Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:22])[CH2:17][C:18]([CH2:20][Cl:21])=[O:19])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:22])[C:17](=[C:3]1[CH:2]=[CH:1][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[C:18](=[O:19])[CH2:20][Cl:21])[CH3:14]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=Cc1cccc2ccccc12
Product: CCOC(=O)C(C(=O)CCl)=C1C=Cc2ccccc2C1

Procedure:
9.85 g of 1-naphthaldehyde were reacted with 15.2 g of 4-chloroacetoacetic acid ethyl ester in the course of 10 hours as described in Example 24. After incipient distillation under a high vacuum had been carried out, a 2:1 isomer mixture which still contained traces of aldehyde remained as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[CH2:16][C:15]4(OCC[O:18]4)[CH2:14][CH2:13][C:12]=3[N:11]([C:22]([NH:24][C@@H:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:26]([NH:28][CH3:29])=[O:27])=[O:23])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[CH2:16][C:15](=[O:18])[CH2:14][CH2:13][C:12]=3[N:11]([C:22]([NH:24][C@@H:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:26]([NH:28][CH3:29])=[O:27])=[O:23])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC1(C2)OCCO1)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC(=O)C2)C(C)(C)C
Yield: 91.1 %

Procedure:
A mixture of compound 63 (0.91 g) and p-toluenesulfonic acid (1.3 g) was heated in acetone and water at 50° C. until starting material was consumed. After evaporation of acetone, the residue was extracted between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 70% to 80% EtOAc/Hex to give (S)-3-(3,4-difluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-oxo-4,5,6,7-tetrahydro-1H-indazole-1-carboxamide (0.75 g, 91% yield), which was reduced with sodium borohydride (1.0 equiv.) in MeOH to give compound 67 as a mixture of two diastereomers after purification with a preparative LC-MS. LCMS (+ESI) m/z=421.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[CH:11]([NH2:13])=O>CCO>[N:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: COC(=O)c1sccc1N
Solvent: CCO
Product: O=c1[nH]cnc2ccsc12
Temperature: 240 °C
Yield: 26 %

Procedure:
A mixture of methyl 3-aminothiophene-2-carboxylate (1 g, 6.3 mmol) and formamide (2 g) is heated at 240° C. for 10 min. Upon cooling a precipitate appeared. It is dissolved in EtOH and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel chromatography eluting with 10% MeOH in CH2Cl2 to yield 3H-thieno[3,2-d]pyrimid-4-one (249 mg, 26%) as a solid. 1H NMR (DMSO) δ 12.61 (1H, brs), 8.20 (1H, s), 8.17 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].Cl.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9].C1COCC1>CCOC(C)=O>[NH2:3][C:2]([N:15]1[CH2:14][CH2:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:8]([O:7][CH3:6])=[O:9])[CH:11]=2)[CH2:16]1)=[S:1]
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)CCN(C(N)=S)C2
Temperature: 100 °C
Yield: 100.1 %

Procedure:
A mixture of ammonium thiocyanate (0.105 g, 1.384 mmol), 6-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.3 g, 1.3176 mmol) and THF (2 mL) was heated in a CEM microwave reactor for 1 h at 100° C. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc, and washed with H2O, 1 N HCl, saturated aqueous NaHCO3 and brine respectively, dried over anhydrous MgSO4, and concentrated under reduced pressure to afford methyl 2-(aminocarbonothioyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (0.33 g, 47%) as a white solid. LCMS: (FA) ES+251.
Reaction SMILES: [CH2:1]([Zn]CC)C.[C:6]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1)(=[O:8])[CH3:7].ICI>C1(C)C=CC=CC=1>[CH:14]1([C:13]2[CH:16]=[CH:17][C:10]([O:9][C:6](=[O:8])[CH3:7])=[CH:11][CH:12]=2)[CH2:1][CH2:15]1
Reactant: CC[Zn]CC
Reactant: C=Cc1ccc(OC(C)=O)cc1
Solvent: ICI
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
To a solution of diethylzinc (200 mL, 0.220 mol, 1.1 M in toluene) in toluene (270 mL) was added 4-acetoxystyrene (16.8 mL, 0.110 mol) and subsequently diiodomethane (23.0 mL, 0.286 mol). After the reaction mixture was stirred at rt for 5 hours, it was heated at reflux for 12 hours. The reaction was quenched with aqueous 2N HCl. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a brown oil (16.1 g, 83%).
Reaction SMILES: [CH3:1][C:2]([O-])(C)C.[K+].O=[C:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1>C1COCC1>[CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1)[CH3:2]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A solution of Ph3PEtBr (84 g, 227 mmol) and KOtBu (76.7 g, 556 mmol) in THF (1100 mL) was stirred at rt under nitrogen atmosphere for 1 h, and then added (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (50 g, 206 mmol) in THF (350 mL) dropwise. The mixture was stirred at room temperature for 4 hs. TLC showed the reaction was completed. The mixture was quenched with NH4Cl aqueous and concentrated to remove THF, and then dissolved in EtOAc and water. The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE: EtOAc=30:1 to 5:1) to afford (S)-1-tert-butyl 2-methyl 4-ethylidenepyrrolidine-1,2-dicarboxylate (18.3 g, 35%) as yellow oil.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)#[N:2].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O.O>[C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)(=[O:22])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(c1)-c1nc(C#N)cn1CCO2
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (220 mg, 0.82 mmol) was dissolved in 4.0 ml of dimethyl sulfoxide and treated with a solution of potassium carbonate (136 mg, 0.980 mmol) in water (1.60 mL, 88.8 mmol). After cooling at 0° C., hydrogen peroxide (0.751 mL, 9.80 mmol) was added slowly. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with 20 ml of water and extracted with ethyl acetate (3×20 ml). The oprganic extracts were washed with 5% sodium thiosufate, sat. NaHCO3, brine, dried over sodium sulfate and concentrated to give 180 mg (77%) of crude methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. MS (ESI+): 288.0.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>C1COCC1>[CH3:2][O:3][CH:4]=[C:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1
Reactant: O=C1CCOCC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C1CCOCC1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
To a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (24.82 g, 72.41 mmol) in THF (250 mL) cooled in an ice-water bath was added n-BuLi (24.76 mL or 2.42M solution in hexane, 59.93 mmol). The reaction mixture was allowed to warm to room temperature for 1 h and then recooled in an ice-water bath and a solution of tetrahydro-4H-pyran-4-one (5.00 g, 49.94 mmol) in THF (10 mL) added. After 20 min the reaction mixture was concentrated to an oily reside, the residue was triturated with Et2O (150 mL), and the supernatant was decanted. This process was repeated (6×75 mL), and the combined supernatants were concentrated to give crude title compound (7.3 g) as an orange oil. Flash chromatography (10×18 cm) eluting with a gradient (5-10%) of EtOAc/hexane gave the title compound (2.25 g, 35%) as a volatile, colorless oil. TLC: Rf 0.13 (5:95 EtOAc:hexane). 1H NMR: δ 5.85 (s, 1H, vinyl), 3.69-3.61 (m, 4H, CH2OCH2), 3.56 (s, 3H, OCH3), 2.32 and 2.06 (pr t, 4H, 2×CH2).
Reaction SMILES: [CH:1]1[C:9](C(OC)=O)=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:17][CH2:16][CH2:15][CH2:14][N:5]12.C1C=CC=C2C=1C=C1CCCCN12.[C:31](Cl)([Cl:33])=[O:32]>>[Cl:33][C:31]([C:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:17][CH2:16][CH2:15][CH2:14][N:5]12)=[O:32]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)cc1n2CCCC1
Agent: c1ccc2c(c1)cc1n2CCCC1
Product: O=C(Cl)c1cccc2c1cc1n2CCCC1

Procedure:
The methyl ester of Formula III wherein Z is --N(R2)-- and R1 and R2 are together --(CH2)3 --, namely methyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-2-carboxylate, is prepared by reacting 6,7,8,9-tetrahydropyrido[1,2-a]indole with phosgene to form 1-chloroformyl-6,7,8,9-tetrahydropyrido[1,2-a]indole and subsequently converting this product to the methyl ester. A more detailed description of this procedure is set forth in Example 1 of this application. The 6,7,8,9-tetrahydropyrido[1,2-a]indole may be prepared via an intramolecular Wittig reaction (M. D. Crenshaw and H. Zimmer, J. Heterocyclic Chem., (1984) 21, 623).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1.[O-]CC.[Na+].[CH3:55][N:56]1[CH:60]=[CH:59][N:58]=[C:57]1[CH2:61][CH2:62][CH:63]=O.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9](/[CH:16]=[CH:63]/[CH2:62][CH2:61][C:57]1[N:56]([CH3:55])[CH:60]=[CH:59][N:58]=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1
Reactant: Cn1ccnc1CCC=O
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(/C=C/CCc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
[6,7-Dimethoxy-4-(3,4-dimethoxyphenyl )-3-ethoxycarbonylquinolin-2-yl]methyltriphenylphosphonium chloride (3.0 g) was added at room temperature to a solution of sodium ethoxide in ethanol (prepared from Na (0.13 g) and ethanol (45 ml)). Then 3-(1-methylimidazol-2-yl)propionaldehyde (0.787 g) was added. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (30/1, v/v) gave ethyl (E)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[2-[2-(1-methylimidazol-2-yl)ethyl]vinyl]quinoline-3-carboxylate (0.36 g, 15%) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]=2[C@@H:6]([CH2:5][C:4]([OH:18])=[O:3])[O:10]1
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(O)cc2c1[C@@H](CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3R)-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.00 g, 4.00 mmol) in THF (9 mL) was added a solution of LiOH (0.479 g, 20.0 mmol) in water (8 mL) at 0° C. The resulting mixture was stirred at room temperature for 1.5 hours then acidified to pH=2 with dilute hydrochloric acid and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM/MeOH/AcOH=20:1:trace) to give pure product as a white powder after lyophilization (0.579 g, 64.9%). 1HNMR (400 MHz, DMSO-d) δ12.26 (s, 1H), 9.25 (s, 1H), 9.04 (s, 1H), 6.86 (d, J=1.95 Hz, 1H), 6.64 (d, J=1.95 Hz, 1H), 5.36 (dd, J=9.76, 2.34 Hz, 1H), 2.98 (dd, J=15.22, 2.34 Hz, 1H), 2.17 (s, 3H), 1.98 (dd, 1H). MS (ESI) m/z=221 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:28])[N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[CH:19])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:28])[N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: Brc1ccccn1
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccccc1F
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1ccccc1F
Yield: 75.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (136 mg, 0.86 mmol) and (2-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (250 mg, 0.86 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 240 mg (0.65 mmol, 76%) of (2-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid-tert-butyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[C:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[C:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][O:14][S:31]([CH3:30])(=[O:33])=[O:32])=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(CCCO)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: -10 °C
Yield: 8.6 %

Procedure:
5-(3-Hydroxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1f (9.20 g, 30 mmol) was dissolved in 150 ml of dichloromethane under stirring, and added with triethylamine (7.0 ml, 50 mmol) to the solution while maintaining the temperature at about −10° C. in an ice-salt bath under an argon atmosphere. Upon completion of the addition, the mixture was added slowly with methanesulfonyl chloride (3.5 ml, 45 mmol). After stirring to mix well, the reaction system was allowed to warm up to room temperature and stirred for 4 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with ice. The reaction mixture was washed successively with dilute hydrochloric acid (0.5 mol/L, 80 ml×2) to remove triethylamine, saturated sodium carbonate solution (80 ml×2) to remove excess hydrochloric acid and saturated brine (80 ml), and concentrated under reduced pressure to obtain the title compound 5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (11.4 g, yield 99%) as a brown oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CC(N(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[C:22]1[CH:29]=[CH:28][CH:27]=[C:24]2[CH2:25][CH2:26][C:23]=12>C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][C:22]1[CH:29]=[CH:28][CH:27]=[C:24]2[CH2:25][CH2:26][C:23]=12
Reactant: Oc1cccc(O)c1
Reactant: Brc1cccc2c1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: Oc1cccc(Oc2cccc3c2CC3)c1
Temperature: 25 °C

Procedure:
Resorcinol (176.2 g, 1.60 moles), dimethylacetamide (DMAC) (550 mL), toluene (75 mL), potassium carbonate (55.2 g, 0.40 moles), 4-bromobenzocyclobutene (73.2 g, 0.40 moles), and cuprous chloride (3.96 g, 0.040 moles) are placed in a 1000 mL 3-necked flask. The flask is equipped with a water separating trap, reflux condenser, nitrogen inlet, and thermometer. The system is purged with nitrogen. The mixture is then heated to reflux, and water and toluene are collected in the trap. Toluene (about 25 mL) is distilled out of the reaction mixture and removed from the trap, until the temperature in the flask reaches 153° C. A sample, removed from the reaction after 5 hours of reflux and analyzed by gas chromatography (GC), shows little bromobenzocyclobutene remaining. The reaction is allowed to cool to room temperature after 6 hours of reflux. During the reaction, the temperature in the flask rises slightly to 156° C. by the end of the reaction.
Reaction SMILES: [C:1]([NH:4][C:5]([C@@H:17]1[CH2:20][C@H:19]([N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH3:36][C:37]1([CH3:44])[C:41]([CH3:43])([CH3:42])[O:40][BH:39][O:38]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]([C@@H:17]1[CH2:18][C@H:19]([N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:20]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:39]1[O:40][C:41]([CH3:43])([CH3:42])[C:37]([CH3:44])([CH3:36])[O:38]1)[C:6]([NH:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)[C@H]1C[C@@H](N(Cc2ccccc2)C(=O)OC(C)(C)C)C1
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@H]1C[C@@H](N(Cc2ccccc2)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
After stirring for 30 min, a solution of cis-tert-butyl 3-(2-acetamido-1-(tert-butylamino)-1-oxohex-5-en-2-yl)cyclobutyl(benzyl)carbamate (5.34 g, 10.5 mmol), chloro-1,5-cyclooctadiene iridium(I) dimer (212 mg, 0.32 mmol, 3 mol %) and 1,2-bis(diphenylphosphino)ethane (252 mg, 0.63 mmol, 6 mol %) in dichloromethane (50 mL) was cooled to 0° C. and carefully treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.1 mL, 21.1 mmol, 2 eq) over 5 min. After slowly warming to room temperature and stirring overnight, the reaction was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 10-40% ethyl acetate in heptane) gave cis-tert-butyl 3-(2-acetamido-1-(tert-butylamino)-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-yl)cyclobutyl(benzyl)carbamate (4.8 g, 7.83 mmol, 74%). ESI MS found for C34H56BN3O6 m/z [614.2 (M+1), 636.2 (M+23)].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:25])[C:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:25])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)[OH:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)C1(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)C1(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}propanoyl)cyclopropanecarboxylate (1.66 g) in methanol (25 mL) was cooled to 0° C., 90% sodium borohydride (305 mg) was added, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/1) to give the title compound as a colorless oil (yield: 1.58 g, 94%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=[O:20]>CO>[CH2:7]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(C=O)cc1OCc1ccccc1

Procedure:
1.2 equivalents of K2CO3 and 1.2 equivalents of benzyl bromide are added to a suspension of 0.33 mol of 3-hydroxy-4-methoxybenzaldehyde in 400 ml of methanol. After 24 hours' reflux, the reaction mixture is filtered while hot and the organic phase is then evaporated off under reduced pressure. The isolated residue is taken up in 300 ml of chloroform and then washed with water. After extraction, drying and filtration, evaporating off the organic phase under reduced pressure allows the expected product to be isolated.
Reaction SMILES: [H-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:14]1[O:19][CH2:18][CH2:17][O:16][N:15]=1)=[CH:11][O:12][CH3:13].[O:20]([C:27]1[C:32]([F:33])=[C:31](F)[N:30]=[CH:29][N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[O:20]([C:27]1[C:32]([F:33])=[C:31]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([C:14]2[O:19][CH2:18][CH2:17][O:16][N:15]=2)=[CH:11][O:12][CH3:13])[N:30]=[CH:29][N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1ncnc(Oc2ccccc2)c1F
Reactant: COC=C(C1=NOCCO1)c1ccccc1O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC=C(C1=NOCCO1)c1ccccc1Oc1ncnc(Oc2ccccc2)c1F
Temperature: 20 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
0.119 g of potassium hydride (60% suspension in mineral oil) is added to a solution of 0.7 g (0.00298 mol) of 3-[1-(2-hydroxyphenyl)-2-methoxyethen-1-yl]-5,6-dihydro-1,4,2-dioxazine and 0.6 g (0.00288 mol) of 4-phenoxy-5,6-difluoro-pyrimidine in 10 ml of dimethylformamide at 0° C., and the mixture is then stirred for 12 hours at 20° C. The reaction mixture is poured into water and extracted using ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (1:1). 0.4 g (82% of theory) of 3-{1-[2-(4-phenoxy-5-fluoropyrimid-6-yloxy)-phenyl]-2-methoxyethen-1-yl}-5,6-dihydro-1,4,2-dioxazine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]([Cl:33])=[O:10])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:4]=1
Reactant: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carboxylic acid (126 mg, 0.37 mmol) from Step A and a drop of DMF (cat.) in methylene chloride (5 mL) was added oxalyl chloride (0.16 mL, 1.85 mmol). The reaction was stirred at rt for 2 h and was then evaporated to dryness in vacuo. The crude acid chloride was used directly in the subsequent amide formations.