Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH:9]([C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1)[CH2:10][CH:11]1[CH2:28][NH:27][C:14]2[N:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[N:17]=[C:18]([OH:19])[C:13]=2[CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].CO>Cl.O>[OH:7][CH2:8][CH:9]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:49][CH:50]=1)[CH2:10][CH:11]1[CH2:28][NH:27][C:14]2[N:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[N:17]=[C:18]([OH:19])[C:13]=2[CH2:12]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(COC2CCCCO2)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(CO)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Yield: 97.8 %

Procedure:
The solution of 942 mg (1.35 mm) of diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl}benzoyl]glutamate in 40 ml of 0.1N methanolic hydrogen chloride was stirred at ambient temperatures for 2 hours. The reaction mixture was neutralized with a solution of 205 mg of sodium carbonate in 10 ml of water and most of methanol was removed by evaporation under reduced pressure. One hundred milliliters of methylene chloride were added the solution was washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated. The residue was triturated with 1:2 ethyl acetate and ether, filtered, and dried to give 810 mg (98%) of diethyl N-[4-{1-hydroxy-3-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl}benzoyl]glutamate. mp 133°-135° C. Analysis calculated for C31H43N5O8 : C, 60.67; H, 7.06; N, 11.41. Found: C, 60.42; H, 7.09; N, 11.34. NMR (CDCl3), delta, 1.22 (t, 3H, J=7 Hz), 1.26 (s, 9H), 1.30 (t, 3H, J=7 Hz), 1.78-1.87 (m, 3H), 2.01-2.23 (m, 3H), 2.23-2.36 (m, 1H), 2.38-2.54 (m, 2H), 2.59-2.69) (m, 1H), 2.83-3.12 (m, 2H), 3.14-3.18 and 3.28-3.32 (m, m, 1H), 3.72-3.78 (m, 2H), 4.12 (q, 2H, J=7 Hz), 4.23 (q, 2H, J=7 Hz), 4.74-4.84 (m, 2H, CH, NH), 7.24 (d, NH, J=7 Hz), 7.26-7.30 (m, 1H), 7.72-7.76 (m, 1H), 8.09 (brs, NH), 11.23 (brs, NH).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8])=[CH:4][CH:3]=1.[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20]>>[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@@H:23]([C:24]1[CH:25]=[CH:26][C:27]([C:2]2[S:6][C:5]([CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8])=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)[OH:34])=[O:20]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)s1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Yield: 30.8 %

Procedure:
The compound is prepared from tert-butyl (1-(5-bromothiophen-2-yl)ethyl) -carbamate (138 mg, 0.45 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (200 mg, 0.45 mmol) in a manner analogous to Example 74, Step 2 to give the title compound (70 mg): 1H-NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 1.57 (d, J=6.8 Hz, 3H), 2.68 (bs, 1H), 4.25-4.38 (m, 1H), 4.42-4.48 (m, 0.5H), 4.53-4.60 (m, 1H), 4.65-4.72 (m, 0.5H), 4.77-4.89 (m, 1H), 4.98-5.09 (m, 1H) 5.11 (d, J=4.0 Hz, 1H), 5.87 (s, 1H), 6.90 (d, J=3.5 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 7.14 (d, J=3.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.55 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)CCO
Solvent: ClCCl
Product: CC(=O)OCCC(C)(C)O
Reaction time: 5 h

Procedure:
A solution of 16 mL 3-methylbutane-1,3-diol in 10 mL methylene chloride with a catalytic amount of 4-dimethylpyridine was cooled to 0° C. Acetic anhydride (4.084 g, 40 mmol) was then added drop wise and the solution was stirred for 5 hours. An additional 10 mL of methylene chloride was added and the solution was washed with 10% aqueous ammonium chloride (2×20 mL), 5% sodium carbonate (2×20 mL) and brine (1×20 mL), dried over sodium sulfate and evaporated to dryness to yield a clear, yellow liquid. (2.402 g) 1H NMR (400 MHz, CDCl3): δ 1.24 (s, 6H), 1.56 (b, 1H), 1.80-1.83 (t, J=6.8, 2H), 2.02 (s, 3H), 4.22 (t, J=6.9, 2H).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[CH2:9][CH:8](O)[C:7]=2[CH:20]=1.[Cl-].[Ca+2].[Cl-]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([Cl:1])[C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)Sc1cc(OC)c(Cl)cc1C(O)C2
Reactant: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(c1)Sc1cc(OC)c(Cl)cc1C(Cl)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Anhydrous hydrogen chloride was passed at 0° C. into a stirred solution of the alcohol from the above experiment (22.5 g) in methylene chloride (500 ml) for 3 hours. Anhydrous calcium chloride (5 g) was added, the mixture stirred at room temperature for 3 hours and filtered. The filtrate was evaporated under diminished pressure, yielding 23.4 g of crude 8,10-dichloro-3,7-dimethoxy-10,11-dihydrodibenzo(b,f)-thiepine. The compound was crystallized from methylene chloride and melted in the pure state at 151°-153° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65](=[O:75])[C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([NH:73][CH3:74])[CH:67]=1>>[CH3:63][O:64][C:65](=[O:75])[C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:68]([NH:73][CH3:74])[CH:67]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CNc1cc(C(=O)OC)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Yield: 44.5 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.5 g, 0.86 mmol), was reacted with diisopropylethylamine (0.56 g, 4.3 mmol), diphenylphosphinic chloride (0.41 g, 1.7 mmol), then reacted with 4-amino-3-methylamino-benzoic acid methyl ester prepared in Example 165 (0.19 g, 1 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methylamino-benzoic acid methyl ester as a light yellow solid (Yield 0.24 g, 44%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[CH3:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[O:16][CH2:17][CH:18]=O>>[CH3:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[O:16][CH2:17][CH:18]1[NH:11][CH2:10][CH2:9][N:4]2[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]12
Reactant: Cc1ccc(OCC=O)cc1C
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2COc1ccc(C)c(C)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (6.000 mmol) and (3,4-dimethyl-phenoxy)-acetaldehyde (0.985 g; 6.000 mmol) afforded 8-(3,4-dimethyl-phenoxymethyl)-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.70 min.; [M+H]+=412.12 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:30]([F:33])([F:32])[F:31])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])=[C:17]4[CH2:27][CH2:28][CH2:29][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)C(C)C)(C)C.[F:43][CH2:44][CH2:45][NH2:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:43][CH2:44][CH2:45][NH:46][C:24]([CH2:23][NH:22][C:20]([C:18]1[S:19][C:15]([C:12]2[CH2:11][C:10]([C:4]3[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)([C:30]([F:31])([F:32])[F:33])[O:14][N:13]=2)=[C:16]2[CH2:29][CH2:28][CH2:27][C:17]=12)=[O:21])=[O:26]
Reactant: NCCF
Reactant: O=C(O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2)NCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of compound ({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-acetic acid (100 mg, 0.19 mmol) in acetonitrile (5 mL) is added N,N-diisopropylethylamine (49.3 mg, 0.38 mmol), 2-fluoro-ethylamine (14.4 mg, 0.23 mmol) and HATU (108.8 mg, 0.29 mmol), after finished the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is concentrated and the residue is purified by column chromatography to afford desired product (100 mg, 92%). MS (m/z): 570.1 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)(=[O:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([Cl:21])=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)OCCc1ccc2c(c1)NC(=O)C1CCCC21
Solvent: CN(C)C=O
Product: CC(=O)OCCc1cc2c(cc1Cl)C1CCCC1C(=O)N2
Yield: 82.3 %

Procedure:
A solution of 400 mg (1.5 mmol) of 7-acetoxyethyl-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one and 193 mg (1.5 mmol) of N-chlorosuccinimide in 40 ml of DMF is heated for 6 days to 100° C. The batch is poured onto ice water and extracted with ethyl acetate. The organic phase is washed with 10% sulfuric acid and water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 380 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])Cl.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])[C:18]1[NH:17][CH:21]=[CH:20][N:19]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)C(Cl)(c1ccccc1)C(C)(C)C
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)(c1ncc[nH]1)C(C)(C)C

Procedure:
12.7 g (0.05 mole) phenyl-tert.-butyl-chloroacetic acid methyl ester (b.p. 96°C./0.3 mm Hg) are heated to the boil for 17 hours with 10 g imidazole and 100 ml acetonitrile. After the solvent has been distilled off in a vacuum, treatment with 70 ml of water is effected followed by extraction with methylene chloride. The methylene chloride is again extracted with 30 ml of water, dried and distilled off in a vacuum. There is so obtained the phenyl-tert.-butyl-imidazolyl-acetic acid methyl ester as oil, which solidifies after a long time.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br-].[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Zn+])#[N:14].O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[C:15]([C:13]#[N:14])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: N#Cc1ccccc1[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (9.68 g, 44 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.53 g, 1.3 mmol) was treated with 2-cyanophenylzinc bromide (100 ml of a 0.5M solution in tetrahydrofuran, 50 mmol) then heated under reflux for 8 h. After cooling to ambient temperature the reaction mixture was poured into water (1000 ml). After stirring for 30 min the resulting solid was collected by filtration and dried under vacuum over phosphorus pentoxide to afford 4′-fluoro-3′-nitrobiphenyl-2-carbonitrile as a tan solid (10.7 g, 100%) which was used without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1.O=S(Cl)[Cl:19]>C(Cl)Cl>[Cl:19][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CCl)ccn1

Procedure:
tert-butyl (4-(hydroxymethyl)pyridin-2-yl)carbamate (600 mg, 2.679 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at rt for 2 hrs. The solvent was removed to get a crude tert-butyl (4-(chloromethyl)pyridin-2-yl)carbamate. Then following General Procedure A, the title compound (667 mg, 68%) was prepared from 2-amino-4-chlorobenzenethiol (641 mg, 4.019 mmol), K2CO3 (1.8 g, 13.39 mmol) in DMF (20 ml).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH2:21][CH:22]([F:24])[F:23])=[N:13][C:12]=2OCC(F)F)[CH2:5][CH2:4]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH2:21][CH:22]([F:24])[F:23])=[N:13][C:12]=2[N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:5][CH2:4]1
Reactant: C1COCCN1
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(NCC(F)F)nc1OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(NCC(F)F)nc1N1CCOCC1

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-(2,2-difluoroethylamino)-5-nitro-2-(2,2-difluoroethoxy)-nicotinic acid amide (0.40 g, 0.83 mmol), morpholine (87 mg, 1.0 mmol), K2CO3 (170 mg, 1.24 mmol) and 2.5 mL DMSO is irradiated in a microwave apparatus at 100° C. for 30 min. The mixture is poured into water and the precipitate is collected by filtration and dried. Yield 0.34 g
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:34](=[O:41])[C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1-c1csc(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 4-(4-(4-isopropoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (16-6, 0.25 g, 0.72 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.5 mL, 3.59 mmol) followed by isonicotinoyl chloride hydrochloride (0.35 g, 1.94 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-{4-(4-(4-isopropoxypherioxy)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (16, 0.26 g) as light yellow solids in 79% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J=5.1 Hz, 2 H), 7.98 (d, J=5.7 Hz, 1 H), 7.16 (s, 1 H), 6.95 (m, 4 H), 6.69 (s, 2 H), 4.55 (t, J=6.0 Hz, 2 H), 2.05 (s, 6 H), 1.27 (s, 3 H), 1.26 (s, 3 H). ESI-MS: m/z 460.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]#[N:23].[OH:24]S(O)(=O)=O>>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:19])=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:23])=[O:24]
Reactant: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C#N)c2N)c(Cl)c1
Reactant: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C(N)=O)c2N)c(Cl)c1
Yield: 73 %

Procedure:
Part C: A solution of 1.64 g (4.64 mmol) of 5-amino-4-cyano-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)-pyrazole in 8 mL conc. H2SO4 was stirred at room temperature for 4 hours. The reaction was quenched carefully with ice and diluted with water. The solid was collected by suction filtration, washed with water and dried to give 1.26 g (73%) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole-4-carboxamide, mp 194-196° C. Mass Spec.: (CI+) 371 (M+).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:28]([CH3:34])=[N:29][N:30]([CH3:33])[C:31]=2[CH3:32])=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[C:35](Cl)(=[O:41])[O:36][CH2:37][CH:38]([CH3:40])[CH3:39].Cl>O1CCCC1>[CH2:37]([O:36][C:35]([N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:14]([F:17])([F:15])[F:16])[C:18]([F:20])([F:21])[F:19])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:28]([CH3:34])=[N:29][N:30]([CH3:33])[C:31]=1[CH3:32])=[O:26])=[O:41])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)COC(=O)Cl
Reactant: COC(c1ccc(NC(=O)c2c(C)nn(C)c2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(N(C(=O)OCC(C)C)C(=O)c2c(C)nn(C)c2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
Sodium hydride (29 mg, 60%, 0.73 mmol) was suspended in tetrahydrofuran (10 ml), and a solution of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-1,3,5-trimethylpyrazole-4-carboxamide (260 mg, 0.48 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 30 min, a solution of isobutyl chlorocarbonate (100 mg, 0.73 mmol) in tetrahydrofuran (2 ml) was added, and the mixture was stirred for one day. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired compound (280 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([OH:14])[CH3:13])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(OCC)C>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC(O)c1cc(Cl)cc2c1OCCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1cc(Cl)cc2c1OCCO2
Reaction time: 16 h

Procedure:
1-(6-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethanol (258 mg, 1.20 mmol) was dissolved in 4 mL of dichloromethane. PCC (648 mg, 3.00 mmol) was added portionwise and the mixture was stirred for 16 h (reaction is likely to be completed earlier). Diethyl ether (20 mL) was added and stirred for 10 minutes. The heterogeneous mixture was filtered through a plug of celite. The solvent was removed by rotary evaporation to collect the desired product (248 mg, 97%). 1H NMR (400 MHz, CDCl3): δ 7.28 (d, 1H), 7.01 (d, 1H), 4.33 (m, 4H), 2.59 (s, 3H).
Reaction SMILES: Cl.[C:2]([CH2:4][C:5]1[CH:10]=[CH:9][NH+:8]=[CH:7][CH:6]=1)#[N:3].Cl[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]Cl)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[C:2]([C:4]1([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:21])[CH2:13][CH2:12]1)#[N:3]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1cc[nH+]cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.7 %

Procedure:
4-Cyanomethylpyridinium hydrochloride (1.0 g, 6.5 mmol), 2.0 g tert-butyl bis(2-chloroethyl)carbamate (J. Med. Chem. 1992, 35, 11, 2033-2039) (8.1 mmol), 9.1 g caesium carbonate (28 mmol) and 20 ml DMSO were combined in a round bottom flask and stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and the organic layer washed with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography on silica, using a gradient from 10% to 100% ethyl acetate in hexanes as eluent. 778 mg of the title compound were isolated as an oil (42% yield)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:40]=[CH:39][C:34]3[C:35](=[O:38])[O:36][CH2:37][C:33]=3[CH:32]=2)O1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:40]=[CH:39][C:34]4[C:35](=[O:38])[O:36][CH2:37][C:33]=4[CH:32]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc5c(c4)COC5=O)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-benzofuran-1(3H)-one. LCMS (M+H)+: 456.0/458.0.
Reaction SMILES: [N:1]12[CH2:9][C:5]([C:10]3[CH:11]=[CH:12][C:13](O)=[N:14][CH:15]=3)([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.P(Cl)(Cl)([Cl:19])=O.[OH-].[Na+]>>[Cl:19][C:13]1[N:14]=[CH:15][C:10]([C:5]23[CH2:9][N:1]([CH2:8][CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]3)=[CH:11][CH:12]=1
Reactant: Oc1ccc(C23CCCN(CCC2)C3)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(C23CCCN(CCC2)C3)cn1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 42.4 %

Procedure:
1 g (4.59 mmol) of 5-(1-azabicyclo[3.3.1]non-5-yl)pyridin-2-ol obtained in Example 1, in solution in 12.8 mol (137.7 mmol) of phosphorus oxychloride, is introduced into a sealed tube and the combined mixture is subsequently stirred at 140° C. for 45 minutes. The reaction mixture is subsequently brought back to ambient temperature, poured onto 200 g of crushed ice and stirred for 15 minutes. The medium is then very slowly adjusted to pH 10 with a concentrated sodium hydroxide solution. The combined mixture is subsequently extracted twice with chloroform and the organic phases are subsequently combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 461 mg of the desired compound in the form of a brown powder.