Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][SH:8].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30]Cl)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C.O>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30][S:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: SCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSCc3ccccn3)c2CC1
Reaction time: 2 h
Yield: 39.3 %

Procedure:
Evaporate a solution of 2-pyridine methanethiol (2.5 mL, 10% in EtOH) in vacuo to obtain neat 2-pyridine methanethiol (250 mg). Immediately dissolve 2-pyridine methanethiol (230 mg, 1.84 mmol) in anhydrous DMF (5 mL) under an atmosphere of nitrogen. Add sodium hydride (100 mg, 2.5 mmol, 60% dispersion in mineral oil) and stir for 10 min. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (550 mg, 1.67 mmol) in anhydrous DMF (1 mL) and stir under nitrogen for 2 h. Quench reaction by slow addition of water (10 mL), dilute up to 150 mL with water and extract with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (9:1 to 1:1 gradient over 60 min, 40 mL/min) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(pyridin-2-ylmethylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (275 mg, 40%) as a light yellow syrup.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[C:10]2[CH2:16][N:17]([CH2:20][CH2:21][C:22]3[N:26]([CH3:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[N:23]=3)[C:18](=[O:19])[C:9]=12.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.O>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[CH3:15][N:12]1[C:13](=[O:14])[C:8]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH2:21][C:22]3[N:26]([CH3:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[N:23]=3)[CH2:16][C:10]2=[CH:11]1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccc3n1C)C2
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc2c(c(-c3cccnc3)c1=O)C(=O)N(CCc1nc3ccccc3n1C)C2
Temperature: 120 °C
Yield: 22.3 %

Procedure:
K2CO3 (232 mg, 1.682 mmol) and bis(triphenylphosphine) palladium(II) dichloride (39.3 mg, 0.056 mmol) were each rapidly added in sequence to a suspension of 7-chloro-5-methyl-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (200 mg, 0.561 mmol, see Example c8)) and pyridin-3-ylboronic acid (103 mg, 0.841 mmol) in DMF (3 ml)/water (0.600 ml). The reaction was heated in a microwave at about 120° C. for about 20 min. The reaction was cooled to r.t., DCM (15 ml) and DMF (1 ml) were added, the resulting mixture was filtered and the filtrate was concentrated by evaporating DCM. The concentrate was cooled to r.t., the crystallized solid was filtered off, washed with water and dried to afford the title compound (50 mg, 0.125 mmol, 22.33% yield).
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:15]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[N+:11]([C:8]1[C:9]2[O:10][CH2:15][O:1][C:2]=2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1O
Reactant: ClCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc([N+](=O)[O-])c2c1OCO2

Procedure:
14.2 g of 2,3-dihydroxy-4-nitrobenzaldehyde in 1000 ml of DMF is stirred with 57.6 ml of bromochloromethane and 50.6 g of cesium carbonate at 100° C. for 7 hours. The batch is added to 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed several times with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. The brown solid that is obtained is purified by column chromatography (silica gel, hexane/ethyl acetate 100:0→60:40). 7.4 g of 7-nitro-benzo[1,3]dioxole-4-carbaldehyde is obtained as a light yellow solid. The latter is mixed in 400 ml of acetone at 10° C. with a solution of 11.8 g of potassium permanganate in 190 ml of acetone/water (1:1). It was stirred for 10 hours, added to 2 N hydrochloric acid and filtered through diatomaceous earth. The acetone is removed in a vacuum, and the aqueous phase is made alkaline with sodium hydroxide solution. It is extracted with ether, and then the aqueous phase is acidified with hydrochloric acid. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 4.36 g of7-nitro-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brown solid, flash point 230-239° C.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([CH:15]=[C:16]1[NH:21][CH2:20][CH2:19][CH2:18][S:17]1)([O-:14])=[O:13].C(N(CC)CC)C>O1CCCC1>[C:1]1([CH2:7][S:8]([N:21]2[CH2:20][CH2:19][CH2:18][S:17][C:16]2=[CH:15][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)Cc1ccccc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A solution of 2.29 g of phenylmethanesulfonyl chloride in 20 ml of tetrahydrofuran was added drop-by-drop to a stirred slurry of 1.6 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine and 2.02 g of triethylamine in 10 ml of dry tetrahydrofuran at -50° C. The resulting mixture was stirred at -50° C. for 1 hour, 1.0 g of phenylmethanesulfonyl chloride was added, and the mixture was stirred for a further hour. The mixture was partitioned between methylene chloride and water. The organic phase was separated, washed with water and brine, dried (MgSO4) and stripped of solvent. The residue was flash chromatographed over silica gel, using methylene chloride as eluent, to give N-(phenylmethylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (5A), as a pale yellow solid, m.p.: 140°-141° C.
Reaction SMILES: I[C:2]1[C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>O1CCCC1.O.[Ag]=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)C=C(I)C(=O)CC1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=[Ag]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: N#Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2=CC(C)(C)CCC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Dissolve 2-iodo-4,4-dimethyl-cyclohex-2-enone(Tetrahedron Letters (1994), 35(37), 6787-90) (11 g, 44 mmol) in tetrahydrofuran (200 ml). Add 3-methoxyphenyl boronic acid (10 g, 65.8 mmol), triphenyl arsine (808 mg, 2.64 mmol), silver oxide (15.3 g, 66 mmol) in water (25 ml), bis(benzonitrile)dichloropalladium(II) (506 mg, 1.32 mmol). Stir at room temperature for 1 h. Quench with saturated aqueous ammonium chloride (200 ml), and stir 1 h. Filter reaction mixture through a bed of celite rinsing celite with ether (200 ml). Separate filtrate layers and extract the aqueous layer with additional ether (200 ml), combine organic extracts, and wash with water 2×(200 ml), brine (100 ml), dry, and concentrate. Chromatograph residue on a Biotage eluting with 10% ethyl acetate in hexanes to give (10.1 g, 99%) of the title compound as a yellow oil: 1H NMR (CDCl3) δ 7.26-7.23 (m, 1H), 6.88-6.84 (m, 3H), 6.69 (s, 1H), 3.81 (s, 3H), 2.62 (t, 2H), 1.96 (t, 2H), 1.25 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36]([CH2:57][Cl:58])=[C:37]2[C:41]([O:43][CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([NH:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36]([CH2:57][Cl:58])=[C:37]2[C:41]([O:43][CH:44]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:42])=[O:14])([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)cs1
Temperature: -40 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (30.5 g, 71.0 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, hydrochloride (32.1 g, 71.0 mmol) in dichloromethane (500 mL), stirred under nitrogen at −30° C., was added neat phenyl phosphorodichloridate (12.93 mL, 85 mmol). The reaction mixture was cooled to −40° C. and N-methylmorpholine (23.42 mL, 213 mmol) was added dropwise over 30 min, and stirred for an additional 2 hours at −40° C. The reaction was then quenched by addition of 150 mL of a 10% aq. solution of citric acid, and the phases were separated. The organic phase was concentrated and the residue was then dissolved in 500 mL of ethyl acetate. The organic solution was washed with 100 mL of a 5% aq. sodium bicarbonate, 100 mL of brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified on a 330 g silica gel column eluting with 0-80% ethyl acetate in hexanes to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (42 g, 50.8 mmol, 71.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H) 1.55 (s, 9 H) 1.63 (s, 3 H) 1.66 (s, 3 H) 3.52 (d, J=18.19 Hz, 1 H) 3.66 (d, J=18.19 Hz, 1 H) 4.43 (d, J=4.29 Hz, 2 H) 5.12 (d, J=5.05 Hz, 1 H) 6.08 (dd. J=8.84, 5.05 Hz, 1 H) 6.99 (s, 1 H) 7.30-7.49 (m, 12 H) 8.25 (d, J=8.84 Hz, 1 H). LCMS: (M+H)+: 826.5.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18]Br>CS(C)=O.O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:18][CH2:17]1)#[N:2]
Reactant: COC(=O)c1cccc(CC#N)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of methyl 3-(cyanomethyl)benzoate (1.5 g, 8.6 mmol) in dimethyl sulfoxide (30 mL) was added sodium hydride (60% in oil, 1.0 g, 26 mmol) while cooling to not more than 25° C. without causing solidification. The reaction mixture was stirred at room temperature for 30 min, 1,2-dibromoethane (2.4 g, 12.8 mmol) was added, and the mixture was further stirred at room temperature for 10 hr. The reaction mixture was diluted with water (100 mL), and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→50/50), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (1.3 g, 76%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][C:30]3[CH:32]=[N:33][CH:34]=[CH:35][C:29]=3[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([C:8]([C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[CH2:31][C:30]5[CH:32]=[N:33][CH:34]=[CH:35][C:29]=5[NH:28][C:27]4=[O:36])[CH2:24][CH2:25]3)[CH:3]=1)=[O:9])[CH2:11][CH2:12]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reactant: O=C1Nc2ccncc2CN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(N3Cc4cnccc4NC3=O)CC2)ncn1)N1CCc2cc(F)ccc21

Procedure:
70 mg (0.25 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 60 mg (0.26 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-pyrido[4,3-d]pyrimidin-2-one and 50 μL (0.30 mmol) DIPEA in 5.0 mL DMF were shaken for 2 h at RT. Then the reaction mixture was poured onto water, stirred and the precipitate formed was suction filtered. This was washed with diisopropylether and dried.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C:20]2([CH2:25][CH:26]([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.C(O)C.O.[OH-].[Na+]>O1CCOCC1>[C:9]([C@@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C:20]2([CH2:25][CH:26]([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)([OH:10])=[O:8]
Reactant: CCOCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CCOCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)O
Reaction time: 20 h
Yield: 88.2 %

Procedure:
3-{1-[(cis-4-Benzyloxycarbonyl-cyclohexyl)carbamoyl]cyclopentyl}-2-(2-ethoxyethyl)propanoic acid (225 mg, 0.476 mmole) was dissolved in 1,4-dioxan (20 ml), ethanol (4 ml) and water (6 ml) and was treated with 1N sodium hydroxide solution (2.4 ml, 2.4 mmole). After 20 hours at room temperature, the solution was evaporated to half volume, diluted with water (20 ml) and washed with diethyl ether. The aqueous layer was separated, acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×20 ml). The ethyl acetate layer was separated, dried over magnesium sulphate and the solvent evaporated to give the title product as a colourless foam (161 mg, 88%). Found: C,61.89; H,8.29; N,3.62. C20H33NO6,0.2 H2O requires C,62.06; H,8.69; N,3.62%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].BrC[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COc1ccc(CCBr)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(OC)cc3)CC1)O2
Yield: 83.1 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-4-methoxy-benzene (0.16 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(4-methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (181 mg) as a white solid.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[Cl:16][CH2:17][C:18](Cl)=[O:19]>ClCCl>[Cl:16][CH2:17][C:18]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH3:7])[CH:10]=1)=[O:19]
Reactant: COc1cccc(N)c1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(NC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
2 ml of pyridine is added to 30 ml of a solution of 3-methoxyaniline (4.92 g, 40 mmol) in dichloromethane and the mixture is stirred for 5 minutes, while maintaining the temperature inside vessel at lower than 0° C., and thereto 20 ml of a solution of chloroacetyl chloride (6.78 g, 60 mmol) in dichloromethane is drop-added slowly. A reaction is carried out at room temperature for 12 hours after completion of drop-addition, and then terminated. The reaction solution is washed with 5% of HCl (30 ml×3), 5% of NaOH (30 ml×3), water (30 ml×3), and saturated saline (30 ml) successively, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated to remove the solvent to obtain 6.43 g of 2-chloro-N-(3-methoxyphenyl)acetamide, with a yield of 80.7%.
Reaction SMILES: [CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1)[CH3:2].F[B-](F)(F)F.[CH2:32]([O+](CC)CC)[CH3:33]>O1CCOCC1>[CH2:32]([O:10][C:8]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:6]2[S:26][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[N:9]=1)[CH3:33]
Reactant: CC[O+](CC)CC
Reactant: CCc1cc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCOc1nc2cc(CC)sc2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a mixture of 4′-[(5-ethyl-2-oxo-1,2-dihydro-3H-thieno[2,3-d]imidazol-3-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and 1,4-dioxane was added triethyloxonium tetrafluoroborate (1M methylene chloride solution, 4.2 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was extracted with chloroform and water. The obtained chloroform layer was successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.48 g, 92%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 92.6 %

Procedure:
To ethyl 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.10 g) are added 90% acetic acid--conc. hydrochloric acid (4:1, 81.25 ml) and the mixture is refluxed for 2 hours. After cooling, the precipitated crystals are isolated, washed with water, ethanol, and diethyl ether in this order to give 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4,-dihydro-4-oxoquinoline-3-carboxylic acid (3.47 g), as white needles, m.p. 218°-220° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1.[Si]([C:21]#[CH:22])(C)(C)C.C(N(CC)CC)C.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+].Cl>C1COCC1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO.CN(C=O)C>[C:21]([C:2]1[CH:3]=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1)#[CH:22]
Reactant: CCC(CC)n1c(O)nc2ncc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1cnc2nc(O)n(C(CC)CC)c2c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 44.2 %

Procedure:
Solid 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol (2.0 g, 7.04 mmol, 1.0 equiv), CuI (133 mg, 0.7 mmol, 0.1 equiv), and (Ph3P)2PdCl2 (491 mg, 0.7 mmol, 0.1 equiv) were added to a dry round bottom flask equipped with a stir bar. The flask was sealed and purged with nitrogen and DMF (30 mL), TMS-acetylene (4.22 mL, 8.45 mmol, 1.2 quiv), and triethylamine (4.9 mL, 35.2 mmol, 5.0 equiv) were added by syringe. The resulting mixture was heated to 100° C. for 30 min. After the reaction was allowed to cool, the mixture was concentrated in vacuo and then resuspended in EtOAc. The mixture was washed three times with water, twice with satd. aq. NaHCO3, and once with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC (7%-66% EtOAc/Hexanes) provided the silylated product, which contained triphenylphosphine oxide as a contaminant, was taken on directly into the deprotection. The solid was dissolved in a 1:1 mixture of THF:MeOH (30 mL), and solid KOH (1.97 g, 35.2 mmol, 5.0 equiv) was added in one portion. After 5 min, the reaction was diluted with water and acidified to pH 7 by the addition of 1 N HCl. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC (10%-60% EtOAc/Hexanes) provided 6-ethynyl-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol as a white solid (713 mg, 45%). m/z=230.2 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:7]1=[O:19].[ClH:23]>C(OCC)(=O)C>[ClH:23].[OH:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][C:7]1=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(O)c2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CNCCN1Cc1cccc(O)c1
Reaction time: 0.25 h

Procedure:
Through a solution of the product from Step J (68 mg, 0.22 mmol) in 3.0 mL of ethyl acetate at 0° C. was bubbled anhydrous HCl gas for 5 minutes. After 15 minutes, the solution was concentrated in vacuo to provide the titled salt as a white foam which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])[O:3]1.[Cl-].[NH4+].CCO>[Zn].C1COCC1>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[B:4]1[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:19])([CH3:1])[O:3]1)[NH2:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Intermediate 26A (1 g, 3.80 mmol), ammonium chloride (1.432 g, 26.6 mmol), and zinc (1.491 g, 22.81 mmol) were added to a flask, followed by the addition of EtOH (10.0 mL) and THF (10.0 mL). The reaction mixture was stirred at room temperature for 2 hours and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure to yield Intermediate 26 (885 mg, 100% yield). MS (ES): m/z=234.2 [M+H]+.