Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (0. 19 g ;0.80 mmol) was dissolved in methylene chloride (1 0 mL). 1-Hydroxy-7-azabenzotriazole (0.108 is g; 0.795 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g; 0.87 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3(1-naphthyl)propionamide (0.32 g; 0.80 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (0.14 mL; 0.80 mmol) was added. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (5 mL) was added. The reaction mixture was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 30 mL), an aqueous solution of sodium hydrogen carbonate (saturated; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×30 cm) using ethylacetat/methylene chloride 1:1 as eluent to afford 0.26 g of ((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:6][CH:5]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(CCOCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension under nitrogen of 656.5 mg (16.4 mmol) of NaH (at 60% in oil) in 15 ml of DMF is added over 10 minutes a solution of 3 g (14.9 mmol) of 2-(4-bromophenyl)ethanol in 5 ml of DMF. After stirring for 30 minutes at room temperature, the reaction medium is cooled to 10° C. and a solution of 2.4 g (17.9 mmol) of (bromomethyl)cyclopropane in 10 ml of DMF is added over 15 minutes.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=S)[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH3:16]>>[NH2:16][C:9]1[CH:8]2[CH2:13][CH2:14][CH2:15][CH:7]2[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:11]=2[N:10]=1
Reactant: N
Reactant: Fc1cccc2c1NC(=S)C1CCCC21
Product: NC1=Nc2c(F)cccc2C2CCCC12
Yield: 64 %

Procedure:
Analogously to Example 4, 6-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (100 mg, 0.45 mmol) in 7N methanolic ammonia solution (15 ml) is reacted to form 59 mg (64%) of product.
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1>[CH2:29]([O:28][C:26]([C:23]1([CH2:12][CH2:11][CH:10]=[CH2:9])[CH2:24][CH2:25][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A mixture of THF (160 mL) and diisopropyl amine (9.92 mL, 70.8 mmol, 1.2 eq) was cooled to −78° C. and a 2.5 M solution of n-BuLi in heptanes (28.3 mL, 70.8 mmol, 1.2 eq) was added slowly. The solution was stirred for 15 min, warmed to 0° C. for 20 min and cooled back to −78° C. Ethyl N-Bocpiperidine-4-carboxylate (11 mL, 59 mmol, 1 eq.) in 10 mL of THF was added drop-wise and stirred for 40 min before it was warmed to rt. The reaction mixture was stirred for 12 h, transferred to a separatory funnel, quenched with 500 mL of water and extracted with ethyl acetate (2×300 mL). The combined organics were dried over Na2SO4 and concentrated under vacuum to give the title compound as a yellow oil (13.9 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1([CH:15]=O)[CH2:14][CH2:13]1.C(OC(=O)C)(=O)C.Cl[C:25](Cl)([F:30])[C:26]([O:28][CH3:29])=[O:27]>[Zn].[Cu]Cl.O1CCCC1>[F:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:15][C:12]1([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Yield: 44 %

Procedure:
The method of Example 1 was repeated using zinc powder (1.3 g), copper (I) chloride (0.22 g), molecular sieve 4A (1.6 g), tetrahydrofuran (20 ml), 1-(2-fluoro-4-tri-fluoromethylphenyl)-1-formylcyclopropane (1.39 g), acetic anhydride (0.58 ml) and methyl dichlorofluoroacetate to yield the title compound (0.81 g, 44%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>CN1CCCC1>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: CN1CCCC1
Product: Cc1cc([N+](=O)[O-])c(C)cc1N1CCc2ccccc2C1
Temperature: 140 °C
Reaction time: 15 h

Procedure:
A mixture of 1-chloro-2,5-dimethyl-4-nitrobenzene (1.65 g) and 1,2,3,4-tetrahydroisoquinoline (5 ml) in N-methylpyrrolidine (5 ml) is stirred at 140° C. for 15 h. Dilution in water followed by extraction with diethyl ether and chromatography on silica (eluent: 1/1 petroleum ether/diethyl ether) of the dried and evaporated organic phase gives 2-(2,5-dimethyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (R)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)-phenylboronic acid following a procedure analogous to that described for Intermediate 6. Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: COC(C1C=C(O[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([OH:45])[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].FC1C=CC(CS(CC2C=CC(F)=CC=2)(=O)=O)=CC=1>>[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([O:45][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Agent: O=S(=O)(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)(CO)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 4-fluorophenyl methylsulfone. 1H NMR (400 MHz, CDCl3) δ 7.89-7.94 (m, 2 H) 7.26-7.27 (m, 1 H) 7.22 (d, J=1.26 Hz, 1 H) 7.02-7.11 (m, 2 H) 3.69-3.76 (m, 1 H) 3.60 (dd, J=11.87, 7.58 Hz, 1 H) 3.16 (d, J=16.42 Hz, 1 H) 3.07 (s, 3 H) 2.78 (d, J=16.67 Hz, 1 H) 1.86 (dd, J=7.58, 5.81 Hz, 1 H) 1.57 (s, 9 H) 1.44 (s, 3 H); LCMS for C26H26O7S m/z 435.00 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:24]4=[C:25]([C:27](=[O:37])[C:28]([CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:29][N:23]4[C:22]4[CH:21]=[C:20]([Br:38])[CH:19]=[CH:18][C:17]3=4)[CH:26]=2)[CH:9]=[N:10][CH:11]=1)(=O)C.[OH-].[Na+]>CO.O>[Br:38][C:20]1[CH:19]=[CH:18][C:17]2[C:16]3[C:24]4=[C:25]([C:27](=[O:37])[C:28]([CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:29][N:23]4[C:22]=2[CH:21]=1)[CH:26]=[C:14]([O:13][CH2:12][C:8]1[CH:9]=[N:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=1)[CH:15]=3
Reactant: CC(=O)OCc1cncc(COc2cc3c(=O)c(Cc4cccnc4)cn4c5cc(Br)ccc5c(c2)c34)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(OCc4cncc(CO)c4)cc1c32
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
2-(5-acetoxymethyl-3-pyridylmethyloxy)-9-bromo-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) produced in Example 106 was suspended in methanol (10 ml), and to the suspension was added a solution of sodium hydroxide (85 mg) in water (0.8 ml). The mixture was stirred at room temperature for 10 minutes, and the crystals precipitated were recovered by filtration, and washed with methanol and ether in succession to obtain the title compound (170 mg, 92%).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([C:23]([NH2:25])=[O:24])=[CH:8][C@H:9]2[CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([C:23]([NH2:25])=[O:24])=[CH:8][C@H:9]2[CH2:14][OH:15])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C(N)=O)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON1C(=O)N2C[C@H]1C(C(N)=O)=C[C@H]2CO
Reaction time: 1 h
Yield: 93.5 %

Procedure:
(2S,5R)-6-(allyloxy)-2-((tert-butyldimethylsilyloxy)methyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-4-carboxamide (Intermediate 108, 450 mg, 1.2 mmol) was dissolved in THF (about 7 mL); the atmosphere in the reaction vessel was evacuated and backfilled with argon, and the solution was stirred in an ice bath for ten minutes. To it was then added tetrabutylammonium fluoride (1 M in THF) (1.5 mL, 1.5 mmol) dropwise. After one hour, analysis of the mixture by LCMS indicated consumption of starting material and formation of one major product. The mixture was concentrated and dissolved in methylene chloride. Normal-phase chromatography (0-10% methanol in methylene chloride, 25-g column, 25 minutes) was used to isolate the desired product (284 mg, 92%, white solid).
Reaction SMILES: Br[CH:2]1[C:8](=[O:9])[CH:7](Br)[CH:6]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:3]1[CH:4]=[C:5]2[CH:25]1[CH2:27][CH2:26]1.[NH4+].[Cl-]>[Cu].[Zn]>[CH:25]1([C:5]2[CH:6]3[N:11]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)(=[O:14])=[O:13])[CH:3]([CH:4]=2)[CH2:2][C:8](=[O:9])[CH2:7]3)[CH2:26][CH2:27]1
Reactant: O=C1C(Br)C2C=C(C3CC3)C(C1Br)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Product: O=C1CC2C=C(C3CC3)C(C1)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
Zinc-copper couple (3.21 g, 24.8 mmol) was added to a solution of 2,4-dibromo-6-cyclopropyl-8-(4-(trifluoromethyl)phenylsulfonyl)-8-azabicyclo[3.2.1]oct-6-en-3-one (3.29 g, 6.21 mmol) in a saturated methanolic solution of NH4Cl (24 mL). The reaction mixture was stirred at room temperature for 4 h and was subsequently filtered though Celite. The filtrate was concentrated under vacuum, re-dissolved in CH2Cl2 and washed with saturated aqueous Na2CO3. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 1/1, v/v) to give compound 116 (1.68 g, 4.52 mmol, 73%). MS (ESI) 372.1 (M+H).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][CH2:68][C:69]5[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=5)[CH:66]=4)=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:85]1[CH2:90][CH2:89][N:88]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][CH2:86]1.[OH-].[Na+]>C1COCC1.CO.O>[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][CH2:68][C:69]5[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=5)[CH:66]=4)=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:85]1[CH2:90][CH2:89][N:88]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][CH2:86]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cc2F)CC1
Yield: 75.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(2-fluoro-4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (140 mg, 0.194 mmol) was hydrolyzed by sodium hydroxide (78 mg, 1.947 mmol) in THF/methanol/water (12/4/3 mL) to yield 83 mg (75% yield) of the titled compound. MS: m/z=566.3 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:11][C:12]([NH:14][C:15]1[N:16]=[C:17]([CH2:20][NH:21][C:22](OC(C)(C)C)=[O:23])[S:18][CH:19]=1)=[O:13])[CH:9]=[CH2:10].C(=O)(O)[O-].[Na+]>ClCCl.O.C(O)=O.C(O)(=O)C>[CH2:8]([O:11][C:12]([NH:14][C:15]1[N:16]=[C:17]([CH2:20][NH:21][CH:22]=[O:23])[S:18][CH:19]=1)=[O:13])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)Nc1csc(CNC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)Nc1csc(CNC=O)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 92.4 %

Procedure:
A 24.0 ml portion of trifluoroacetic acid was added to 4.791 g of 4-allyloxycarbonylamino-2-(N-t-butoxycarbonylamino)methylthiazole, and the mixture was then stirred at room temperature for 50 minutes. The reagent was evaporated under reduced pressure to obtain a dark red oil, and this oil was then dissolved in 50 ml of dichloromethane and 50 ml of distilled water, followed by adjustment to pH 5 with sodium bicarbonate. A mixed solution of 7.2 ml of anhydrous acetic acid and 14.4 ml of formic acid was added dropwise to the solution at room temperature over 15 minutes under vigorous stirring. After the pH of the solution was adjusted to 5 again, it was stirred for 2.5 hours. Furthermore, a mixed solution of 2.9 ml of anhydrous acetic acid and 5.8 ml of formic acid was added dropwise to the solution over 25 minutes, and adjustment to pH 5 was carried out with sodium bicarbonate again, followed by stirring for 2.5 hours. After the addition of 250 ml of dichloromethane and sufficient shaking, the resulting precipitate was collected by filtration, and from the filtrate, the organic layer was separated, dried (magnesium sulfate), and then filtered. This filtrate was combined with a liquid eluted from the precipitate with a dichloromethane-methanol mixture solvent, and the solvent was then evaporated under reduced pressure to obtain 3.408 g of 4-allyloxycarbonylamino-2-(formylamino)methylthiazole as a light orange powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+].[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([NH:26][C:27](=[O:28])[NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=C=NCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(NCc1ccccc1)Nc1ccsc1C(=O)O
Reaction time: 5 h
Yield: 39 %

Procedure:
To a solution of methyl 3-amino-thiophene-2-carboxylate 9.43 g (60 mmol) in acetonitrile 12 ml, 2N-sodium hydroxide 36 ml (72 mmol) was added and the mixture was stirred for 5 hrs. at 85° C. The reaction mixture was neutralized with 2N-hydrochloric acid 36 ml (72 mmol), then saturated sodium bicarbonate solution 50 ml and a solution of benzyl isocyanate 7.41 ml (60 mmol) in acetonitrile 36 ml were added and the mixture was stirred overnight. The reaction mixture was basified with 2N-sodium hydroxide 60 ml and washed with ether 100 ml. The aqueous phase was acidified with 2N-hydrochloric acid 85 ml. The aqueous phase was filtered and washed with H2O. The solid was dried in vacuo to obtain the title compound 6.46 g (yield 39%)
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][N:11]([CH2:17][CH2:18][OH:19])[CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: OCCN1CCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCN(CCO)CC1
Yield: 95 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 2-(piperazin-1-yl)ethanol gave 2-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazin-1-yl)ethanol as a cream solid (0.30 g, 95%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.78 (s, 3H), 3.67 (t, J=5.3 Hz, 2H), 3.26 (t, J=4.6 Hz, 4H), 2.72-2.62 (m, 6H). OH not seen
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[S:18])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][O:22][CH3:23].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][S:18][C:10]1[NH:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COCCBr
Reactant: S=C1NN=C(c2ccccc2)C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCSc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 4 h
Yield: 73.2 %

Procedure:
To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.5 g, 1.981 mmol) in DMF (5 mL), were added 1-bromo-2-methoxyethane (0.275 g, 1.981 mmol) and K2CO3 (0.274 g, 1.981 mmol) at room temperature. After stirring for 4 h, the reaction was poured into water and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (0.45 g). LCMS m/z=311.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23 (s, 3H), 3.12-3.54 (m, 4H), 7.22-7.49 (m, 10H), 13.2 (s, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:13][F:14])([CH2:11][F:12])[CH:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:31].[K+]>O.C(Cl)Cl>[F:12][CH2:11][C:9]1([CH2:13][F:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:6]2[CH:21]=[C:2]([I:31])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: [I-]
Reactant: Nc1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: FCC1(CF)C=C(c2ccccn2)c2cc(I)ccc2O1
Yield: 67.7 %

Procedure:
A mixture of 6.2 g of 2,2-bisfluoromethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran, 11.7 g of stannous chloride and 80 mnl of ethanol was refluxed with heating for 3 hours. The solvent was distilled off and sodium hydroxide solution was added to form an alkaline solution. The solution was extracted with methylene chloride and the organic layer was extracted with 2N hydrochloric acid. To the aqueous layer was added 2N sodium hydroxide to form a strongly alkaline solution, which was then extracted with methylene chloride. The organic layer was washed with water and dried and the solvent was distilled off to obtain 4.8 g of 6-amino-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran. To a mixture of 4.8 g of the above-obtained 6-amino-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran, 1.0 ml of concentrated sulfuric acid and 80 ml of water was added 1.20 g of sodium nitrite dissolved in 10 ml of water with stirring under ice-cooling. After the mixture was stirred for 20 minutes, 3.31 g of potassium iodide dissolved in 10 ml of water was added. After addition of 100 ml of methylene chloride, the mixture was stirred at room temperature for 2 hours. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with sodium hydroxide solution and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 4.50 g of oily 2,2-bisfluoromethyl-6-iodo-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][C:24](=O)[CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO.C(O)(=O)C>[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][CH:24]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[O:8])[CH2:3][CH2:2]3)[CH2:23]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(C1CCNCC1)N1CCOCC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)N1CCOCC1
Temperature: 120 °C
Yield: 83.2 %

Procedure:
4-(Piperidin-4-ylcarbonyl)morpholine (0.30 g, 1.26 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.30 g, 1.5 mmol) were dissolved in a mixture of methanol (5 mL) and acetic acid (0.1 mL). (Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.38 g) was added and the reaction mixture was heated for 10 min at 120° C. using microwave single node heating. The mixture was filtered through a phase separator and the resin washed with methanol. The solvent was removed by evaporation and the residue was dissolved in methylene chloride. The solution washed twice with a saturated solution of NaHCO3. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol). There was obtained 0.44 g (83%) of 4-({1-[1-(diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholine as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.9 (m, 4H), 2.2 (m, 1H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 4H), 3.3-3.5 (m, 3H), 3.5-3.7 (m, 6H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 420 (M+1)+.