Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH:5][C:28]([C:27]1[C:26]([Cl:25])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:35])=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
To a suspension of 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.128 mmol, 47 mg) and 2,6-dichlorobenzoyl chloride (0.153 mmol, 32 mg) in dichloromethane (1 mL) was added diisopropylethylamine (0.45 mmol, 77 uL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting brown solution was diluted with dichloromethane (25 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×25 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 52 mg (81% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C24H23Cl2N3O5 (M+Na) 526.0907, found 526.0912.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13](=[O:15])[CH2:12][C:11](=[O:16])[N:10]2[CH2:17][C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH:5]=[C:6]([F:8])[CH:7]=1>CO>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13](=[O:15])[CH2:12][C:11](=[O:16])[N:10]2[CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(CN1C(=O)CS(=O)C[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Solvent: CO
Product: O=C(O)CN1C(=O)CS(=O)C[C@H]1c1cc(F)cc(F)c1
Reaction time: 2.25 h

Procedure:
A solution of benzyl [(3R)-3-(3,5-difluorophenyl)-1-oxido-5-oxothiomorpholin-4-yl]acetate (24.5 mg, 0.062 mmol, minor isomer, from the preparation of Intermediate 4, Step B) in MeOH (2 mL) was purged with nitrogen. The septum sealing the reaction vessel was briefly removed to allow introduction of Pd/C (˜6 mg, 10% Pd/C). The vessel was then purged with hydrogen from a balloon, before a fresh balloon of hydrogen was attached. After LCMS analysis indicated that the reaction was progressing slowly, a suspension of 10% Pd/C was introduced via syringe. After 2.25 hours the hydrogen atmosphere was replaced with nitrogen. The mixture was then filtered through a pad of celite, washing with MeOH as needed. The filtrate was concentrated in vacuo to provide the title compound, which was used without further purification. MS: m/z=304 (M+1).
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16]=2[OH:17])(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[OH:17][C:16]1[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13][C:12]=1[S:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)c2oc3ccccc3c2O)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)c2oc3ccccc3c2O)n[nH]1
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6-(3-hydroxy-benzofuran-2-sulfonyl)-pyridazine (2.7 mmol, 820 mg), conc. HCl (2 mL), and dioxane (10 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. The dried residue was extracted with EtOAc (2×20 mL). The extract was dried, filtered, and the filtrate was evaporated to a residue, which was purified by silica gel chromatography (eluent: EtOAc:n-hexanes::3:1), triturated with water (10 mL), and filtered to obtain the desired product: 6-(3-hydroxy-benzofuran-2-sulfonyl)-2H-pyridazin-3-one (35%, 284 mg); mp 186° C.-189° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@@H:28]([N:36]=[N+]=[N-])[C@H:27]([O:39][C:40](=[O:42])[CH3:41])[C@H:26]1[O:43][C:44](=[O:46])[CH3:45])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@@H:28]([NH2:36])[C@H:27]([O:39][C:40](=[O:42])[CH3:41])[C@H:26]1[O:43][C:44](=[O:46])[CH3:45])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](N)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 95 %

Procedure:
4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-2,3,6-tri-O-acetyl-β-D-glucopyranosyl azide (178 mg, 0.26 mmol) was dissolved in MeOH (5 ml) and hydrogenated over Pd/C (10%) (10 mg) for 5 h. The suspension was filtered, and the filtrate was evaporated to give 4-O-(2,3,4,6-tetra-O-acetyl-α-D-galacto-pyranosyl)-2,3,6-tri-O-acetyl-β-D-glucopyranosyl amine (26) (157 mg, 92%).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](=[NH:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:46][O:47][C:48]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][C:49]=1[C:50](O)=[O:51]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9]/[C:8](=[N:10]\[C:50](=[O:51])[C:49]2[CH:53]=[C:54]([C:57]([F:59])([F:60])[F:58])[CH:55]=[CH:56][C:48]=2[O:47][CH3:46])/[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\oc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of Example 66A (100 mg, 0.45 mmol) in tetrahydrofuran (4 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (85.0 mg, 0.45 mmol), 1-hydroxybenzotriazole (68.3 mg, 0.45 mmol), triethylamine (93 μL, 0.67 mmol) and 2-methoxy-5-trifluoromethylbenzoic acid (Alfa) (98.0 mg, 0.45 mmol). The mixture was stirred at 60° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with 1 M aqueous NaHCO3, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to provide the title product. MS (ESI+) m/z 428 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.15-1.19 (m, 1H), 1.20 (s, 9H), 1.61-1.72 (m, 1H), 1.83-1.96 (m, 2H), 2.02-2.15 (m, 1H), 3.68 (dd, J=14.3, 7.1 Hz, 1H), 3.75-3.87 (m, 2H), 3.89 (s, 3 H), 4.02-4.12 (m, 1H), 4.14-4.25 (m, 1H), 6.53 (s, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.4 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[NH2:16].CN1CCN(C)C2C=NC=CC1=2.[K+].[Br-]>C(O)C.CCOC(C)=O.CCCCCC>[CH:11]1[C:10]2=[N:9][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[N:16]=[C:15]2[CH:14]=[CH:13][N:12]=1
Reactant: Nc1ccncc1N
Reactant: O=C1CCCCC1=O
Agent: CN1CCN(C)c2cnccc21
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: c1cc2nc3c(nc2cn1)CCCC3
Temperature: 70 °C
Reaction time: 36 h

Procedure:
1,2-Cyclohexanedione (1.52 g, 13.93 mmol) was added to a suspension of 1.56 g (13.93 mmol) of 3,4-diaminopyridine in 50 ml of ethanol. The reaction mixture was subsequently heated at an oil bath temperature of 70° C. for 5 hours, then cooled to room temperature and the solvent was then distilled off on a rotary evaporator. The product obtained was purified by flash chromatography using ethyl acetate as eluent. This gave 1.84 g (71%) of a white solid which was stored in a refrigerator and processed further after 1-2 days. Allowing the solid to stand in an open flask in sunlight resulted in the color changing to greyish green. Rf=0.25 (EtOAc/hexane, 20:1). 1H NMR: (200 MHz, CDCl3): δ=2.05 (m, 4H, H-7,8), 3.18 (m, 4H, H-6,9), 7.79 (d, 3J=5.8 Hz, 1H), 8.72 (d, 3J=5.8 Hz, 1H), 9.38 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ=22.8 (CH2, C-7,8), 33.7 (CH2, C-6,9), 121.2 (CH), 136.9 (Cq), 144.1 (Cq), 146.8 (CH), 153.9 (CH), 156.8 (Cq) 159.9 (Cq) ppm. GC-MS (EI): RT 8.44 min, m/e (%) 186 (11), 185 (M+, 100), 184 (39), 183 (3), 182 (3), 171 (2), 170 (21), 169 (4), 158 (2), 157 (5), 156 (5) 131 (2), 104 (2), 103 (4), 78 (3), 76 (4), 67 (2), 64 (2), 51 (2), 50 (6); IR (KBr): ν=3435 (vs), 2947 (s), 2864 (m), 1594 (s), 1557 (w), 1461 (w), 1421 (m), 1385 (s), 1365 (w), 1330 (w), 1297 (m), 1211 (m), 1140 (w), 979 (m), 949 (w), 901 (m), 849 (m), 679 (w), 629 (w), 570 (w), 412 (w) cm−1. HRMS (EI): calculated for C11H11N3 185.0953 [M+], found: 185.0935
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][NH:5][NH:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[C:12]1([CH2:11][O:9][C:8](=[O:10])[CH2:7][NH:6][NH:5][CH:4]=[N:3][NH2:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN=CNNCC(=O)O
Reactant: OCc1ccccc1
Agent: Cl
Product: NN=CNNCC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
HCl (g) was bubbled through a suspension of [2-(aminoiminomethyl)hydrazino]-acetic acid (2.00 g, 15.2 mmol) in benzyl alcohol (30 mL). The reaction was stirred for about an hour until everything was in solution. The crude product was precipitated out by adding Et2O. This material was recrystallized from MeOH/EtOAc to yield [2-(aminoiminomethyl)hydrazino] acetic acid phenylmethyl ester monohydrochloride (3.20 g, 82%) as a white crystalline solid. MP: 162-164 ° C. 1H NMR (CD3OD): δ 3.69 (s, 2H), 5.24 (s, 2H), 7.34-7.42 (m, 5H).
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][O:8][B:7]([OH:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[C:58]([NH:62][NH2:63])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C>[C:58]([NH:62][NH:63][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[B:7]([OH:11])[O:8][CH2:9][C:10]=2[C:2]=1[F:1])=[O:14])([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)NN
Reactant: O=C(O)c1ccc2c(c1F)COB2O
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: CN(C)C=O
Product: CC(C)(C)NNC(=O)c1ccc2c(c1F)COB2O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Following the general procedure, mixed together 4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxylic acid (0.500 g, 2.55 mmol), PyBOP (1.34 g, 2.55 mmol), DIEA (0.89 mL, 5.10 mmol) in DMF (6 mL) followed by the addition of tert-butyl hydrazine hydrochloride (0.318 g, 2.55 mmol) and stirred the mixture at 40° C. for 1 h. LCMS showed a main peak at 2.43 with the expected product mass of 267.01 (M+1). After the general work up procedure, the crude dry sample (SKC-07-069, 0.800 g, contains some DMF) was used for the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:19])[CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][OH:2])=[CH:6][C:7]=1[F:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccc(OCc2ccccc2)c(F)c1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of (4-benzyloxy-3-fluoro-phenyl)-acetic acid methyl ester (7.1 g, 25.7 mmol) in ether (150 mL), was LAH (1.07 g, 28.3 mmol) added portionwise at 0° C. The reaction mixture stirred for 2 hours at the same temperature. The reaction was quenched with H2O (5 mL) at 0° C. The solid material was filtrated off and washed with ether (50 mL). The ether was dried over MgSO4 and concentrated under vacuum to afford the desired compound (5.2 g, 82%) as a white solid. The crude compound was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.34-7.48 (m, 5H), 7.09-7.17 (m, 2H), 6.96-6.98 (m, 1H), 5.17 (s, 2H), 4.66 (s, 1H), 3.60 (b, 2H), 2.68 (m, 2H). LCMS 246.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.S(=O)(=O)(O)O.[Br:17]Br>S([O-])([O-])(=O)=O.[Ag+2]>[Br:17][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:11])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: O=[N+]([O-])c1cc(Br)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of 4-chloro-2-fluoronitrobenzene (1.00 g), silver sulfate (1.95 g) and concentrated sulfuric acid (5 ml), bromine (0.32 ml) was added under ice cooling and the resulting mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h. The reaction mixture was put into ice water and subjected to extraction with ether. The organic layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution sequentially, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 1.38 g of the titled compound (yield, 95%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:24][NH:25][CH2:26][CH2:27][CH3:28]>>[CH3:24][N:25]([CH2:26][CH2:27][CH3:28])[C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:23])[F:22])=[N:4]2)=[CH:13][CH:14]=1
Reactant: CCCNC
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: CCCN(C)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-methylpropylamine using a similar procedure to that described for Example 2, product further purified by mass directed auto-prep.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.[I:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>CN(C=O)C>[I:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(I)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Nc2cccc(I)c2)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 57.5 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitril (1.82 g, 10 mmol) in dry DMF (25 ml) is added triethylamine (1.54 ml, 11 mmol) and 3-iodoaniline (1.2 ml, 10 mmol) and the mixture is heated to 80-100° C. over night. After cooling the mixture is poured into four volumes of ice-water. The precipitate is filtered off, washed with water and dried. This crude product is washed with hot ethanol to yield 2.1 g (58%) of the title compound. Mp. 211-212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1.CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[C:9]3[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=2)[CH:22]=[CH:26][CH:25]=[CH:24]1
Reactant: Nc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=C(O)c1cc2ccccc2n1-c1ccc(-n2cccc2)cc1
Yield: 0 %

Procedure:
A solution of 1-(4-aminophenyl)-1H-indole-2-carboxylic acid (0.4 g, 1.59 mmol) and 2,5-dimethoxytetrahydrofuran (0.50 g, 3.78 mmol) in 15 mL of glacial acetic acid was heated at 90° C. for 1.5 hours. After removing the solvent the residue was purified by by semi-preparative HPLC to afford the title compound (0.095 mg, 20%) as a beige solid: 1H NMR (DMSO-d6) δ 6.32 (s, 2H), 7.08 (d, J=8.4 Hz, 1H), 7.15-7.25 (m, 1H), 7.25-7.35 (m, 1H), 7.40-7.55 (m, 5H), 7.60-7.70 (m, 3H), 12.82 (br s, 1H); MS (ESI) m/z 303 (MH+); MS (ESI) m/z 301 ([M−H]−); HRMS calcd for C19H15N2O2: 303.1122; found (ESI+): 303.1124; Anal. calcd for C19H14N2O2.0.1H2O: C, 75.0; H, 4.71; N, 9.21. Found: C, 74.90; H, 4.42; N, 9.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.[H-].[Na+].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[O-]S(C(F)(F)F)(=O)=O.[CH3:50][O:51][C:52]1[CH:60]=[C:59]2[C:55]([CH2:56][N:57]([CH:61]3[CH2:64][O:63][CH2:62]3)[CH2:58]2)=[CH:54][C:53]=1[NH2:65]>CN(C)C=O>[CH3:50][O:51][C:52]1[CH:60]=[C:59]2[C:55]([CH2:56][N:57]([CH:61]3[CH2:62][O:63][CH2:64]3)[CH2:58]2)=[CH:54][C:53]=1[NH:65][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Reactant: COc1cc2c(cc1N)CN(C1COC1)C2
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4OC)n3n1)CN(C1COC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (50.00 mg, 0.207) was dissolved in N,N-Dimethylformamide (4.0 mL) at 0° C. and sodium hydride (60% dispersion in mineral oil; 10.4 mg, 0.259 mmol) was added and the reaction was let to stir for 30 minutes. Then, N-phenylbis(trifluoromethanesulphonimide) (81.4 mg, 0.228 mmol) was added and the reaction was allowed to warm to room temperature. After 100% conversion to the triflate, 6-methoxy-2-oxetan-3-yl-2,3-dihydro-1H-isoindol-5-ylamine (57.1 mg, 0.259 mmol 1) was added the reaction was allowed to stir at room temperature. The reaction mixture was partitioned between dichloromethane and saturated aqueous Na2CO3. The aqueous layer was extracted with dichloromethane, the combined organics were dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the product was isolated by preparative reverse phase hplc (Gilson) as a brown foam (11 mg, 12%). 1H-NMR (CDCl3) δ 8.70 (s, 1H), 8.27 (s, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.51 (br s, 1H), 7.42 (m, 1H), 7.08 (m, 2H), 7.02 (d, J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H) 6.74 (br s, 1H), 4.78 (m, 4H), 4.09 (m, 1H), 3.95 (br s, 2H), 3.89 (s, 3H), 3.85 (br s, 2H), 3.83 (s, 3H); LC/MS (ESI+): 444.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([Cl:27])[CH:3]=1.C([Li])CCC.CCCCCC.[CH:39](N1CCCCC1)=[O:40].[Cl-].[NH4+]>O1CCCC1>[O:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:39]=[O:40])=[CH:3][C:4]=1[Cl:27])[Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CN1CCCCC1
Reactant: CC(C)(C)[Si](OCc1ccc(Br)cc1Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1ccc(C=O)cc1Cl)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
To a solution of 4-bromo-1-((tert-butyldiphenylsiloxy)methyl)-2-chlorobenzene (8.65 g) in tetrahydrofuran (22 ml) was added 1-butyl lithium/hexane solution (1.54M, 13.5 ml) at −75° C. in a nitrogen atmosphere, and the mixture was stirred for 15 min. The reaction mixture was once heated to 10° C. and again cooled to −75° C. and 1-formyl piperidine (2.55 g) was added dropwise over 10 min. The reaction mixture was heated to room temperature over 3 hr. To the reaction mixture was added aqueous ammonium chloride solution and the resulting product was extracted twice with hexane. The organic layers were combined, washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was applied to silica gel column chromatography (hexane/ethyl acetate=40/1) to give 4-((tert-butyldiphenylsiloxy)methyl)-3-chlorobenzaldehyde (3.26 g) as a pale-yellow oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:35]#[N:36])[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])=[O:21])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:35]([CH:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=1)[C:20]([N:22]([CH:32]1[CH2:34][CH2:33]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[Cl:31])=[O:21])#[N:36]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(CC(C#N)C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#CC(Cc1ccc(CCCO)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)phenyl]-2-cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)propanamide from the previous step (1 eq.) in THF (0.1 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 1.5 eq.). The resulting reaction mixture was stirred at RT for 3 h. After quenching the reaction with 10% aq. HCl, the mixture was extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 10:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH:1]([O:3][C@H:4]([C@@H:6]1[C@:14]2([CH3:15])[C@H:9]([C@@H:10]([OH:16])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)[CH3:5])=[O:2]>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]([O:3][C@H:4]([C@@H:6]1[C@:14]2([CH3:15])[C@H:9]([C:10](=[O:16])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)[CH3:5])=[O:2]
Reactant: C[C@H](OC=O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Product: C[C@H](OC=O)[C@H]1CC[C@H]2C(=O)CCC[C@]12C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
Under a nitrogen atmosphere, a solution of (S)-1-{(3S,3aS,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-indene-3-yl}ethyl formate (Compound 16: 899.6 mg, 3.975 mmol) in acetonitrile (10 ml) was cooled in an ice bath, and tetra-n-propylammonium perruthenate (35 mg, 0.0994 mmol) was added thereto. The reaction mixture was stirred in the ice bath for 3 minutes, and at room temperature (23° C.) for 45 minutes. The reaction mixture was filtered through Celite, and the resulting mixture was washed with ethyl acetate, followed by evaporation under reduced pressure. The crude product was purified by flash column chromatography to obtain (S)-1-{(3S,3aR,7aR)-octahydro-3a-methyl-7-oxo-1H-indene-3-yl}ethyl formate (865.1 mg).