Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH3:8])[CH2:3][CH3:4].[CH2:11]([N:13]([CH2:25][CH3:26])[C:14](=[O:24])[C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1)[CH3:12]>>[CH3:4][CH:3]([O:21][C:20]1[CH:22]=[CH:23][C:15]([C:14]([N:13]([CH2:25][CH3:26])[CH2:11][CH3:12])=[O:24])=[CH:16][C:17]=1[O:18][CH3:19])[CH2:2][CH2:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH3:8]
Reactant: CCC(Br)CC(C)=C(C)C
Reactant: CCN(CC)C(=O)c1ccc(O)c(OC)c1
Product: CCN(CC)C(=O)c1ccc(OC(C)CCC(C)=C(C)C)c(OC)c1

Procedure:
2-bromo-1,4,5-trimethyl-hex-4-ene was reacted with vanillic acid N,N-diethyl amide to obtain p-[(1,4,5-trimethyl-hex-4-enyl)-oxy]-m-methoxy-N,N-diethyl-benzamide (boiling point = 160°-162°C/0.02 mmHg, nD28 = 1.5185);
Reaction SMILES: CC(O)=O.[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:32]([O:34][CH3:35])=[O:33])=[CH:16][C:17]=3[N:18]3[C:25]=2[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH2:21][C@H:20]([NH:30][CH3:31])[CH2:19]3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:36][CH2:37]C=O.[BH3-][C:41]#N.[Na+]>CO>[Cl:36][CH2:37][CH2:31][N:30]([CH3:41])[C@@H:20]1[CH2:19][N:18]2[C:17]3[CH:16]=[C:15]([C:32]([O:34][CH3:35])=[O:33])[CH:14]=[CH:13][C:12]=3[C:11]([CH:5]3[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)=[C:25]2[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1
Reactant: O=CCCl
Reactant: [BH3-]C#N
Reactant: CN[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCCl)COc1ccccc1-3
Temperature: 60 °C

Procedure:
HOAc (cat.) was added to a stirred mixture of methyl (7R)-14-cyclohexyl-7-(methylamino)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 1, Step 5) (0.03 M) and chloroacetaldehyde (50 wt % in water; 1.5 eq) in MeOH. NaCNBH3 (1.5 eq) was introduced and the reaction heated at 60° C. for 2 h. The reaction was allowed to cool to RT and partitioned between water and EtOAc. The organics were washed with saturated NaHCO3 (aq), brine before being dried (Na2SO4) filtered and concentrated in vacuo. The material was taken on without further purification. (ES+) m/z 480 (M+H)+; 482 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.COC(C)(C)C>[CH2:14]([O:13][C:11]([C:10]1[C:9]([CH3:16])=[N:8][N:7]2[C:2]([O:1][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])=[CH:3][C:4]([CH3:17])=[CH:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Reactant: CC(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 180 mg (0.768 mmol) of 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 8A in 7 ml of dry tetrahydrofuran was admixed with 0.167 ml (1.537 mmol) of 3-methylbutan-1-ol (CAS 123-51-3), 423.2 mg (1.614 mmol) of triphenylphosphine and 0.32 ml (1.614 mmol) of diethyl azodicarboxylate. The resulting mixture was stirred at room temperature for 1 h. Some of the solvent was drawn off under reduced pressure and the residue was admixed with 5 ml of tert-butyl methyl ether. The resulting precipitate was filtered off and the mother liquor was partitioned between dichloromethane (15 ml) and water (10 ml). The organic phase was removed and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 225 mg (69% of theory, 72% pure) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (52 mg, 45%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:41])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:41])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:35]5[CH2:36][CH2:37][CH2:38][CH2:39]5)[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCCC4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(N4CCCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (5-methyl-2-{3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M291) (311 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (154 mg, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:13][CH:12]=[C:11]([O:22]CCCCl)[CH:10]=1)[C:2]1[CH:7]=CC=CC=1.C([C:29]1[CH:45]=[CH:44][CH:43]=[CH:42][C:30]=1[O:31][C:32]1[C:33]([CH2:39][CH2:40][CH3:41])=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1)#N.[I-].[K+].[C:48](=[O:51])([O-])[O-:49].[K+].[K+]>CC(=O)CC.CCOCC.CS(C)=O>[OH2:8].[CH2:13]([C:14]1[CH:15]=[C:16]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[C:11]([OH:22])=[CH:10][C:9]=1[O:8][CH2:1][CH2:2][CH2:7][O:38][C:34]1[C:33]([CH2:39][CH2:40][CH3:41])=[C:32]([CH:37]=[CH:36][CH:35]=1)[O:31][C:30]1[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=1[C:48]([OH:49])=[O:51])[CH3:12]
Reactant: CCCc1c(O)cccc1Oc1ccccc1C#N
Reactant: ClCCCOc1ccc(CCc2ccsc2)c(OCc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccsc3)cc2CC)cccc1Oc1ccccc1C(=O)O
Product: O
Temperature: 25 °C
Yield: 147.3 %

Procedure:
A mixture of 4-(benzyloxy)-2-(3-chloropropoxy)-5-(thiophen-3-yl)ethylbenzene (1.25 g, 3.23 mmol), 3-(2-cyanophenoxy)-2-propylphenol (0.82 g, 3.2 mmol), potassium iodide (0.21 g, 1.3 mmol), potassium carbonate (1.12 g, 8.08 mmol), and methyl sulfoxide (2 mL) in 2-butanone (10 mL) was refluxed for 60 h. The mixture was cooled to room temperature, diluted with ether, and washed with water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 5% ethyl acetate/95% hexane) of the residue provided 1.31 g (67%) of the title product as a colorless oil. 1H NMR (CDCl3) δ 7.66 (d, J=7.8. Hz, 1H), 7.57 (d, J=2.9 Hz, 1H), 7.48 (d, J=5.2 Hz, 1H), 7.45-7.25 (m, 8H), 7.20 (t, J=8.2 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.64 (s, 1H), 6.63 (d, J=6.4 Hz, 1H), 5.11 (s, 2H), 4.26 (t, J=6.0 Hz, 2H), 4.22 (t, J=6.0 Hz, 2H), 2.65 (m, 4H), 2.36 (quintet, J=5.9 Hz, 2H), 1.58 (hextet, J=7.5 Hz, 2H), 1.24 (t, J=7.5 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS FD m/e 603 (p); IR (CHCl3, cm−1) 2967, 2250, 1613, 1501. Anal. Calcd for C38H37NO4S: C, 75.59; H, 6.18; N, 2.32. Found: C, 74.65; H, 6.21; N, 2.57.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:38])[C:28]=1[N:29]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[N:30]1)[O:5][CH:6]([C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].O.O1CCCC1.O.[OH-].[Li+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:38])[C:28]=1[N:29]1[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[N:30]1)[O:5][CH:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:24][CH:25]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a flask containing ethyl 3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoate (117 mg, 0.22 mmol) was added water (0.55 mL), tetrahydrofuran (0.55 mL), and methanol (0.55 mL). Lithium hydroxide monohydrate (508 mg, 12.1 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was concentrated and acidified to pH=3 with citric acid (10%). A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (+/−)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (90 mg, 81%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 7.88 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J=8.4 Hz, 2H), 6.80 (t, J=5.9 Hz, 1H), 6.56 (s, 2H), 5.16 (dd, J=7.8, 5.1 Hz, 1H), 3.71 (q, J=5.9 Hz, 2H), 2.69 (t, J=5.8 Hz, 2H), 2.04-1.91 (m, 1H), 1.88 (s, 6H), 1.86-1.67 (m, 1H), 1.63-1.31 (m, 2H), 0.96 (t, J=7.3 Hz, 3H). MS (M+1): 504.
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[CH2:14]([CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O[K])(C)(C)C.O>COCCOC.C(O)C>[CH2:14]([CH:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[C:11]#[N:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC1CCCC1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CCCCCCCC1CCCC1C#N
Temperature: 0 °C
Yield: 63.2 %

Procedure:
27.6 g of tosylmethyl isocyanide and 20 g of 2-heptylcyclopentanone were dissolved in 400 ml of 1,2-dimethoxyethane and 10 ml of ethanol. The solution was cooled to 0° C. with an ice-bath, and 29 g of tBuOK were added in 1 hour maintaining the temperature between 0 and 10° C. After completion of the reaction, the reaction mixture was poured into water and extracted with cyclohexane. The organic layer was washed 3 times with water until neutral pH. Purification by bulb-to-bulb distillation (150° C./0.06 mbar) gave 13.4 g of the pure 2-heptylcyclopentanecarbonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:7][CH2:6][CH2:5]1.[C:8](N1C=CN=C1)(N1C=CN=C1)=[O:9].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([C:8]([NH:1][CH2:2][CH2:3][N:4]3[CH2:7][CH2:6][CH2:5]3)=[O:9])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCN1CCC1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: O=C(NCCN1CCC1)N1CCN(c2ccccc2)CC1

Procedure:
Following the procedure of Example 5, N-(2-aminoethyl)azetidine and 1,1'-carbonyldiimidazole are reacted together in tetrahydrofuran and the product thereof is reacted further with 1-phenylpiperazine to give the title compound.
Reaction SMILES: N1C=CC=CC=1.CS(C)=O.Cl[S:12]([C:15]1[N:25]=[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([Cl:23])[N:17]2[N:16]=1)(=[O:14])=[O:13].[NH2:26][C:27]1[C:28]([C:35]([F:38])([F:37])[F:36])=[N:29][N:30]([CH2:33][CH3:34])[C:31]=1[CH3:32]>C(#N)C>[CH2:33]([N:30]1[C:31]([CH3:32])=[C:27]([NH:26][S:12]([C:15]2[N:25]=[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([Cl:23])[N:17]3[N:16]=2)(=[O:14])=[O:13])[C:28]([C:35]([F:37])([F:36])[F:38])=[N:29]1)[CH3:34]
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Cl)nc2c1
Reactant: CCn1nc(C(F)(F)F)c(N)c1C
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CS(C)=O
Product: CCn1nc(C(F)(F)F)c(NS(=O)(=O)c2nc3cc(C)cc(Cl)n3n2)c1C
Reaction time: 18 h

Procedure:
Pyridine (0.31 g (3.9 mmol)) and dimethyl sulfoxide (0.03 g (0.4 mmol)) were added to a solution of 1.0 g (3.9 mmol) of 2-chlorosulfonyl-5-chloro-7-methyl-[1,2,4]triazolo[1,5-a]pyridine and 0.76 g (3.9 mmol) of 4-amino-1-ethyl-5-methyl-3-(trifluoromethyl)pyrazole in 15 mL of acetonitrile at ambient temperature with stirring. After 18 hours, the volatiles were removed by evaporation under reduced pressure and the residue was partitioned between dichloromethane and water, stirring for 10 min before separation. The solids were recovered by filtration and washed with ether. They were then resuspended in water and the mixture stirred for 30 min. The solids were recovered by filtration, washed with ether, and dried under reduced pressure at 40° C. overnight. The resulting 1.24 g (68 percent of theory) of white powder melting at 224°-226° C. was the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][C:13]=1[F:26])[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C.O>CN(C)C(=O)C>[CH:27]1([C:30]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:14][C:13]=2[F:26])[N:5]=3)=[O:31])[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc3nc(N)sc3n2)c(F)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.7 %

Procedure:
To a solution of tert-butyl {4-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-3-fluorophenyl}carbamate (2.02 g, 5.37 mmol) in N,N-dimethylacetamide (20.2 mL) were added cyclopropanecarbonyl chloride (0.97 mL, 10.7 mmol) and triethylamine (2.24 mL, 16.1 mmol), and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, methanol (20 mL) and 5% aqueous sodium carbonate solution (10 mL) were added to the residue, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (=1/1) and collected by filtration to give the title compound (1.33 g, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[Br-].[CH2:19]([O:21][C:22](=[O:25])[CH2:23][Zn+])[CH3:20]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])([OH:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: O=c1c2cc(I)ccc2oc2ncc(Br)cc12
Reactant: CCOC(=O)C[Zn+]
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)c2cc(I)ccc2Oc2ncc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of tetraethoxytitanium (3.40 g, 14.93 mmol) in THF (16.58 ml) was added 3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-one (2.00 g, 4.98 mmol). The suspension was cooled to 0° C. and (2-ethoxy-2-oxoethyl)zinc(II) bromide (149 ml, 14.93 mmol) was added drop wise. The reaction mixture was allowed to warm to RT and stirred 1 h. The reaction mixture was quenched with aqueous, half-saturated NaHCO3 solution (20 mL) and stirred for 30 min. The solution was filtered through a pad of celite and the filter cake was rinsed with EtOAc. The organic layer was separated and concentrated under reduced pressure to afford ethyl 2-(3-bromo-5-hydroxy-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate as a yellowish solid.
Reaction SMILES: [N:1]1([C:9]([O:11]C(C)(C)C)=O)[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Cl.[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([NH-:29])[CH:20]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.CN1CCCC1=O>[CH2:22]1[CH2:21][NH:29][C@H:24]([C:9]([N:1]2[C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][CH2:8]2)=[O:11])[CH2:23]1.[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([NH-:29])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: COc1cc([NH-])cc2ccccc12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Pro (32 mg, 0.15 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluoronium tetrafluoroborate (53 mg, 0.15 mmol) and Pro-4-methoxy-β-naphthylamide hydrochloride (46 mg, 0.15 mmol) were dissolved in anhydrous N,N-dimethylformamide/tetrahydrofuiran 1:1 (4 ml). N-ethyldiisopropylamine (0.26 ml, 0.44 mmol) dissolved in N-methylpyrrolidone (1.7 molar) was added and the mixture was stirred at room temperature overnight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Brc1ccc(-c2cc[nH]n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccn(C3CCCCO3)n2)cc1
Yield: 94 %

Procedure:
To a heated (80° C.) solution of 3-(4-bromophenyl)-1H-pyrazole (1.0 g, 4.5 mmol) and trifluoroacetic acid (0.02 mL, 0.23 mmol) in toluene (5 mL) was added 3,4-dihydro-2H-pyran (0.43 mL, 4.7 mol) over 1 hour. The reaction mixture was stirred for an additional hour and was then concentrated and dried to provide 3-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.3 g, 94% yield). MS (EI) for C14H15BrN2O: 308 (MH+).
Reaction SMILES: ClCCCl.[NH2:5][C:6]1[C:7]([OH:13])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:12][CH:10]1[CH2:9][NH:8][CH:7]([OH:13])[CH:6]([NH:5][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cc(Cl)cnc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC2CC(Cl)CNC2O)CC1
Yield: 62.1 %

Procedure:
To a 1,2-dichloroethane suspension (177 ml) of 3-amino-5-chloropyridin-2-ol (8.85 g) and tert-butyl 4-oxopiperidine-1-carboxylate (24.4 g) was added sodium triacetoxyborohydride (26.0 g), followed by stirring under heating at reflux for 4 hours. Tert-butyl 4-oxopiperidine-1-carboxylate (12.4 g) and sodium triacetoxyborohydride (13.7 g) were further added, and stirred under heating at reflux for 2 hours. After the reaction solution was brought back to room temperature, water and dichloromethane were added, and the solution was separated. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[(5-chloro-2-hydroxypiperidin-3-yl)amino]piperidine-1-carboxylate (12.7 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:4]=2[O:3]1.C(Cl)(=O)OCC.[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH2:31]>CN(C)C=O.CC(C)=O.C(N(CC)CC)C>[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH:31][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=1)=[O:13]
Reactant: CN1CCCC1CN
Reactant: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)O)c2O1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)NCC3CCCN3C)c2O1
Reaction time: 15 h

Procedure:
2-Methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid, 5.0 g, is dissolved in a mixed solvent of 50 ml of dimethylformamide and 50 ml of acetone, 6.5 ml of triethylamine is added and the solution is stirred. Under cooling at 15°-18° C., 2.2 g of ethyl chlorocarbonate is added dropwise for 10 minutes, and the solution is stirred at room temperature for one hour. Thereafter, 2.7 g of 1-methyl-2-aminomethylpyrrolidine is added and the whole is stirred at room temperature for 3 hours and allowed to stand for 15 hours. Excess triethylamine and acetone are distilled off under reduced pressure and the resulting residue is poured into 300-400 ml of water. The aqueous layer is extracted via with chloroform three times and the extract layer is washed with aqueous sodium bicarbonate solution, water and sodium chloride saturated water in this sequence. After drying, the chloroform is distilled off under reduced pressure and the residue obtained is recrystallized from ethyl acetate to give crystals of N-(1-methyl-2-pyrrolidinyl-methyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 187°-189° C.
Reaction SMILES: [CH3:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Cl:15]N1C(=O)CCC1=O.[ClH:23]>C(#N)C>[Cl:23][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14](=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[CH:2]([CH3:1])[C:3]=2[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cl
Reactant: CC1c2ccccc2-c2ccccc21
Solvent: CC#N
Product: CC1c2cc(Cl)ccc2-c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
9-Methylfluorene (43.6 g, 0.24 mol) and N-chlorosuccinimide (64.5 g, 0.48 mol) were suspended in 25 mL of acetonitrile and cooled in an ice-water bath. Then 20 mL of concentrated HCl was added dropwise and the solution was stirred at room temperature overnight. The precipitate was filtered and dried. Recrystallization from EtOH and water gave 24 g (41%) of 2,7-dichloro-9-methylfluorene as white crystals, mp 110°-112° C. FT IR: 3425, 1450, 1407, 1273, 1167, 1070, 851,818 cm-1 ; H1NMR (CDCl3, 300 MHz) δ 7.3-7.8 (m, 6H, 3.9-4.1 (q, 1H), 1.2-1.3 (d, 2H).
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)C)=O)(C)(C)C.C(OCC)(=O)C.[ClH:42]>C(OCC)(=O)C.CC(O)C>[ClH:42].[F:35][C:12]1[C:11]([CH2:10][NH:8][CH3:6])=[CH:15][N:14]([S:16]([C:19]2[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[C:13]=1[C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(C(=O)OC)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of methyl 5-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}-2-furoate (260 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 177 mg, 78%).