: O=Cc1cc(Br)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)Cc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of 4-bromo-2-thiophene carboxaldehyde (5 g, 26.2 mmol) in 1,2-dichloroethane (50 mL) is added sodium triacetoxyborohydride (8.3 g, 39.3 mmol) and dimethylamine (14.5 mL, 28.8 mmol) followed by acetic acid (1.55 mL, 39.3 mmol). The mixture is stirred at room temperature for 2 hours. The insoluble is filtered and washed with diethyl ether. The mother liquor is concentrated. The resulting thick oil that is chromatographed through silica gel (dichloromethane-1.0M ammonia in methanol, 95:05 to 90:10 as eluant) to afford an orange oil. It is dissolved in dichloromethane and was washed with a saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and concentrated to produce (4-bromo-thiophen-2-ylmethyl)-dimethyl-amine [4.08 g, 71%, intermediate (1)] as an orange oil. LC/MS: RT=0.63 minutes, 219.99 m/e (M+H).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[H+].[Cl:7][C:8]1[CH:9]=[C:10]([NH2:24])[CH:11]=[N:12][C:13]=1[O:14][CH:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17].[N:25](OCCC(C)C)=O>C(O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[Cl:7][C:8]1[CH:9]=[C:10]([N+:24]#[N:25])[CH:11]=[N:12][C:13]=1[O:14][CH:15]([C:16]([F:19])([F:18])[F:17])[C:20]([F:21])([F:22])[F:23]
Reactant: Nc1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Reactant: CC(C)CCON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Product: N#[N+]c1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
An aqueous solution of tetrafluoroboric acid (48% weight, 1.86 mL, 14.2 mmol) was added to a solution of 5-chloro-6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)pyridin-3-amine (Preparation 52, 2.0 g, 6.79 mmol) in ethanol (3 mL) at −5° C. Isopentyl nitrite (960 μL, 7.0 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes at −5° C. The suspension was filtered and the solid was washed with cold ethanol and diethyl ether to afford the title compound as a pink solid (728 mg, 27%).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=2)[NH:4]1.[F:21][C:22]([F:35])([F:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:2]=[C:3]1[C:11]2([CH2:16][CH2:15][N:14]([C:31](=[O:32])/[CH:30]=[CH:29]/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:34])([F:35])[F:21])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=2)[NH:4]1
Reactant: COC(=O)c1ccc2c(c1)C1(CCNCC1)C(=O)N2
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C1(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of methyl 2-oxospiro[indoline-3,4′-piperidine]-5-carboxylate hydrochloride (400 mg, 1.46 mmol) in anhydrous CH2Cl2 (10 mL) was added (E)-3-(2-(trifluoromethyl)phenyl)acrylic acid (315 mg, 1.46 mmol), HOBt (394 mg, 2.92 mmol), EDCI (576 mg, 2.92 mmol) and DIEA (942 mg, 7.30 mol) at 0° C. and then stirred overnight at rt under N2. Then the reaction mixture was washed with 1 N aq HCl and water. The organic layer was dried over Na2SO4, filtered and concentrated to afford a residue, which was purified by preparative TLC to give (E)-methyl 2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate (328 mg, 49%). 1H NMR (CDCl3): 1.58 (m, 4H), 1.97 (m, 3H), 3.91 (m, 3H), 4.15 (m, 1H), 4.40 (m, 1H), 6.85 (m, 1H), 6.98 (m, 1H), 7.48 (m, 1H), 7.56 (m, 1H), 7.72 (m, 1H), 7.99 (m, 2H).
Reaction SMILES: [H][H].[NH2:3][CH2:4][CH2:5][CH2:6][NH2:7]>>[NH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[NH:7]1[CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Agent: NCCCN
Product: C1CNC1

Procedure:
A catalyst as described in Example 2 is charged to the reactor and its temperature raised to 150°C under a flow of hydrogen. When a feed of 1,3-diamino propane is passed over the catalyst at LHSV 0.4 at mole ratio H2 :H2N(CH2)3NH2 of 15 a conversion of the feed of 10% at high selectivity to azetidine results.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:4]1.C(N([CH:32]([CH3:34])[CH3:33])CC)(C)C.C(OC1(O[Si](C)(C)C)CC1)C.C([BH3-])#N.[Na+]>CO.C1COCC1.C(O)(=O)C>[CH:32]1([N:3]2[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:14][CH2:15]3)[CH2:4]2)[CH2:34][CH2:33]1
Reactant: O=C(OCc1ccccc1)N1CCN(C[C@@H]2CCCNC2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCN(C[C@H]2CCCN(C3CC3)C2)CC1
Temperature: 81 °C
Yield: 62 %

Procedure:
Benzyl 4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxylate dihydrochloride (389 mg) was dissolved in MeOH (5 mL) and di-isopropylethylamine (0.52 mL) added under argon. Freshly dried 3 Å molecular sieves (413 mg) were added, followed sequentially by glacial acetic acid (0.2 mL), 1-ethoxy-1-trimethylsilyloxycyclopropane (1.2 mL) and sodium cyanoborohydride as a 1M solution in THF (4.5 mL). The mixture was heated at 81° C. for 2 hours, allowed to cool, filtered through Celite, washed through with 1:1 MeOH-THF (10 mL) and evaporated. The residue was partitioned between ethyl acetate and 1M aqueous sodium hydroxide solution, the organic extract washed with brine, dried over MgSO4 and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (222 mg, 62%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([I:26])=[C:22]([CH3:27])[CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[NH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>C(#N)C>[I:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:28])=[CH:21][C:22]=1[CH3:27]
Reactant: NCc1cccnc1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1I
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1I
Yield: 96.1 %

Procedure:
To a solution of 2,2,2-trichloro-1-[10-(4-iodo-3-methylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]ethanone of Step B (1 g, 1.74 mmol) in dry acetonitrile (30 mL) at room temperature under nitrogen was added dimethyl sulfoxide (0.62 mL, 8.72 mmol) followed by 3-(aminomethyl)pyridine (0.36 mL, 3.49 mmol) and the reaction mixture heated to reflux for 36 hours. The cooled reaction mixture was concentrated in vacuo to a small volume then partitioned between ethyl acetate (50 mL) and 1 M sodium hydroxide (50 mL). The organic layer was separated, washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using ethyl acetate as solvent afforded a white foam (0.94 g). Recrystallization from ethyl acetate/hexane gave the title compound (0.77 g, 79%) as white solid, m.p. 176-177° C.
Reaction SMILES: [CH2:1]1[O:8][C@@H:7]2[O:9][C@H:2]1[CH:3]=[CH:4][C:5]2=[O:6].[BH4-].[Na+].CC(C)=O>O>[C@@H:7]12[O:8][CH2:1][C@@H:2]([O:9]1)[CH:3]=[CH:4][C@@H:5]2[OH:6]
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.1 %

Procedure:
16.0 g (127 mmol) of levoglucosenone was dissolved in 700 ml of water, followed by adding 8.00 g (211 mmol) of sodium borohydride to! the solution. The resultant system was kept stirred at room temperature for 5 minutes. Then, 400 ml of acetone was added to the mixture, and solvent was removed by distillation under reduced pressure, followed by adding chloroform to the residue so as to remove insoluble components by means of filtration. The filtrate was distilled under reduced pressure so as to remove the solvent. Further, the residue was recrystallized from a mixed solvent consisting of 4 parts of hexane and 1 part of diethyl ether so as to obtain 5.55 g of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose (compound 2). The yield of the compound 2 was 34.1%. Further, the mother liquor after the recrystallization was refined with a silica gel column chromatograph by using, as an eluent, a mixed solvent consisting of 1 part of hexane and 1 to 2 parts of ether, and recrystallization was achieved again using a mixed solvent consisting of 1 part of hexane and 3 parts of ethyl acetate so as to obtain 2.14 g of the compound (2). The total yield of the compound (2) was 7.69 g, i.e., 60.1%. The 1H-NMR spectrum of the compound (2) thus obtained was found to be as follows, which was equal to that of the compound (2) obtained in step a) of Example 1:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([CH3:10])[CH:3]=1.[C-:11]#[N:12].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Cc1cc(Cl)ccc1CCl
Agent: [K+]
Solvent: CCO
Product: Cc1cc(Cl)ccc1CC#N
Temperature: 100 °C
Yield: 70.4 %

Procedure:
Step B To a solution of 4-chloro-2-methylbenzyl chloride (5.2 g, 30 mmol) in ethanol (40 mL) was added an aqueous solution (30 mL) of KCN (5 g, 77 mmol) at room temperature. The reaction mixture was then heated at 100° C. for 2 h. The mixture was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10, then 1:4) to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (3.5 g, 66%).
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=2)[CH:9]([CH3:11])[CH3:10])[CH2:3]1.[H-].[Na+].[CH3:26]I>C1COCC1>[F:23][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]([N:12]([CH3:26])[C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=2)[CH:9]([CH3:11])[CH3:10])[CH2:3]1
Reactant: CI
Reactant: Cc1ccc(C(=O)N[C@H](CN2CCC(F)(F)C2)C(C)C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N(C)[C@H](CN2CCC(F)(F)C2)C(C)C)cc1C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
To a mixture of (S)—N-(1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-2-yl)-3,4-dimethylbenzamide (Compound P) (167 mg, 0.51 mmol) in THF (1 mL) was sodium hydride (0.024 mL, 0.51 mmol) added. After 30 min was MeI (0.032 mL, 0.51 mmol) added and the resultant mixture was stirred at rt overnight. Additional sodium hydride (0.013 mL, 0.51 mmol) and MeI (0.032 mL, 0.51 mmol) was added and the resulting mixture stirred for 2 h. The reaction was quenched with MeOH (0.5 mL). The solvent was removed under reduced pressure and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (47 mg, 27%). HRMS (M+H)+: calculated 339.2248. found 339.2277.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:12][C:13](=[O:36])[C@@H:14]([NH:16][C:17](=[O:35])[C@@H:18]([NH:20][C:21](=[O:34])[CH:22]([NH:26][C:27]1[S:28][C:29]([CH:32]=[O:33])=[CH:30][N:31]=1)[CH:23]([CH3:25])[CH3:24])[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[BH4-].[Na+]>CCO.O>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:12][C:13](=[O:36])[C@@H:14]([NH:16][C:17](=[O:35])[C@@H:18]([NH:20][C:21](=[O:34])[CH:22]([NH:26][C:27]1[S:28][C:29]([CH2:32][OH:33])=[CH:30][N:31]=1)[CH:23]([CH3:24])[CH3:25])[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)C(Nc1ncc(CO)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the material from Example 21 (21.5 mg, 0.033 mmol) in EtOH/H2O (4:1) (2.5 mL) is added sodium borohydride (8.35 mg, 0.221 mmol) in 2 portions, separated by ˜5 min and the resulting off white slurry is allowed to stir at room temp for 1.5 h. The reaction is quenched with MeOH (750 μlit) and evaporated to dryness under a gentle stream of N2 to give the title compound that is used directly in the next step. LC/MS (Condition A): ret. T=1.74 min, (M+H)+ 535.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH3:12])[N:9]=[C:8]([C:13]#[N:14])[CH:7]=1.C([O-])(=O)C.[K+].[Br:20]Br>C(O)(=O)C>[Br:20][C:7]1[C:8]([C:13]#[N:14])=[N:9][N:10]([CH2:11][CH3:12])[C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: BrBr
Reactant: CCn1nc(C#N)cc1CCCCCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCn1nc(C#N)c(Br)c1CCCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (10.8 g, 51.0 mmol) was treated with potassium acetate (10.0 g, 102 mmol) and bromine (2.9 mL, 56 mmol) in acetic acid (102 mL), and the reaction was stirred overnight at ambient temperature. The acetic acid was removed under reduced pressure, and the residue was partitioned between water and chloroform. The mixture was adjusted to pH 10 with the addition of 2 N aqueous sodium carbonate. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow oil was purified by chromatography on a HORIZON HPFC system (eluting with hexanes/ethyl acetate in a gradient from 95:5 to 50:50) to provide 4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCCN(C)C1=O>C(Cl)Cl>[CH:27]1[CH:26]=[CH:25][N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:7][CH:8]=3)=[O:13])[CH2:15][C:16]=12
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CN1CCCN(C)C1=O
Product: O=C(CN1CCOCC1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 20 h
Yield: 106.8 %

Procedure:
A stirred suspension of 0.19 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamide in 1 ml of methylene chloride is added 0.44 g of morpholine followed by 1 ml of 1,3-di-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and stirring continued for 20 hours. The methylene chloride is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The brown solid is dissolved in 15 ml of ethyl acetate and washed with saturated NaHCO3, brine and dried with Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to give 0.23 g of a colorless gum which is stirred with ethyl acetate-hexanes to give 0.21 g of white solid. MS(CI): 431(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:8]2[CH:17]=[CH:18][O:19][C:7]=2[CH:6]=1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C1C(=O)N([Br:50])C(=O)C1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[C:8]2[CH:17]=[C:18]([Br:50])[O:19][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2occc2n1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc2oc(Br)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 4-tert-butoxycarbonyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester (100 mg, 0.38 mmol) in DCM (1 mL) was added a solution of TBAF in THF (1.0 M, 0.57 ml, 0.57 mmol) followed by the addition of NBS (87 mg, 0.49 mmol). The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (10 mL), washed with 10 mL of water and then with 10 mL of brine and dried with Na2SO4. The solid was removed by filtration. The filtrate was concentrated by evaporation. The crude product was purified by chromatography (0-20% EtOAc in hexane) to give 85 mg of 4-tert-butoxycarbonyl-2-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester (85 mg, 65%). 1H NMR (400 MHz, CDCl3) δ (ppm) 6.81 (s, 1H), 6.61 (s, 1H), 3.83 (s, 3H), 1.59 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH2:2][CH3:3].C(N(CC)CC)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>ClCCl.O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCCOCCO
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOCCOS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
To a solution of 2-propoxy-1-ethanol (1.5 g, 14.4 mmol) and triethylamine (2.2 g, 21.6 mmol) in dichloromethane (20 mL) at 0° C. was added 4-bromobenzenesulfonyl chloride (3.86 g, 15.1 mmol) in dichloromethane (10 mL) dropwise over 30 minutes. The reaction was then warmed to room temperature and stirred for 16 hours. The mixture was then poured into water (50 mL) and acidified with 2N aqueous hydrochloric acid (15 mL). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with hexane:ethyl acetate (9:3), to give the title compound (2.2 g, 48%) as a colourless oil.