Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[O:7][C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=1.C[O:16][C:17](=[O:67])[C@@H:18]([NH:34][C:35]([C@@H:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][NH:38]1)=[O:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([NH:34][C:35]([C@@H:37]3[CH2:46][C:45]4[CH:44]=[C:43]5[O:47][CH2:48][C@H:49]([C:51]6[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]7[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=7)=[CH:53][CH:52]=6)[O:50][C:42]5=[CH:41][C:40]=4[CH2:39][N:38]3[C:11]([C:9]3[N:10]=[C:6]([CH3:5])[O:7][C:8]=3[CH3:14])=[O:13])=[O:36])[C:17]([OH:67])=[O:16])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)#[N:33]
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.67 h

Procedure:
EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. To this solution was added (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (22 mg). LCMS (m/z): 860.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)/[C:8]([OH:10])=O)[N:6]=1.[NH2:17][C@@H:18]1[C:36](=[O:37])[N:20]2[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][O:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:23][S:24][C@H:19]12>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)/[C:8]([NH:17][C@@H:18]2[C:36](=[O:37])[N:20]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][O:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:23][S:24][C@H:19]23)=[O:10])[N:6]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Nc1nc(/C(=N/OCC2CC2)C(=O)O)cs1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC3CC3)c3csc(N)n3)[C@H]2SC1

Procedure:
Starting from 2-(2-aminothiazol-4-yl)-2(Z)-cyclopropylmethoxyiminoacetic acid and 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, the titled compound is obtained by the procedure of Reference Example 3.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][C:7](=[O:10])[CH2:8][Cl:9].[CH3:15][O:16][CH2:17]Cl>>[CH3:1][O:2][CH2:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[N:6]([CH2:15][O:16][CH3:17])[C:7](=[O:10])[CH2:8][Cl:9]
Reactant: COCc1ccccc1NC(=O)CCl
Reactant: COCCl
Product: COCc1ccccc1N(COC)C(=O)CCl

Procedure:
Following the above procedure, but using 2'-(methoxymethyl)-2-chloroacetanilide as the sec-amide starting material and chloromethyl methyl ether as the alkylating agent, the product 2'-(methoxymethyl)-N-(methoxymethyl)-2-chloroacetanilide was obtained.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]=[C:2]=[O:1])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(N=C=O)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a dichloromethane (400 mL) solution of diphosgene (74 mmol, 14.8 g) at 0° C. was added a dichloromethane (1100 mL) solution of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine (Formula IIa, 41 mmol, 11.7 g) and triethylamine (93 mmol, 9.4 g) over a period of 3.5 hours. Once the addition was complete, the reaction was stirred in an ice bath for an additional 30 minutes. The reaction solvent was evaporated, the residue dissolved in tetrahydrofuran (300 mL), and the insolubles removed by filtration. The filtrate was concentrated by rotary evaporation to give 4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenylisocyanate as a beige solid (12.8 g, 100% crude yield). The product was advanced to the next reaction step without purification. 1H NMR (400 MHz, CDCl3) δ 7.08-6.85 (m, -Ar), 3.79 (s, 3 H, OCH3), 3.45-3.20 (m, 8 H, CH2).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@H:27]2[N:31]3[C:32](=[O:45])[CH:33](P(=O)(OCC)OCC)[CH2:34][CH2:35][CH2:36][C@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26].C(O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]([C@H:27]2[N:31]3[C:32](=[O:45])/[C:33](=[CH:8]/[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[CH2:34][CH2:35][CH2:36][C@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CCC[C@H]2CC[C@@H](c3ccc(F)c(F)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CCC[C@H]3CC[C@@H](c4ccc(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Lithium hydroxide (0.0668 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.20 g) and diethyl [(3S,9aS)-3-(3,4-difluorophenyl)-5-oxooctahydropyrrolo[1,2-a]azepin-6-yl]phosphonate obtained above (0.52 g) in tetrahydrofuran (1 mL)-ethanol (4 mL), and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was added to ice-sodium bicarbonate water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.223 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[S:5][C:6]=1[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[C:11]([O:10][C:8]([NH:7][C:6]1[S:5][C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:2]=1[NH:1][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cc(N)c(NC(=O)OC(C)(C)C)s1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNc1cc(C(=O)OC)sc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of methyl 4-amino-5-(tert-butoxycarbonylamino)thiophene-2-carboxylate 89 (0.037 mmol, 10 mg) in CH2Cl2 (1 mL), triethylamine (0.367 mmol, 51.2 μL) and methyl bromoacetate (0.184 mmol, 17.45 μL) were added and stirred at rt for 3 h. The reaction was quenched in water and extracted with CH2Cl2. The organic layer was dried with phaseseparator whereafter and concentrated under reduced pressure to give methyl 5-(tert-butoxycarbonylamino)-4-(2-methoxy-2-oxoethylamino)thiophene-2-carboxylate 90 (10 mg, 79%). NMR (400 MHz, CDCl3) 1.54 (s, 9H), 3.31 (br s, 1H), 3.77 (s, 3H), 3.79 (d, J=6.3 Hz, 2H), 3.82 (s, 3H), 7.38 (s, 1H), 7.54 (br s, 1H). (m/z)=345 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-3-carboxylic acid (3.00 g; 13.1 mmol) is dissolved in methylene chloride (100 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (4.77 g; 15.7 mmol), diisopropylethylamine (5.41 g; 41.9 mmol), and PyBOP (8.17 g; 15.7 mmol) are added sequentially. The mixture is stirred for 17 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product as an oil. ESMS: MH− 479.4
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5].[C:7]([O-])(=[O:9])[CH3:8].[Na+]>C(OC(=O)C)(=O)C>[C:7]([O:6][CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])(=[O:9])[CH3:8]
Reactant: CCCC(C)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCC(C)OC(C)=O
Yield: 77 %

Procedure:
2-Pentanol (176 g, 2.0 mol, Aldrich) and sodium acetate (18 g, 10 Aldrich) were heated to 90° C. and then acetic anhydride (240 ml, BDH GPR) was added over a 1 hour period at 100-110° C. The mixture was heated to reflux for 4 hours. The reaction mixture was then cooled, washed with water, washed with aqueous sodium bicarbonate to neutrality, dried over sodium sulfate, and then concentrated. Fractional distillation of the crude residue under vacuum provided 1-methylbutyl acetate (80-81°/140-145 mm Hg, 77% yield), the structure of which was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy, and infra red spectroscopy (not shown).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[OH-].[Na+].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH2:19]>O.ClCCl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:19]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: NCc1ccccn1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: c1ccc(CN(Cc2ccccn2)Cc2ccccn2)nc1
Temperature: 0 °C
Yield: 54.2 %

Procedure:
5.0 g (30.5 mmoles) of 2-picolyl chloride hydrochloride were dissolved in 13 ml of water and 6 ml of 5.3 N NaOH were added to the resulting solution while cooling with ice. The red suspension obtained was cooled to 0° C. and a solution of 1.64 g (15.25 mmoles) of picolylamine in 26 ml of dichloromethane was added. The mixture was heated to room temperature and reacted with another 6 ml of 5.3 N NaOH over a period of several days during which measures were taken to ensure that the pH value did not rise above 9.5. The mixture was then washed twice with 7 ml of 15% NaOH and the organic phase was dried over sodium sulfate. After the drying agent had been removed, the solvent was evaporated off. The brown residue was extracted with ether and the solid obtained was recrystallized from ether. 2.4 g of tris-(2-pyridylmethyl)-amine were obtained.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C(Cl)=S)C1C=CC=CC=1>ClCCCl.CN(C)C1C=CN=CC=1>[C:1]([O:9][C@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: S=C(Cl)Oc1ccccc1
Solvent: ClCCCl
Product: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)C[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of 1-(3,5-di-O-benzoyl-β-L-arabinofuranosyl)uracil 12 (5.2 g, 11.4 mmoL) in anhydrous 1,2-dichloroethane (120 mL) were added phenoxythiocarbonyl chloride (4.7 mL, 34.3 mL) and 4-(dimethylamino)pyridine (DMAP, 12.5 g, 102.6 mmoL). The resulting solution was stirred at room temperature under argon atmosphere for 1 h and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (300 mL) and the organic solution was successively washed with an ice-cold 0.2 N hydrochloric acid solution (3×200 mL) and water (2×200 mL), dried over Na2SO4 then evaporated under reduced pressure. The crude material was co-evaporated several times with anhydrous dioxane and dissolved in this solvent (110 mL). To the resulting solution were added under argon tris-(trimethylsilyl)silane hydride (4.2 mL, 13.7 mmol) and α,α′-azoisobutyronitrile (AIBN, 0.6 g, 3.76 mmol). The reaction mixture was heated and stirred at 100° C. for 1 h under argon, then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-5%)] to give 13 (2.78 g, 56%) which was crystallized from EtOH: mp=223-225° C.; H-NMR (DMSO-d6): δ 11.4 (br s, 1H, NH), 8.0-7.5 (m, 11H, 2 C6H5CO, H-6), 6.28 (t, 1H, H-1′, J=7 Hz), 5.5 (m, 2H, H-1′ and H-5), 4.6-4.4 (m, 3H, H-4′, H-5′ and H-5″), 2.6 (m, 2H, H-2′ and H-2″); MS: FAB>0 (matrix GT) m/z 437 (M+H)+, 3325 (S)+; FAB<0 (matrix GT) m/z 435 (M−H)−, 111 (B)−; Anal. Calcd for C23H20N2O7: C, 63.30; H, 4.62; N, 6.42. Found: C, 62.98; H, 4.79; N, 6.40.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)[C:13]([O:15]CC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCc1nnn[nH]1)C(=O)O)OCc1ccccc1

Procedure:
Prepared analogously to Example 30b from ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyrate and lithium hydroxide in a mixture of solvents from water and THF.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[N:3]=1.[CH3:10][Si:11]([CH2:14][N:15]=[N+:16]=[N-:17])([CH3:13])[CH3:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:17]=[N:16][N:15]([CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:9]=2)[N:3]=1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#Cc1cccc(Br)n1
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[Si](C)(C)Cn1cc(-c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-ethynylpyridine (Example 465, Step 1) (350 mg, 1.92 mmol) and trimethylsilylmethyl azide (323 mg, 2.50 mmol) were combined in t-BuOH (4.0 mL) and water (3.0 mL). CuSO4.5H2O (24 mg, 0.096 mmol) in water (0.50 mL) was added, followed by sodium ascorbate (76 mg, 0.39 mmol) in water (0.50 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a yellow residue that was purified by flash chromatography (0-50% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[C:11](#[N:14])[CH:12]=[CH2:13]>CO>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:13][CH2:12][C:11]#[N:14])=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: Oc1ccc2c(c1)CCO2
Reactant: C=CC#N
Solvent: CO
Product: N#CCCOc1ccc2c(c1)CCO2

Procedure:
40.8 g of 2,3-dihydro-5-hydroxybenzofuran (the synthesis of which is described in Synthesis 1988, 950-952), 3 ml of a 40% solution of Triton B in methanol and 200 ml of freshly distilled acrylonitrile are mixed at room temperature. The mixture is heated at reflux for 46 hours, then the acrylonitrile is evaporated off as far as possible. The residue is taken up in ethyl acetate, washed with 2N sodium hydroxide solution, N hydrochloric acid and water. The organic phase, dried over magnesium sulphate, is concentrated in vacuo, and then the residue is recrystallised from 300 ml of isopropanol to yield 38 g of the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][O:10][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:3][CH:2]=1
Reactant: OCCCc1ccncc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccncc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
In a round bottom flask was charged with 4-pyridinepropanol (5 g, 36.45mmol), triethylamine (5.7 mL, 72.9 mmol), methylene chloride (80 mL). The solution was cooled down to 0° C. and mesyl chloride (5.7 mL, 72.9 mmol) in methylene chloride (20 mL) was slowly added. The ice bath was removed, and the mixture was stirred at room temperature overnight before being concentrated. The residue was diluted with ethyl acetate, and the organic was washed with water (2×) and brine (1×). It was dried over anhydrous sodium sulfate and concentrated to give methanesulfonic acid 3-pyridin-4-yl-propyl ester as a dark oil (6.52 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([OH:16])[N:7]=[C:6]([SH:17])[N:5]=1.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.O>CN(C=O)C>[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][S:17][C:6]1[N:7]=[C:8]([OH:16])[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([OH:3])[N:5]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: CCOC(=O)Cc1c(O)nc(S)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1c(O)nc(SCc2cccc(F)c2F)nc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride in oil (1.37 g) in dry DMF (10 ml) was added a solution of the product from example 1, step (a) (7.9 g) in dry DMF (30 ml). After the addition the mixture was stirred at room temperature for 1 hour. To the solution was added 2,3-difluorobenzylbromide (4.45 ml) and the mixture allowed to stir overnight. The mixture was poured into water (200 ml) and the product collected by filtration to give the subtitle compound (8.1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccc(F)cc1
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and 4-fluorobenzyl chloroformate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:18][CH:19]1[CH2:22][NH:21][CH2:20]1>CN(C=O)C.CCOC(C)=O>[F:18][CH:19]1[CH2:22][N:21]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:20]1
Reactant: FC1CNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(N2CC(F)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 98 %

Procedure:
To a solution of 6-chloro-2-methyl-3-nitropyridine (0.5 g, 2.9 mmol) in DMF (5 mL) was added Cs2CO3 (1.9 g, 5.8 mmol) followed 3-fluoroazetidine (0.64 g, 5.8 mmol) and the reaction mixture was heated for 2 h at 80° C. The reaction mixture was then diluted with EtOAc and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3%) to afford the title compound (0.6 g, 92%). LCMS (ES+) 211.95 (M+H)+, RT 2.33 minutes (method 1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[S:44][C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=1)CCC.[F-].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[S:44]1[C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5s4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C
Yield: 45.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0895 mmol), 2-(tributylstannyl)-1,3-benzothiazole (76.0 mg, 0.179 mmol), bis (tri-tert-butylphosphine)palladium(0) (9.15 mg, 0.0179 mmol) and cesium fluoride (88.4 mg, 0.582 mmol) in dioxane (1.00 mL) was heated at 130° C. under microwave irradiation for 2 hours under nitrogen. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=4:1→2:1→1:1) and PTLC (DCM/EtOAc=95:5) to afford desired product (24.8 mg, 45.2%) as pale yellow solid. 1HNMR (CDCl3) 500 MHz δ: 8.23 (dd, J=7.7, 1.4 Hz, 1H), 8.06-8.01 (m, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.53-7.38 (m, 5H), 7.36-7.29 (m, 2H), 7.17 (td, J=7.4, 1.1 Hz, 1H), 6.99-6.96 (m, 1H), 6.93-6.85 (m, 1H), 6.62 (dd, J=8.0, 4.6 Hz, 1H), 6.49-6.45 (m, 1H), 5.20 (br s, 1H), 2.69-2.26 (m, 4H), 2.21-2.09 (m, 1H), 1.97-1.85 (m, 1H), 1.41 (br s, 9H).