Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.C(O)C(N)(CO)CO>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: NC(CO)(CO)CO
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c[nH]1
Temperature: 60 °C
Yield: 48.4 %

Procedure:
Ethylpyrrole-2-carboxylate (1.0195 g, 7.33 mmol) in a minimal amount of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (1.934 g, 14.5 mmol) and 4-chlorobenzeneacetyl chloride (2.7841 g, 14.73 mmol) in dichloroethane (10.9 mL, 0.67 M) under N2. After stirring 10 min, the ice bath was removed, and the reaction was stirred at room temperature for 60 minutes, with little change by TLC (9:1 Hexanes:EtOAc): After heating to 60° C. for an additional hour, only a small quantity of starting material was left by TLC. The reaction was cooled to room temperature, PS-Trisamine™ resin (6.3954 g, 24.30 mmol) and dichloroethane (10 mL) were added, and the reaction was stirred for 3 hours. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 95:5 to 50:50 Hexanes:EtOAc) to obtain 1.0345 g (48.4%) 37 as a pale orange solid. Note. A small amount of CH2Cl2 was required to solubilize the crude product before placement on the silica column. 1H (CDCl3, 400 MHz): δ 10.07 (1H, broad s), 7.55-7.52 (1H, m), 7.33-7.30 (1H, m), 7.27 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz), 4.35 (2H, q, J=7.0 Hz), 4.04 (2H, s), 1.37 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 192.55, 160.97, 133.10, 132.75, 130.76, 128.69, 126.80, 126.25, 124.30, 114.95, 61.06, 45.79, 14.31 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.31; CH2 carbons: 61.06, 45.79; CH carbons: 130.76, 128.69, 126.80, 114.96 ppm. HPLC: 10.049 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[C:12]([N:19]1[CH:23]=[CH:22]N=C1)(N1C=CN=C1)=[O:13].NC1C=[CH:39][C:28]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36](=[O:38])[CH3:37])[CH:31]=2)=[CH:27][CH:26]=1>ClCCCl.C1COCC1>[C:36]([C:32]1[CH:31]=[C:30]([O:29][C:28]2[CH:39]=[CH:22][C:23]([NH:19][C:12]([NH:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[N:3]=[CH:4]4)=[O:13])=[CH:26][CH:27]=2)[CH:35]=[CH:34][N:33]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: Cn1ncc2cc(N)ccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(cnn4C)c3)cc2)ccn1
Temperature: 65 °C
Yield: 74.1 %

Procedure:
To a solution of 1-methyl-5-aminoindazole (48.4 mg, 0.33 mmol) in anhydrous DCE (1.1 mL) and anhydrous THF (1.1 mL) was added 1,1′-carbonyldiimidazole (65.1 mg, 0.39, 1.2 eq), and the reaction mixture was stirred at 65° C. under argon. After 16 h a solution of 1-[4-(4-aminophenoxy)pyridin-2-yl]ethanone (75 mg, 0.33 mmol, 1.0 eq) in anhydrous DCE (3.3 mL) was added at ambient temperature, and the reaction mixture was stirred at 65° C. under argon for 20 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification on MPLC (biotage) eluted with 60 to 80% EtOAc/Hex and crystallization from ethyl acetate—hexane afforded 98.2 mg (74.4%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 8.79 (s, 1H), 8.68 (s, 1H), 8.58 (d, J=5.7 Hz, 1H), 7.93 (d, J=1.0 Hz, 1H), 7.89 (d, J=1.2 Hz, 1H), 7.58 to 7.53 (m, 3H), 7.35 (dd, J=9.0, 2.1 Hz, 1H), 7.26 (d, J=2.7 Hz, 1H), 7.21 (dd, J=5.4, 2.4 Hz, 1H), 7.13 (d, J=8.7 Hz, 2H), 3.99 (s, 3H), 2.59 (s, 3H); MS LC-MS [M+H]+=4.02, RT=2.41 min; TLC (75% EtOAc/Hex), Rf=0.11.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[F:7][C:8]([F:18])([F:17])[O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]([F:7])([F:17])[F:18])=[CH:11][CH:12]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetic acid methyl ester (8 ml, 84.2 mmol) was added to a mixture of 4-(trifluoromethoxy)phenol (10 g, 56.1 mmol) and potassium carbonate (11.6 g, 84.2 mmol) in N,N-Dimethylformamide (50 ml) and stirred at room temperature overnight. The reaction mixture was poured into water and neutralized with a 1 N hydrochloric acid aqueous solution, followed by extraction with diethylether. The result was concentrated and used for the subsequent reaction.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(#N)C>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
4-Hydroxyindole (500 mg, 3.76 mmol), K2CO3 (1.04 g, 7.51 mmol), and n-nonylbromide (817 mg, 3.94 mmol) was dissolved in acetonitrile (10 mL) and stirred at 25° C. for 10 min in a 250 mL round bottom flask. The reaction mixture was refluxed for 24 h and cooled to 25° C. The reaction mixture filtered to remove insoluble impurities and solvent evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 100% hexanes and 30% EtOAc/hexanes to afford 4-nonyloxyindole as pale yellow solid (847 mg, 87%). Rf=0.8 (30% EtOAc/hexanes).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2.[Cl:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[N:25]([CH3:26])[C:24]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[N:23][N:22]=1>>[ClH:16].[CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][N:10]([CH2:17][CH2:18][CH2:19][S:20][C:21]3[N:25]([CH3:26])[C:24]([CH:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[N:23][N:22]=3)[CH2:11][CH2:12][C:6]=1[CH:5]=2
Reactant: Cn1c(SCCCCl)nnc1C1CCOCC1
Reactant: Cc1nc2cc3c(cc2o1)CCNCC3
Product: Cc1nc2cc3c(cc2o1)CCN(CCCSc1nnc(C2CCOCC2)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.25 mmol) and 3-[(3-chloropropyl)thio]-4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazole and was obtained as a faint yellow slightly hygroscopic solid (0.025 mmol).
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:29])[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([O:25]C)[C:18]=2[O:27]C)[CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl.CO>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:30])=[O:4])=[CH:7][C:8]=1[NH:13][C:14](=[O:29])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:25])[C:18]=1[OH:27].[CH3:3][O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:29])[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:25])[C:18]=2[OH:27])[CH:7]=1
Reactant: COC(=O)c1ccc(C)c(NC(=O)C=Cc2ccc(OC)c(OC)c2OC)c1
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C)c(NC(=O)C=Cc2ccc(O)c(O)c2O)c1
Product: Cc1ccc(C(=O)O)cc1NC(=O)C=Cc1ccc(O)c(O)c1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 19 %
Yield: 25 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve anilide (53) (40 mg, 0.10 mmol) in anhydrous DCM (1.3 mL) at −78° C., add dropwise a 1M solution of BBr3 in DCM (830 μL, 0.83 mmol) and stir for additional 30 min at −78° C. After slowly warming up stir the reaction solution for additional 4 h at rt. Cool reaction mixture to 0° C., add dropwise water and DCM under vigorous stirring followed by MeOH to homogenize the mixture. Partition the hydrolized reaction mixture between water and EtOAc, extract the aqu. layer with EtOAc (3×), wash combined organic layer with brine and dry it with Na2SO4. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain 4-Methyl-3-[3-(2,3,4-trihydroxy-phenyl)-acryloylamino]-benzoic acid (54) (6.5 mg, 19%) as an yellowish solid and 4-Methyl-3-[3-(2,3,4-trihydroxy-phenyl)-acryloylamino]-benzoic acid methyl ester (55) (9 mg, 25%) as an yellowish solid. 1H NMR (400 MHz, CD3OD) (54): 2.40 (s, 3H); 6.43 (d, 1H, J=8.6 Hz); 6.90 (d, 1H, J=15.6 Hz); 6.97 (d, 1H, J=8.6 Hz); 7.40 (d, 1H, J=8.1 Hz); 7.83 (dd, 1H, J1=8.1 Hz, J2=1.5 Hz); 7.93 (d, 1H, J=15.6 Hz); 8.17 (br.s, 1H); (55): 2.40 (s, 3H); 3.93 (s, 3H); 6.43 (d, 1H, J=8.6 Hz); 6.90 (d, 1H, J=15.7 Hz); 6.97 (d, 1H, J=8.6 Hz); 7.40 (d, 1H, J=8.1 Hz); 7.82 (dd, 1H, J1=7.8 Hz, J2=1.7 Hz); 7.93 (d, 1H, J=15.9 Hz); 8.18 (br.s, 1H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[C:20]2[C:16](=[CH:17][N:18]([CH3:21])[N:19]=2)[C:15]([CH2:22][OH:23])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[C:20]2[C:16](=[CH:17][N:18]([CH3:21])[N:19]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1
Reactant: Cn1cc2c(CO)ccc(F)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cn1cc2c(C=O)ccc(F)c2n1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of dimethyl sulfoxide (4.30 mL, 60.5 mmol) in dichloromethane (50 mL) was added oxalyl chloride (2.65 mL, 30.3 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (7-fluoro-2-methyl-2H-indazol-4-yl)methanol (1.82 g, 10.1 mmol) in dichloromethane (51 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (12.8 mL, 91.0 mmol) at −78° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (1.60 g, yield 89%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[CH2:16][C:15]3[N:14]=[C:13]([CH3:17])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:31])=CC=1>C1COCC1.O>[CH3:17][C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:4]3[NH:3][C:2](=[S:31])[NH:1][CH:5]=3)[CH2:16][C:15]=2[N:14]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Cc1ccc2c(n1)CC(Cc1c[nH]cn1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)CC(Cc1c[nH]c(=S)[nH]1)CC2
Reaction time: 5 h

Procedure:
A solution of 7-(1H-imidazol-4-ylmethyl)-2-methyl-5,6,7,8-tetrahydro-quinoline (Intermediate 200A5) (5.16 g, 22.7 mmol) in THF (20 mL) and water (20 mL) was treated with NaHCO3 (11.5 g, 136 mmol) and phenyl chlorothionoformate (7.9 mL, 57 mmol). Stirring was continued for 5 h at rt. The mixture was diluted with water and extracted with ethyl acetate (2×). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (10 mL) and treated with NEt3 (140 mL) for 18 h. The mixture was evaporated to dryness, diluted with water and extracted with chloroform:isopropanol (3:1). The organic portions were combined, dried over MgSO4, filtered and concentrated onto SiO2. The solvent was removed under vacuum and the product was purified on a column of SiO2 with a gradient elution of 60% acetone:hexanes to 100% acetone to give enantiomeric 4-(2-methyl-5,6,7,8-tetrahydro-quinolin-7-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 201, racemic mixture) as a white solid, 3.0 g (51%). Individual enantiomers can be obtained from the racemic mixture as described below.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]([O:15]C(C)(C)C)=O)[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][C:3]1=[O:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH2:31][NH:32][CH3:33].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH3:33][N:32]([CH2:31][C:23]1[N:22]([CH3:21])[C:30]2[C:25]([CH:24]=1)=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]([C:10]1[CH:11]=[CH:12][C:6]2[NH:5][CH2:4][C:3](=[O:20])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1)=[O:15]
Reactant: CNCc1cc2ccccc2n1C
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2NCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CN1Cc2cc(C(=O)N(C)Cc3cc4ccccc4n3C)ccc2NCC1=O
Yield: 91.8 %

Procedure:
According to the procedure of Example 8, except using tert-butyl 4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.60 g, 2.2 mmole), 1-methyl-2-(methylaminomethyl)indole (0.35 g, 2.2 mmole), Et3N (0.62 mL, 4.4 mmole), HOBt.H2O (0.30 g, 2.2 mmole), and EDC.HCl (0.42 g, 2.2 mmole), the title compound (0.76 g, 92%) was prepared as an off-white solid following flash chromatography on silica gel (5% MeOH/CHCl3): MS (ES) m/e 377.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC(=O)[NH:32][CH2:33][CH2:34][CH2:35][NH2:36])(C)(C)C.C(Cl)CCl>CN(C=O)C>[NH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[N:16]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NCCCNC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (1 mmol) was coupled with (3-Amino-propyl)-carbamic acid tert-butyl ester (3 mmol) using EDC (2 mmol) in DMF (10 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 392. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.68 (s, 1H) 8.35-8.5 (m, 3H) 8.1 (d, 1H) 7.7 (m, 1H) 7.48 (d, 1H) 7.2 (d, 2H) 6.68 (d, 2H) 3.8 (m, 2H) 3.55 (m, 2H) 3.05 (m, 2H) 2.9 (m, 4H) 2.0 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:17])[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](=[NH:25])[NH2:24])[CH3:19].C(O)C.CN(C=O)C>C(O)C>[CH2:18]([O:20][C:21]([C:22]1[CH:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[C:11]2[C:10](=[O:17])[CH2:15][CH2:14][CH2:13][C:12]=2[NH:24][C:23]=1[NH2:25])=[O:26])[CH3:19]
Reactant: Cc1cccc(C=O)n1
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C1CCCC(=O)C1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1cccc(C)n1
Yield: 46 %

Procedure:
Upon heating a solution of 4.8 g of 6-methylpyridin-2-aldehyde, 4.5 g of cyclohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in 120 ml of ethanol for 8 hours, 2-amino-4-(6-methylpyrid-2-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point >260°C (ethanol/DMF) is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=O)[NH2:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13]#[N:14])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C#N)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, ((1R,3R)-3-carbamoyl-cyclopentyl)-carbamic acid tert-butyl ester (96 mg, 0.42 mmol) was suspended in THF (2.5 ml). The reaction mixture was cooled to 0° C. and triethylamine (0.28 ml, 2.01 mmol) followed by trifluoroacetic anhydride (0.095 ml, 0.67 mmol) were added. The homogeneous reaction mixture was stirred at 0° C. for 1.5 h then quenched with water and extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford ((1R,3R)-3-cyanocyclopentyl)-carbamic acid tert-butyl ester as an off-white waxy solid which contained some triethylamine trifluoroacetate as a major impurity. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5](C[CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C([OH:18])C>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[O:18][CH2:7][CH2:8][CH:9]2[OH:12]
Reactant: CCO
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: OC1CCOc2ccc(Br)cc21

Procedure:
To a suspension of 7-bromo-3,4-dihydronaphthalen-1(2H)-one (3.95 kg, 17.4 mol) in ethanol (20 L) at room temperature add sodium borohydride (221 g, 5.84 mol) in portions over 3 hr. Concentrate the clear red solution. Add the residue into ice (about 3 kg) to form a suspension and then slowly add ice-cooled 0.5 M HCl (10 L) into the above suspension with stirring. Extract the mixture with methyl tert-butyl ether (20 L and 5 L). Wash the combined organic phase with saturated aqueous sodium bicarbonate (10 L) and brine (2×10 L), concentrate the solvent under reduced pressure and dry the wet solid in air overnight to obtain the title compound as a pale yellow solid (4.10 kg, quantitative). LC-ES/MS m/z 211 [M−H-2O+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:15]1([CH2:18][N:10]2[C:11](=[O:12])[C:6]3=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]3[C:8]2=[O:9])[CH2:17][CH2:16]1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CC1CC1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
4-Nitrophthalimide (6.15 g, 32.0 mmol) was dissolved in DMF (60 mL). Cyclopropylmethyl bromide (9.3 mL, 96 mmol) and potassium carbonate (8.85 g, 64.0 mmol) were added and the mixture was heated to 100° C. for 4 hours. The mixture was allowed to cool to room temperature, and then partitioned between water (500 mL) and ethyl acetate (400 mL). The organic phase was collected, dried with Na2SO4, filtered and taken to dryness using rotary evaporation. The residue was dried overnight in a vacuum oven to afford 6.49 g (82%) of pure N-cyclopropylmethyl4-nitrophthalimide as a powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[Cl:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[SH:81]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:74].[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13]([S:81][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][C:75]=2[Cl:74])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: Sc1ccccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(Nc2ncc(Sc3ccccc3Cl)cc2OCc2ccccc2)n1
Product: Cl
Yield: 31.6 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.125 g, 0.332 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0192 g, 0.0332 mmol), Pd2dba3 (0.0152 g, 0.0166 mmol), N-ethyl-N-isopropylpropan-2-amine (0.116 mL, 0.664 mmol), 2-chlorobenzenethiol (0.048 g, 0.3322 mmol) were reacted according to Example 42 to provide 3-(benzyloxy)-5-(2-chlorophenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.025 g, 17.10% yield) after salt formation. 1H NMR (DMSO-d6) δ 8.04 (d, 1H), 7.62 (d, 1H), 7.54 (m, 2H), 7.50 (m, 1H), 7.37 (m, 3H), 7.20 (m, 2H), 6.77 (s, 1H), 6.73 (m, 1H), 5.32 (s, 2H), 2.30 (s, 3H). Mass spectrum (apci) m/z=440.0 (M+H-HCl).
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]([C:31]2[N:32]=[N:33][NH:34][CH:35]=2)[CH:23]=[CH:24][C:25]=1[O:26][C:27]([F:30])([F:29])[F:28].S(OC)(O[CH3:40])(=O)=O.O>C1COCC1.C(OCC)C>[CH3:2][N:33]1[N:32]=[C:31]([C:22]2[CH:23]=[CH:24][C:25]([O:26][C:27]([F:28])([F:29])[F:30])=[C:20]([Br:19])[CH:21]=2)[CH:35]=[N:34]1.[CH3:40][N:34]1[CH:35]=[C:31]([C:22]2[CH:23]=[CH:24][C:25]([O:26][C:27]([F:28])([F:29])[F:30])=[C:20]([Br:19])[CH:21]=2)[N:32]=[N:33]1
Reactant: FC(F)(F)Oc1ccc(-c2c[nH]nn2)cc1Br
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COS(=O)(=O)OC
Agent: [F-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(OC(F)(F)F)c(Br)c2)nn1
Product: Cn1ncc(-c2ccc(OC(F)(F)F)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20 %
Yield: 53 %

Procedure:
Tetra n-butyl ammonium fluoride solution (1M in THF, 12.5 ml, 12.5 mmol) was added over 5 minutes to a stirred solution of 4-[3-bromo-4-(trifluoromethoxy)phenyl]-1H-1,2,3-triazole (Description 59) (2.73 g, 8.85 mmol) and dimethyl sulfate (2.10 ml, 22.1 mmol) in THF (50 ml). The mixture was stirred for at room temperature for 1.5 hours, then water (100 ml) and diethyl ether (100 ml) were added. The layers were separated and the aqueous layer was extracted with ether (200 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (75:25 increasing to 50:50) to give 2-methyl-4-[3-bromo-4-(trifluoromethoxy)phenyl]-2H-1,2,3-triazole as a colorless solid (1.50 g, 53%), 1H NMR (250 MHz, CDCl3) δ 8.07 (1H, d, J=2.1 Hz), 7.81 (1H, s), 7.73 (1H, dd, J=8.5, 2.1 Hz), 7.36 (1H, dq, J=8.5, 1.4 Hz), and 4.25 (3H, s), m/z (ES+) 322, 324 (M+1), and 1-methyl-4-[3-bromo-4-(trifluoromethoxy)phenyl]-1H-1,2,3-triazole as a colorless solid (566 mg, 20%), 1H NMR (250 MHz. CDCl3) d 8.12 (1H, d, J=2.1 Hz), 7.80 (1H, dd, J=8.5, 2.1 Hz), 7.78 (1H, s), 7.36 (1H, dq, J=8.5, 1.5 Hz), and 4.17 (3H, s), m/z (ES+) 322, 324 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:28]([O:29][CH3:30])[CH3:27])=[O:13])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 65 °C
Yield: 91 %

Procedure:
To a solution of 5-bromo-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (XVIII) (0.242 g, 1 mmol) in dry DMF (5 mL) was added CDI (0.178 g, 1.1 mmol) and heated for 3 h at 65° C. under nitrogen. The solution was cooled to room temperature and N,O-dimethyl hydroxylamine hydrochloride (0.107 g, 1.1 mmol) was added to the solution. The solution was again heated for 3 h at 65° C. under nitrogen. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, washed successively with a 10% HCl solution, a saturated aqueous NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XIX) as a white solid (260 mg, 0.91 mmol, 92% yield). 1H NMR (CDCl3) δ ppm 3.55 (s, 3H), 3.78 (s, 3H), 8.59 (d, J=3.01 Hz, 1H), 8.67 (d, J=3.01 Hz, 1H); ESIMS found for C9H9BrN4O2 m/z 285.4 (M+H).