Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C(#N)C.Cl[CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Cs+]>C(Cl)Cl>[CH3:27][N:26]([CH3:28])[C:24](=[O:25])[CH2:23][N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O=[N+]([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: CN(C)C(=O)CN1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine; compound with nitric acid (763 mg, 2.99 mmol) was suspended in acetonitrile (50.0 mL, 957 mmol) and 2-chloro-N,N-dimethyl-acetamide (400 mg, 3.29 mmol) was added. Cesium carbonate (2.44 g, 7.48 mmol) and cesium iodide (77.7 mg, 0.299 mmol) were added and the reaction was heated at reflux for 3 hours. The reaction was cooled to room temperature and then diluted with DCM (50 mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-15% MeOH/DCM as the eluting solvent to obtain N,N-Dimethyl-2-(7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide as an orange solid (778 mg, 94%). m.p.=94-96° C.; LCMS (m/e) 278 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.02-7.97 (m, 2H), 7.25 (d, 1H, J=7.9 Hz), 3.34 (s, 2H), 3.12 (s, 3H), 3.08-3.02 (m, 4H), 2.99 (s, 3H), 2.80-2.73 (m, 4H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:22])=[CH:7][C:8]([C:18](OC)=[O:19])=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][O:15][C:13]2=[O:14])[CH:10]=1)(=[O:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(N(CC)CC)C>[C:23]([N:4]([C:1](=[O:3])[CH3:2])[C:5]1[C:6]([Cl:22])=[CH:7][C:8]2[C:18](=[O:19])[C:12]3([CH2:17][CH2:16][O:15][C:13]3=[O:14])[O:11][C:9]=2[CH:10]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1CCOC1=O
Solvent: CCN(CC)CC
Product: CC(=O)N(C(C)=O)c1cc2c(cc1Cl)C(=O)C1(CCOC1=O)O2

Procedure:
A mixture of 23 g. of α-[(5-acetylamino-4-chloro-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone, 46 ml. of triethylamine and 230 ml. of acetic anhydride was heated at 120° C. for 5 hours. The solvents were evaporated off under reduced pressure, then the residue was poured into ice-water. The precipitating crystals were collected by filtration, washed with water and dried, followed by recrystallization from ethyl acetate to give 6-diacetylamino-5-chloro-4',5'-dihydrospiro[benzo[b]furan-2(3H), 3'(2'H)-furan]-2',3-dione melting at 181°-185° C. Yield 6.8 g.
Reaction SMILES: [CH2:1]([C@@H:3]1[N:8]([C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)[CH3:2]>[Pd].CO>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([N:8]2[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:4][C@@H:3]2[CH2:1][CH3:2])=[CH:14][CH:13]=1
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A 100-mL single-neck round-bottomed flask was purged with nitrogen and charged with 111a (0.7 g, 2.08 mmol), 10% palladium on carbon (50% wet, 208 mg), and methanol (40 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 6 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 111b (568 mg, 89%). MS: [M+H]+ 306
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:14][CH:15]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.05 (s, br, 1H), 7.74-6.68 (m, 12H), 5.08-4.99 (m, 1H), 3.67-3.56 (m, br, 2H), 3.02-2.82 (br, 2H), 2.80-2.57 (m, br, 4H), 2.57-2.38 (m, br, 2H), 2.05-1.80 (m, br, 6H), 1.64-1.40 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C32H39Cl2FN2O2.1.3EtOAc: C, 64.93; H, 7.24; N, 4.07. Found: C, 65.01; H, 6.97; N, 3.85. ESMS m/e: 537.1 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH3:16])[C:10]([OH:12])=O)[N:8]=1)=[O:2].C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:37][CH:38]1[C:59](=[O:60])[N:40]2[C:41]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=3)=[O:47])=[C:42]([OH:45])[CH2:43][S:44][C@H:39]12>C(OCC)(=O)C.O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH3:16])[C:10]([NH:37][CH:38]2[C:59](=[O:60])[N:40]3[C:41]([C:46]([O:48][CH2:49][C:50]4[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=4)=[O:47])=[C:42]([OH:45])[CH2:43][S:44][C@H:39]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
N,N-Dimethylformamide (0.114 g.), phosphoryl chloride (0.240 g.) and ethyl acetate (0.5 ml.) were reacted in a conventional manner to give a Vilsmeier reagent. Ethyl acetate (5 ml.) and 2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 0.35 g.) were added at the same temperature for 30 minutes to give the activated acid solution. On the other hand, trimethylsilylacetamide (1.31 g.) and bis(trimethylsilyl)acetamide (1.14 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.50 g.) in ethyl acetate (7.5 ml.) and stirred at room temperature for an hour. To the solution was added the activated acid solution obtained above all at once at -10° C., and stirred at the same temperature for 30 minutes. Water (15 ml.) and ethyl acetate (15 ml.) were added to the resultant solution. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (15 ml.) and water (10 ml.), dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 0.634 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1I.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>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].C1(C)C=CC=CC=1>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(I)c1F
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(Nc2ccccc2)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
In a reaction vial were placed aniline (0.200 g. 2.182 mmol); 2-fluoro-1-iodo-3-methoxybenzene (0.500 g., 1.984 mmol), Pd2(dba)3 (0.091 g. 0.099 mmol), BINAP (0.185 g, 0.298 mmol), NaOtBu (0.286 g. 2.98 mmol), and toluene (3 mL). The reaction was stirred at 80° C. overnight and quenched with water. The organic layer was separated and concentrated. The residue was purified by flash column chromatography to provide the title compound as a brown oil (0.313 g). LCMS m/z=218.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.82 (s, 3H), 6.73 (ddd, J=10.93, 8.15, 1.64 Hz, 1H), 6.88-7.05 (m, 3H), 7.15 (d, J=7.33 Hz, 2H), 7.25-7.31 (m, 2H), 7.80 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[NH2:9][CH2:10][C:11](O)=O>Cl>[NH2:9][CH2:10][C:11]1[NH:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: NCC(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Product: NCc1nc2ccccc2[nH]1
Reaction time: 24 h
Yield: 59.8 %

Procedure:
A solution of 2-aminoaniline (27 g, 0.25 mol), glycine (27.7 g, 0.37 mol) and 250 ml of 5.5M hydrochloric acid is refluxed for 30 hours and then stored in a refrigerator for 24 hours. The precipitate formed is filtered off with suction and then taken up in 400 ml of methanol and treated with carbon black. The mixture is filtered and the solvent is removed to give 22 g (49%) of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.[CH3:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1>>[CH:9]1([NH:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([N:17]3[C:16]([CH3:15])=[CH:20][C:19]([CH3:21])=[N:18]3)[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1cncc(NC2CCCCC2)n1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2cncc(NC3CCCCC3)n2)n1

Procedure:
Was prepared according to Example 3 from (6-chloro-pyrazin-2-yl)-cyclohexylamine and 3,5-dimethylpyrazole.
Reaction SMILES: [CH3:1][C:2]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1>C1(C=CC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][C:2]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[S:5][C:4]=2[N:3]=1
Reactant: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCNC3
Agent: [Pd]
Agent: C(=Cc1ccccc1)c1ccccc1
Product: CC(=O)c1c(C)nc2sc3cnccc3c2c1-c1ccccc1
Temperature: 150 °C
Yield: 10.9 %

Procedure:
To a stirred solution of 0.70 g (2.17 mmol) 1-(2-methyl-4-phenyl-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl)-ethanone in 10 ml diphenylethylene was added 325 mg palladium on charcoal 10%. The mixture was stirred over night at 150° C., and then poured onto ethyl acetate (about 150 ml), and extracted three times aqueous HCl (1M). The combined aqueous phases were basified with K2CO3 until ph=8, and then the product was extracted with ethyl acetate. The combined organic phase were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 1:1) afforded 75 mg (11%) 1-(2-methyl-4-phenyl-9-thia-1,7-diaza-fluoren-3-yl)-ethanone as a light yellow solid. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: ClCl.[OH-:3].[Na+:4].[N+:5]([C:8]1[CH:9]=[C:10]([S:15]([OH:18])(=[O:17])=[O:16])[C:11]([CH3:14])=[CH:12][CH:13]=1)([O-:7])=[O:6].[O-][Cl:20].[Na+].[Cl-].[Na+]>O>[N+:5]([C:8]1[CH:9]=[C:10]([S:15]([O-:18])(=[O:16])=[O:17])[C:11]([CH2:14][CH2:14][C:11]2[C:10]([S:15]([O-:18])(=[O:16])=[O:17])=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=2)=[CH:12][CH:13]=1)([O-:6])=[O:3].[O-:3][Cl:20].[Na+:4]
Reactant: [OH-]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: ClCl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(CCc2ccc([N+](=O)[O-])cc2S(=O)(=O)[O-])c(S(=O)(=O)[O-])c1
Temperature: 65 °C
Reaction time: 0.42 h

Procedure:
4,4'-Dinitrobibenzyl-2,2'-disulfonate was prepared as described in A. Ya. Zheltov, E. N. Avramenko, and B. I. Stepanov, Zhurnel Organicheskoi Khimii, 16, (2) 384-390 (1980), the disclosure of which is totally incorporated herein by reference. More specifically, 4,4'-dinitrobibenzyl-2,2'-disulfonate was prepared as follows. A solution (220 mL) of NaOCl (17.8 g) was prepared by passing chlorine through sodium hydroxide (20 g) in water (100 mL) with crushed ice (120 g) at 1° to 3° C. until the weight of the solution increased by 17 grams. To a stirred solution of 4-nitrotoluene-2-sulfonic acid (90.4 g, obtained from Pfaltz & Bauer, Waterbury, Conn.) in water (1 L) at 60° C. was added sodium hydroxide (16.8 g), NaOCl solution (50 mL), and gradually a solution of sodium hydroxide (200 g) in water (470 mL). To the resulting suspension was added NaOCl solution (120 mL). The reaction mixture was stirred 25 minutes at 65° C. More NaOCl solution (50 mL) was added and the mixture was transferred to a container containing 2 kg of ice. A 20 gram portion of finely ground sodium chloride was added, and the mixture was stirred for 20 minutes. The resulting white precipitate of disulfonic acid was filtered off, washed with saturated sodium chloride solution, and then dissolved in water (2 L). An aqueous solution containing 6 percent by weight potassium permanganate was added to the solution at 20° C. until a permanent light pink color was achieved. The mixture was filtered, and sodium chloride (80 g) was added to the filtrate at 50° C. in portions. The mixture was then stirred at 10° C. for 2 hours. The resulting precipitate was filtered off, washed with acetone, and then dried. The yield of disodium 4.4'-dinitrobibenzyl-2,2'-disulfonate was 64 grams.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][OH:5].CCN(C(C)C)C(C)C.Br[CH:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21]>CN(C=O)C>[OH:5][CH2:4][CH2:3][CH2:2][S:1][CH:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21]
Reactant: OCCCS
Reactant: O=C1OCCC1Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCCC1SCCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-mercapto-propan-1-ol (1685 μmol) in DMF (2 ml) were added DIEA (1.5 eq) and 3-bromo-dihydro-furan-2-one (1 eq). The reaction mixture was stirred at RT for 4 hours. The precipitate was filtered and the solvent was removed under reduced pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:10]3[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:29])[C:25]=1[C:26](O)=[O:27])=[O:20].CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:29][N:24]1[C:25]([C:26](=[O:27])[NH:15][C:12]2[CH:13]=[CH:14][N:9]3[N:8]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[N:16]=[C:10]3[CH:11]=2)=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:22]=[N:23]1
Reactant: COC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
A mixture of 2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (468 mg, 2.22 mmol), 4-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (490 mg, 2.66 mmol), propylphosphonic anhydride (50% in ethyl acetate, 3.26 ml, 5.54 mmol) and N,N-diisopropylethylamine (1.51 ml, 8.86 mmol) in tetrahydrofurane (15 ml) is stirred for 18 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording methyl 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (564 mg, 67.5%) as a light brown solid. mp.: 228-231° C. MS: m/z=378.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][CH:6]=[N:5][C:4]=2[C:3]=1[Cl:12].C[O-].[Na+].[CH3:16][O:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH3:27])=[O:25])[C@H:19]1[CH2:28][C:29](=[O:32])[CH2:30]Br.N1C2C=CS(=O)C=2C=NC=1>CO>[Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:30][C:29](=[O:32])[CH2:28][C@H:19]3[C@H:18]([O:17][CH3:16])[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][CH3:27])=[O:25])[CH:6]=[N:5][C:4]=2[C:3]=1[Cl:12]
Reactant: O=c1[nH]cnc2c(Cl)c(Cl)sc12
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Agent: C[O-]
Agent: O=S1C=Cc2ncncc21
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2c(Cl)c(Cl)sc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen in a flame dried round bottom flask with magnetic stirring, a solution of 0.440 g (0.002 moles) of 6,7-dichlorothieno[3,2-d]pyrimidin-4(3H)-one [M. Robba, J- M. Lecomte, and M. Cugnon de Sevricourt, Bull. soc. chim. France, 1970, 3630-3636], 5 ml of methanol, and 2.0 ml of 1.0N sodium methoxide in methanol was treated with a solution of 0.002 moles of methyl trans-3-methoxy-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate and 2 ml of methanol. A colorless precipitate formed almost immediately; the reaction mixture was stirred for two hours at room temperature. The solid matter was some starting thienopyrimidinone, and was filtered. The filtrate was evaporated under reduced pressure to afford a greenish oil which was chromatographed under moderate pressure ("flash" chromatography) on a column of silica gel (Woelm 32-63 micrometers, i.d. 5 cm×height 18 cm); the eluant was initially 1% ethanol in chloroform but was changed to 2% ethanol later on. There was obtained the title compound: m.p. 58°-62° C.; yield 0.270 g (30%); mass spectrum peaks at 447 (molecular ion), 415 (--32, --CH3OH), 195 (parent) among others; 13C-nmr delta (CDCl3) 19.05 ppm, 23.42, 39.33, 40.81, 50.53, 52.93, 53.62, 56.35, 76.01, 119.92, 121.68, 149.62, 152.19, 155.49, 157.01, 199.22; 1H-nmr (CDCl3) delta 3.36 ppm (OCH3), 3.66 (CO2CH3) among others.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([Cl:25])[CH:10]=[C:11]3[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[C:13]=1[C:12]=23)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([Cl:25])[CH:10]=[C:11]3[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[C:13]=1[C:12]=23)=[O:4]
Reactant: COC(=O)c1[nH]c2cc(Cl)cc3c2c1C(CC(=O)OC(C)(C)C)CC3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1[nH]c2cc(Cl)cc3c2c1C(CC(=O)O)CC3
Yield: 114.2 %

Procedure:
A mixture of 7-chloro-3-tert-butoxycarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acid methyl ester (54 mg, 0.148 mmol) and p-toluenesulfonic acid (3 mg) in toluene (1 mL) was refluxed for 1 h, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated to give 52 mg of the title compound (quant): 1H NMR (DMSO-d6) δ12.17 (bs, 1H), 11.60 (s, 1H), 7.17 (s, 1H), 6.84 (s, 1H), 3.88 (s, 3H), 3.77 (m, 1H), 2.94 (mt, 1H, J=13.9 Hz), 2.80 (md, 1H, J=17.2 Hz), 2.56 (dd, 1H, J=15.2, 4.3 Hz), 2.37 (dd, 1H, J=15.2, 10.6 Hz), 2.11 (md, 1H, J=12.5 Hz), 1.88 (m, H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH:4](O)[CH:5]=[CH2:6].C=CCCC=C.S(Br)([Br:18])=O>ClCCCl>[Br:18][CH2:6]/[CH:5]=[CH:4]/[CH2:3][C:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: O=S(Br)Br
Reactant: C=CC(O)CC(C)(C)C
Agent: C=CCCC=C
Solvent: ClCCCl
Product: CC(C)(C)C/C=C/CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of Example 35A (2.38 g, 18.56 mmol) and 1,5-hexadiene (1.65 mL, 13.9 mmol) in 1,2-dichloroethane (30 mL),stirring at 0° C., was added thionyl bromide (2.16 mL, 27.8 mmol). The reaction was stirred for 2 hours at 0° C. and then quenched with water. The mixture was extracted with diethyl ether and the diethyl ether layer was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound 3.15 g, 89%). 1H NMR (300 MHz, CDCl3): δ ppm 0.87 (m, 9 H) 1.94 (m, 2 H) 3.97 (m, 2 H) 5.74 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:15])[C:6]=1[NH:7][C:8](=[O:14])[CH2:9][O:10]C(=O)C.N>CO>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:15])[C:6]=1[NH:7][C:8](=[O:14])[CH2:9][OH:10]
Reactant: CC(=O)OCC(=O)Nc1c(C)csc1C
Agent: N
Solvent: CO
Product: Cc1csc(C)c1NC(=O)CO

Procedure:
Through a stirred solution of 15.9 g (0.07 mol) of N-(2,4-dimethyl-thien-3yl)-acetoxyacetamide in 300 ml of methanol is bubbled a gentle stream of ammonia gas for 30 minutes.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:25]3[N:30]=[CH:29][C:28]([C:31]4[N:35]=[C:34]([CH2:36][OH:37])[O:33][N:32]=4)=[CH:27][CH:26]=3)([CH3:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)[CH:11]=[N:12][CH:13]=1.C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH3:1][S:2]([O:37][CH2:36][C:34]1[O:33][N:32]=[C:31]([C:28]2[CH:29]=[N:30][C:25]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:10]4[CH:11]=[N:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=4)=[CH:15][CH:16]=3)([CH3:24])[CH:21]([CH3:22])[CH3:23])=[CH:26][CH:27]=2)[N:35]=1)(=[O:4])=[O:3]
Reactant: COc1cncc(-c2ccc(C(C)(c3ccc(-c4noc(CO)n4)cn3)C(C)C)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cncc(-c2ccc(C(C)(c3ccc(-c4noc(COS(C)(=O)=O)n4)cn3)C(C)C)cc2)c1
Reaction time: 0.33 h

Procedure:
Methanesulfonyl chloride (28.0 μL, 0.362 mmol) was added to a stirred solution of 1d (104 mg, 0.241 mmol) and N,N-diisopropylethylamine (105 μL, 0.602 mmol) in DCM (2.00 mL) at 0° C. After approximately 20 min, the reaction mixture was poured into water and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 1e, which was used without further purification.
Reaction SMILES: N#N.C(OC([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1
Reactant: O=C(N[C@H]1CC[C@H](CO)CC1)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: N[C@H]1CC[C@H](CO)CC1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of trans-4-benzyloxycarbonylaminocyclohexane-methanol (110 mg, 0.42 mmol) in MeOH (5 mL) was hydrogenated in the presence of Pd/C (10%) at rt until completion of the reaction. The mixture was then filtered and concentrated under reduced pressure. The title compound was obtained as a light brown solid. LC-MS-conditions 07: tR=0.11 min; [M+H]+=130.24.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:31]([NH2:33])[CH3:32])[N:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:33]([CH:31]([C:19]3[N:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:29])([F:30])[CH:26]([F:28])[F:27])=[C:17]([CH3:16])[CH:18]=3)[CH3:32])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)nnc1OCC(F)(F)C(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)nnc1OCC(F)(F)C(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (612 mg, orange oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (605 mg, 2.17 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanamine hydrochloride (600 mg, 1.98 mmol, Amine-77, single enantiomer) in a similar manner to Intermediate-2.